Skip to main content
  • Review
  • Published:

Alveolar epithelial type II cell: defender of the alveolus revisited

Abstract

In 1977, Mason and Williams developed the concept of the alveolar epithelial type II (AE2) cell as a defender of the alveolus. It is well known that AE2 cells synthesise, secrete, and recycle all components of the surfactant that regulates alveolar surface tension in mammalian lungs. AE2 cells influence extracellular surfactant transformation by regulating, for example, pH and [Ca2+] of the hypophase. AE2 cells play various roles in alveolar fluid balance, coagulation/fibrinolysis, and host defence. AE2 cells proliferate, differentiate into AE1 cells, and remove apoptotic AE2 cells by phagocytosis, thus contributing to epithelial repair. AE2 cells may act as immunoregulatory cells. AE2 cells interact with resident and mobile cells, either directly by membrane contact or indirectly via cytokines/growth factors and their receptors, thus representing an integrative unit within the alveolus. Although most data support the concept, the controversy about the character of hyperplastic AE2 cells, reported to synthesise profibrotic factors, proscribes drawing a definite conclusion today.

Introduction

As early as 1954, CC Macklin had postulated some of the most important functions of the great pneumocyte, ie the pneumocyte type II or alveolar epithelial type II (AE2) cell (Fig. 1) [1]. Macklin presumed that these cells secrete material that provides low surface tension, enhances clearance of inhaled particles, is bacteriostatic, and helps prevent transudation of interstitial fluid into the alveolus. He further reported that these cells proliferate after lung injury by osmium tetroxide fumes [1]. By 1977, enough data had been collected to stimulate Mason and Williams [2] to formulate the concept of the AE2 cell as a "defender of the alveolus". It was established that the main functions were synthesis and secretion of surface-active material, hyperplasia in reaction to alveolar epithelial injury, and serving as the progenitor for AE1 cells, which form the epithelial component of the thin air–blood barrier. Nevertheless, several "postulated" functions were listed, for example, secretion of other substances, modulation of the alveolar hypophase, and adaptation in response to lung injury [2]. In the following 23 years, an increasing number of studies revealed many more details concerning the role of the AE2 cell in surfactant delivery and alveolar epithelial repair (see Supplementary Table 1) and a considerable number of supplementary functions have been established (see Supplementary Table 2). This review covers most aspects of current knowledge of AE2 cell functions.

Figure 1
figure 1

Human lung AE2 cells. (a) Scanning electron micrograph of human lung. Two AE2 cells (P2) are seen to protrude above the largely smooth alveolar epithelial surface. A pore of Kohn (K) and the cell–cell junction (arrowheads) between two AE1 cells are denoted. (b) Transmission electron micrograph of human AE2 cell displaying typical ultrastructural features, such as lamellar bodies (Lb) and apical microvilli (arrows). Nu = nucleus.

Supplementary Table 1 Main functions: surfactant delivery and epithelial repair
Supplementary Table 2 Supplementary functions: alveolar fluid balance, host defence, coagulation-fibrinolysis, cytokines, growth factors, cell–cell interaction, extracellular matrix formation

The AE2 cell as the source of alveolar surfactant

Composition of surfactant

Although the presence of a surface-active agent in the mammalian lung was postulated by von Neergaard as early as 1929 [3], it was the work of Pattle [4] and Clements [5] that opened a new scientific field (for review of historical aspects, see [6]). This surface-active agent, termed surfactant, was characterised in numerous biochemical studies of bronchoalveolar lavage (BAL) material and is now known to be composed of ≅ 90% (mass) lipids (with ≅ 80–90% phospholipids) and of ≅ 10% proteins. Its composition may deviate greatly in pathologic states (for review, see eg [7]). Unlike most other lipid-rich components of cells and organs, the surfactant lipids are characterised by an unusually high level of saturated fatty acid chains, such as the predominant dipalmitoylphosphatidylcholines, which contribute substantially to the unique properties of pulmonary surfactant (for review, see eg [8]). The protein fraction comprises a highly variable amount of serum proteins (50–90% of protein) [7] and four apoproteins that are associated with surfactant and contribute to its specific functions [9]. Since the 1988 consensus-conference, the surfactant proteins (SPs) have been termed SP-A, -B, -C, and -D [10]. With the progress of cell and molecular biology many aspects of the proteins' structures, genes, and regulation have been established (for comprehensive overview, see [11]). Surfactant protein gene polymorphisms, already demonstrated for SP-A, SP-B, and SP-D, have just begun to be studied, and may reveal potential new genetic markers or even susceptibility factors for lung diseases such as chronic obstructive pulmonary disease, acute respiratory distress syndrome, or alveolar proteinosis [12,13,14,15].

Distribution of surfactant

Cryoscanning electron microscopy of frozen tissue demonstrated surfactant to cover extended areas of alveolar surface as a continuous, thin layer. For methodological reasons, however, this approach was restricted to the outermost subpleural alveoli, and is not applicable to central regions [16]. While chemical fixation allows for the stereological analysis of a collection of tissue samples that are representative of the whole lung, this approach resulted in preservation of surfactant over a fraction of only about 15% of the total alveolar surface despite the use of lipid-stabilising tissue processing [17]. Although definite proof of a continuous covering of total alveolar surface is still lacking, this is a reasonable and widely accepted assumption.

Surfactant-like lipid material and SP-A, SP-B, and SP-D have been detected in association with mammalian tissues outside the lung (for reviews, see [18,19]). Surfactant is clearly not restricted to mammals, but is widely distributed within vertebrates [20,21]. Its composition has been largely conserved during vertebrate phylogenesis [20,21], as indicated by studies of the Australian lungfish Neoceratodus forsteri, which evolved about 300 million years ago [22]. Although nothing is known about the presence of surfactant in the vertebrates' closest relatives, the tunicates and acrania, surfactant-like material was demonstrated in the gas mantle of the air-breathing snail Helix aspersa [23]. Thus, it remains to be examined if surfactant has independently evolved more than once with the evolution of gas-containing organs, or if surfactant is a very ancient anti-adhesive material that was developed near the base of the phylogenetic tree.

Functions of surfactant

Regulation of surface tension

The phylogenetic original function of surfactant in vertebrates can be deduced from studies of non-mammalian vertebrates such as fish, lungfish, amphibia, and reptiles (for reviews, see [18,21]). It has been proposed to be that of an 'anti-glue' to prevent adhesion of the surfaces of gas-containing organs, such as swim bladder and lungs, which might occur during collapse. There are some indications that surfactant acts as an anti-oedema factor in non-mammalian lungs, too [21]. In mammals its primary function is to regulate alveolar surface tension in relation to alveolar size, which is an important clue to efficient ventilation and alveolar stability (for reviews, see [19,24]). According to the equation of Young and Laplace, the actual surface tension is much lower in small alveoles than would be expected from pure geometry. Because neighbouring alveoles communicate with each other via alveolar ducts and pores of Kohn (Fig. 1a), their surface tensions must be different (if they are different in size) in order to prevent the collapse of small alveoles in favour of large ones. Mechanical coupling of alveoles via the interstitial tissue of the septum acts as an additional mechanism to prevent alveolar collapse [25]. However, absence or inactivation of surfactant alone results in alveolar collapse at end-expiration and in atelectasis [26].

Although regulation of surface tension can be considered as the primary function of pulmonary surfactant in mammals, this is only one of a number of different functions [24]. Some critical aspects of current points of view have recently been discussed in detail [19].

Alveolar fluid balance

Surfactant has long been postulated to prevent the formation of alveolar oedema through the effect of surface tension acting as an additional force to direct net fluid flow across the air–blood barrier [1,27]. The maintenance of fluid homeostasis in the alveolus is considered to represent one of its phylogenetically ancient functions [18]. A comprehensive discussion of the mechanism of surface-tension-dependent alveolar fluid balance predicted by different surfactant models is given by Hills [19].

In order to be effective in keeping the alveolar space free of excess fluid, ions and serum proteins, the AE2 cell is equipped with a number of membrane-bound water channels and ion pumps as well as an albumin-binding immunoglobulin receptor (for review, see [28]; Supplementary Table 2). However, instead of removing fluid completely, a very thin aqueous film is preserved, termed the hypophase, covering the alveolar surface. The hypophase is delimited at the alveolar face by the surfactant lining layer and at the septal face by the alveolar epithelium. It was estimated to comprise ≅0.37 ± 0.15 ml/kg body weight in sheep [29]. The hypophase can be considered as a reaction milieu for extracellular biochemical processes as well as a 'medium' for intra-alveolar cells such as alveolar macrophages. AE2 cells are thought to control various properties of this extracellular aqueous milieu, for example pH [30] and [Ca2+] [31]. Since many biochemical processes, such as the extracellular transformation of surfactant (see below), depend on the actual pH and [Ca2+], regulation of these parameters is important for controlling what happens in the alveolus. Furthermore, within a certain distance, any factor secreted into this continuous film is likely to reach other cells within the alveolus.

Host defence

Another function of alveolar surfactant postulated by Macklin [1], host defence, has attracted major scientific interest in recent years (for reviews, see [32,33]). This function of surfactant relies on the nature of SP-A and SP-D as collectins. Both proteins are able to bind to the surface of various pathogens, thus acting as opsonins to facilitate their elimination by alveolar macrophages [32,33,34]. Moreover, AE2 cells are able to secrete several other products that are involved in host defence, such as the bacteriolytic lysozyme [35,36]. In rat lungs, lysozyme was detected in lamellar bodies of AE2 cells [36], whereas in humans it was identified in serous submucosal glands but not in alveolar AE2 cells [35].

Surfactant cycle

Originating from an intracellular source, the surfactant coat of the alveolar walls is an extracellular and all but homogeneous material, which can be recovered by BAL. It is synthesised by the AE2 cells and released upon appropriate stimuli by exocytosis from special intracellular storage organelles termed lamellar bodies. Once released into the alveolar space, freshly secreted lamellar body material undergoes several steps of transformation that are necessary to establish the surface-active lining layer. Cyclic compression and expansion during ventilation result in a fraction of spent surfactant that will largely be recycled by the AE2 cells. Thus, single constituents of surfactant may run through several cycles before being removed by alveolar macrophages and replaced by de novo synthesis (for comprehensive review, see [11]).

Synthesis

Although the bronchiolar Clara cells synthesise and release the mature proteins SP-A, SP-B, and SP-D (Fig. 2a) [37,38], the AE2 cell is the only type of pulmonary cell that produces all the surfactant components (phospholipids [Fig. 3] as well as all four surfactant proteins). The mature 3.5–3.7 kDa small SP-C (Fig. 2b) is thought to be released by AE2 cells only [39,40].

Figure 2
figure 2

Indirect immunofluorescence double labelling of rat parenchyma. (a) AE2 cells are stained for surfactant protein D (green) and contrasted by labelling of AE1 cells with Lycopersicon esculentum lectin (red). (b) AE2 cell double-labelled for surfactant protein C (red) and adhesion molecule CD44v6 (green).

Figure 3
figure 3

Transmission electron micrograph of canine lamellar body at high power magnification. The densely packed stacks of phospholipid membranes are bound by a single limiting membrane (arrowheads).

The lamellar bodies of AE2 cells have long been recognised as storage granules from which surfactant is released into the alveolus [41,42]. The biochemical composition of this intracellular storage form is largely identical to the composition of the extracellular material obtained by BAL [43]. The stored phospholipids are bound by a limiting membrane (Fig. 3), which is characterised both by typical lysosomal/endosomal [44] as well as by specific integral membrane proteins [45] probably involved in intra-cellular trafficking. The lamellar body membrane is further equipped with transport proteins for regulation of internal acidic pH and high [Ca2+] [46]. High levels of Ca2+ interspersed between the stacks of phospholipids were demonstrated by microanalytical techniques [31].

The pathway of lipid and protein synthesis has been traced by means of electron microscopic autoradiography [47] to involve the organelles of the classical pathway, ie rough endoplasmic reticulum, Golgi apparatus, multivesicular bodies, and lamellar bodies. Immunoelectron microscopy confirmed this pathway for SP-B and SP-C, and by means of double- and triple-labelling, the different steps of processing and maturation of SP-B and SP-C were localised to specific intracellular structures [40,48,49,50]. Although the synthetic pathway of both SP-A and SP-D also involves endoplasmic reticulum and Golgi apparatus, mature SP-D is barely detectable in lamellar bodies [38]. It is thought that SP-D is released via a constitutive pathway [34], and a subpopulation of lamellar bodies has been proposed to be involved in recycling of SP-D [51].

The problem of differentiating between newly synthesised and recycled proteins is reflected in the controversy of whether or not SP-A is present in lamellar bodies (for review, see [52]). Although SP-A was detected in lamellar bodies by immunoelectron microscopy [48] and lamellar bodies have been reported to be enriched in SP-A [53,54], other studies reported only a relatively low amount of SP-A [55,56,57]. These contradictory data may result from the fact that most of the SP-A released into the alveolar hypophase is taken up again by the AE2 cell (see also below). The captured SP-A is directed to the lamellar bodies [57,58], while newly synthesised SP-A is likely to follow a constitutive pathway of secretion [59]. Re-secretion of internalised SP-A may be very rapid, at least in vitro, and may be achieved via a different pathway than the one used by internalised lipids [60]. Little attention has been given to potential species-specific differences, which may be another source for controversial data.

Secretion

Surfactant material is released from its intracellular stores by exocytosis upon various stimuli. A number of physiologic and pharmacologic agents act via β-adrenergic receptors (epinephrine, terbutaline, isoproterenol), P1-purinoreceptors (receptors of adenosine and its analogues) or P2-purinoreceptors (ATP, UTP, ATP analogues; Supplementary Table 1), while several membrane-permeable substances act intracellularly, such as cholera toxin, forskolin, phorbol esters, and calcium ionophores (for review, see [52]). A number of agents have been reported to stimulate surfactant secretion, such as arachidonic acid, prostaglandins, histamine, and endothelin-1 [52]. Ventilation of the alveolus is a major physiologic stimulus of surfactant secretion and a single deep breath is considered to be sufficient [61,62]. An elegant in vitro study indicated that direct mechanical stretching of AE2 cells can trigger the release of surfactant [63]. However, a recent real-time study examining exocytosis in situ by means of vital stains in isolated perfused rat lungs demonstrated that lung expansion induced synchronous intracellular [Ca2+]-oscillations in all alveolar cells and lamellar body exocytosis in AE2 cells, with the exocytosis rate correlating with the frequency of the oscillations [64]. The authors' exciting conclusion is that AE1 cells may act as mechanotransducers that translate the mechanical stimulus into an intracellular Ca2+ signal, which is transmitted via gap junctions to the AE2 cell to regulate surfactant secretion.

Three pathways of signal transduction are now known (for a comprehensive review, see [52]). The first acts through activation of adenylate cyclase, formation of cyclic AMP and activation of cAMP-dependent protein kinase A. This pathway is followed, for example, by agents binding to β-adrenergic receptors or adenosine receptors A2b. The second pathway acts through activation of protein kinase C (PKC), either by direct interaction with permeable substances or indirectly as a consequence of the activation of membrane receptors. Direct activation of PKC can be achieved by 12-O-tetradecanoylphorbol-13-acetate (TPA) and membrane permeable diacylglycerols (DAGs), while ATP and UTP, for example, activate the PKC pathway after binding to purine receptor P2Y2. The third known pathway acts via an increase in intracellular Ca2+ levels, through either the uptake of extracellular calcium (using ionophores, for example), the transmission of calcium through gap junctions from neighbouring AE1 cells, or the release of calcium from intracellular stores. All of these may activate the Ca2+-calmodulin dependent protein kinase. The release of calcium from intracellular stores, for example, can be induced by binding of ATP to purine receptor P2Y2 and subsequent formation of inositol-3-phosphate.

Activation of one of these signal cascades results in an increase in surfactant secretion by about two- to threefold (adenylate cyclase, Ca2+-ionophores) or about fivefold (TPA, PKC-activating agonists). Simultaneous activation of several pathways using several agonists, by mastoparan or ATP, which may activate all three pathways, results in a 5- to 12-fold increase above basal secretion (see references in [52]). Thus, an enormous redundancy is achieved through the existence of these different pathways of signal transduction and the great number of agonists, which guarantees a high degree of safety in the regulation of surfactant release and underlines the great importance of surfactant delivery to the alveolus.

The final step of the secretory pathway is accomplished via the classic mechanism of secretion by exocytosis, which results in the release of surfactant material from lamellar bodies into the alveolus. While it is well established that cytoskeletal components, such as microtubules [65] and actin filaments [66], are necessary for transport of the granules to the cell membrane and release of their contents, nothing is known about the mechanisms of release of constitutively formed SP-A and SP-D. Fusion of the lamellar body limiting membrane with the AE2 cell plasma membrane is mediated by annexins [67]. Single cell monitoring may provide new insights into the details of how exocytosis is regulated [68]. Secreted surfactant lipids as well as SP-A may inhibit subsequent surfactant release by negative feedback mechanisms [69,70], although this has not yet been proven in vivo.

Transformation (conversion)

Once released into the alveolar aqueous hypophase, the lamellar body material transforms into tubular myelin. This is an amazingly regular phospholipid/SP-A assembly (Fig. 4), which gives rise to the surface-active lining layer from which, in turn, small vesicular forms derive that are thought to represent spent surfactant (for review, see [71]). These categories of surfactant subtypes were defined by early ultrastructural studies and were consistently seen in both chemically and cryofixed surfactant [72,73]. By differential centrifugation of BAL material, surfactant is separated into large and small aggregates, while equilibrium buoyant density gradient centrifugation separates light, heavy and ultraheavy fractions. Correlative studies showed that large aggregates and the ultraheavy fraction correspond to tubular myelin and freshly secreted lamellar bodies, while small aggregates and the light fraction largely represent vesicular surfactant forms [43,55,74]. However, neither do the individual subfrac-tions represent a single ultrastructural subtype [74,75] nor is there congruence of fractions obtained by differential centrifugation and equilibrium buoyant density gradient centrifugation [76].

Figure 4
figure 4

Transmission electron micrograph of rat intra-alveolar surfactant with the typical lattice-like appearance of tubular myelin, which is in close contact with the alveolar lining layer (arrowheads). Vesicular surfactant (small arrows) is seen near the apical surface of the alveolar epithelium.

Being an extracellular process, transformation or conversion of surfactant can be studied in vitro. Surfactant subtypes can be reconstituted from individual components [55,77], and surfactant conversion can be mimicked by surface area cycling [74,78,79]. Thus, surfactant transformation was demonstrated to depend on various characteristics of the hypophase milieu, such as concentration of electrolytes [80], in particular of Ca2+[81], pH [82], and the presence of surfactant proteins, especially of SP-A [83].

The first step of transformation of freshly secreted lamellar body material into tubular myelin requires an increased [Ca2+] (probably derived from lamellar bodies [31]) and SP-A [84] which is finally observed at the corners of tubular myelin lattices [36,85]. The presence of tubular myelin is thought to be associated with the ability of surfactant lipids to rapidly adsorb to the lining layer at the gas/liquid interface. This second step of conversion appears to be promoted by SP-B (for review, see [71]). Refinement of the lining layer is the next step that results in an increase in its dipalmitoylphosphatidylcholine fraction, thereby achieving minimal surface tension [86]. This process is thought to involve both SP-B [87] and SP-C (for review, see [71,86]). The final step of conversion, from surface-active surfactant into inactive vesicular forms, appears to depend on an AE2-cell-derived enzyme termed convertase [88,89].

The balance between large aggregates and small aggregates has turned out to be an important parameter in assessing the functional integrity of alveolar surfactant obtained by BAL (for review, see [90]). This is corroborated by quantitative ultrastructural studies. While normal lungs showed little quantitative variation in the relative amount of tubular myelin under different ventilation strategies [91], tubular myelin was considerably decreased in different lung injury models [17,92]. In the context of lung injury, the ultrastructural approach offers the unique opportunity to examine surfactant retained in situ [93], which allows for the analysis of local surfactant inhomogeneities in relation to other structural changes [17].

Absence of tubular myelin was associated with reduced intracellular labelling for SP-A and with severe respiratory dysfunction in neonatal respiratory distress syndrome [94]. Paradoxically, targeted SP-A deletion in mice had minor effects on pulmonary function despite a severe depletion of tubular myelin [95]. This discrepancy is still a matter of debate.

Recycling

Today it is established that most of the secreted surfactant — estimated at about 85% [24] — is taken up again, metabolised and re-secreted by the AE2 cells. Re-uptake and recycling have been demonstrated for surfactant lipids [58] and all four surfactant proteins [51,58,96,97]. SP-A, SP-B, and SP-C have been reported to enhance the uptake of phospholipids by AE2 cells in vitro; in the case of SP-A at least, this may be a receptor-mediated process [98,99]. SP-D, however, appeared to be ineffective in enhancing lipid uptake [51]. The significance of lipid uptake enhanced by surfactant protein in vivo is still unclear. The intracellular processes of metabolism and recycling are essentially associated with multivesicular bodies, which may exist as functionally heterogeneous populations [58]. Electron microscopic autoradiography [58] and confocal fluorescence microscopy [60] indicated that internalised lipids and SP-A are rapidly re-secreted by AE2 cells, probably along different pathways.

Degradation

The degradation of surfactant is accomplished by the alveolar macrophages with only minimal contribution, if any, from AE2 cells. Phospholipids and SP-A appear to be degraded along different pathways [100]. Failure of surfactant removal and degradation may be one reason for alveolar proteinosis observed in transgenic mice lacking granulocyte-macrophage colony-stimulating factor (GM-CSF) [101].

AE2 cell as the stem cell of the alveolar epithelium

The alveolar epithelium can be classified as a continuously renewing tissue since it comprises a population of cells (AE2) that are characterised by the almost unlimited potential to proliferate. Such a population of cells, capable of both self-maintenance and terminal differentiation, is termed the stem cell population of a tissue. In a continuously renewing tissue, the stem cell population generates a greater progeny than necessary. The excess cells are removed by cell loss to avoid a steady increase in cell mass [102]. Consequently, in the physiological situation, proliferation, terminal differentiation, and cell loss must be in a balanced state which allows for a dynamic regulation of the epithelial cell population. It is still a matter of debate whether all AE2 cells or only a subpopulation act as the alveolar epithelial stem cell population (for review, see [103]).

The time needed to replace all cells of a given population, termed cell turnover time, is quite variable and depends on the specific tissue, developmental stage or age, and pathogenic conditions. It has been reported to last only 2–10 days for bronchial epithelium of adult mammals, and 4–5 weeks for the alveolar epithelium [104]. Cell turnover time may be much faster in case of injury, for example only 3 days in mice after hyperoxic alveolar epithelial damage [105]. This difference is supported by the ≅10-fold increase in alveolar surface covered by AE2 cells within 3 days of in vivo instillation of keratinocyte growth factor (KGF), an AE2 cell mitogen [106,107].

Proliferation

The concept of the AE2 cell as a stem cell of the adult alveolar epithelium was proposed by Kapanci and coworkers [108], and is widely accepted today (for review, see [103]). During ontogenesis, the AE2 cell may derive from a precursor cell common to AE2 and Clara cells [109]. In order to divide, the AE2 cell, like any other type of cell, must enter the cell cycle to accomplish DNA replication and mitosis (Fig. 5). The cell cycle is tightly controlled at several checkpoints that control the transition from one phase (G1, S, G2, M) to the next, and it is linked to programmed cell death, thus avoiding replication of cells with genetic defects [110].

Figure 5
figure 5

Indirect immunoperoxidase staining of rat lung for proliferation marker Ki-67. One day after instillation of recombinant human KGF, many epithelial cells at alveolar corners, the typical AE2 cell location, exhibit nuclear staining. The cell in the centre is just about to complete mitosis.

According to [3H]-thymidine labelling experiments, the duration of the complete cell cycle is about 22 hours in AE2 cells of adult mice [111], which is equivalent to the duration in NO2-injured rat lungs [112]. In mice, duration of cell cycle and of the individual phases appears to depend largely on the developmental stage and the presence or absence of any noxious agents [113]. Notably, the time frames observed in vitro were different from the in vivo estimates (see Table 1 in [103]). The duration of the S-phase (7–9 hours) appears to be largely independent of species, developmental stage, presence of noxious agents, and cell culture conditions. The duration of G2- and M-phases appears to be most variable (1–12 hours) [103]. The observation that in primary culture only a sub-population of AE2 cells is capable of clonal proliferation with several successive mitotic cycles indicates that AE2 cells are not a uniform population [114].

Differentiation

Nondevelopmental studies of AE2 cell differentiation generally use lung injury models to induce epithelial damage, with the consequence of AE2 cell proliferation and subsequent repair to re-establish a functional air–blood barrier (for reviews, see [115,116]). Recently, differentiation of AE2 cells into AE1 cells has been shown to be involved in the resolution of short-time hyperplasia of AE2 cells following airway instillation of KGF [107]. This approach may be used as an alternative model in the study of adult AE2 cell differentiation.

In their fundamental ultrastructure/microautoradiography study of the incorporation of [3H]-thymidine into proliferating cells of NO2-challenged rat lungs, Evans and co-workers [117] reported that, 1 h after the radiographic pulse, the population of labelled alveolar epithelial cells (≅35% of total lung parenchymal cells) was composed of 88% AE2 cells, less than 1% AE1 cells, and 12% cells that could not be unambiguously assigned to one or both [117]. As has been emphasised by Uhal [103], this remarkably short time period after which a large proportion of AE2 cells were labelled is a strong argument against any small, yet unknown, stem cell population other than AE2 cells.

The study of differentiation of AE2 cells into AE1 cells crucially depends on the possibility to distinguish both cell types. Today, the gold standard is still the complex of ultrastructural criteria with the presence of lamellar bodies, apical microvilli, cell–cell junctions, and cuboid shape, which allows for the clearest distinction of the AE2 cells and AE1 cell phenotypes [118,119]. A number of alternative methods have been validated, such as modified Papanikolaou-staining [120], cell-type-specific lectins, and immunohistochemical markers [119,121]. The expression of markers, however, may depend on the developmental stage [122] and can be affected by pathogenic processes [123]. The situation is further complicated by the transient appearance of an intermediate phenotype during differentiation of AE2 cells into AE1 cells after lung damage [112] as well as after KGF-induced hyperplasia [107]. The most plausible explanation for this observation is that differentiation of AE2 cells is accomplished by continuous transformation into AE1 cells via an intermediate cell type, a concept that is widely accepted today [103].

Isolated AE2 cells cultured in vitro lose their specific features within days and acquire AE1 cell characteristics [124,125,126]. Although this process, which greatly depends on the specific culture conditions [127], is frequently termed transdifferentiation, one has to take into account that it has not been shown to yield a terminally differentiated AE1 cell. Interestingly, transdifferentiation in vitro is a least partially reversible [125,128]. However, it is unknown if reversibility of the differentiation of AE2 cells into AE1 cells is a potential regulatory mechanism in vivo.

Cell death

One important mechanism of cell removal that was recognised almost a century ago [129] is programmed cell death or apoptosis [130]. Although an exploding number of studies revealed fundamental details of the inducers, pathways, and effectors of apoptosis in general (for reviews, see eg [130,131]), relatively little is known about apoptosis in the lung in particular (for reviews, see [132,133]).

AE2 cells are known to express the membrane receptor Fas (CD95, APO-1), ligation of which may initiate the apoptotic cascade [134]. This can be achieved by binding of Fas-ligand or the Fas-stimulating antibodies. There is some evidence that apoptosis of AE2 cells is an integral mechanism of alveolar septal modelling in lung morphogenesis [135,136]. The presence of many apoptotic cells during the resolution phase after acute lung injury in humans [137] as well as during epithelial restoration after KGF-induced AE2 cell hyperplasia in rats [138] indicates that apoptosis may also be an integral part of alveolar epithelial repair. Notably, apoptotic AE2 cells (Fig. 6) appeared to be removed not only by alveolar macrophages but also by AE2 cell neighbours [138]. Knowledge of AE2 cell apoptosis in adult lung physiology and pathology is still rudimentary [133].

Figure 6
figure 6

Transmission electron micrograph of apoptotic AE2 cells (*) engulfed by their AE2 cell neighbours at day 5 after intrabronchial instillation of recombinant human KGF into rat lung in vivo. A = air space; Lb = lamellar bodies; Nu = nuclei of phagocytic AE2 cells.

The AE2 cell as an integrative unit of the alveolus

The mammalian lung comprises more than 40 different cell types [139]. AE2 cells have been estimated to constitute about 60% of alveolar epithelial cells and about 15% of all lung parenchymal cells, while they cover only about 5% of the alveolar surface in adult mammals [140]. These estimates relied on quantitative methods that can no longer be considered adequate, and re-evaluation using modern stereological methods [141] is much needed. In order to act in a way that is beneficial to the whole alveolus, it is essential for the AE2 cell to interact with its resident as well as its mobile neighbour cells. Consequently, the AE2 cell expresses a number of molecules necessary for the perception as well as the generation of signals involved in cell–cell as well as in cell–matrix interactions. Cell–cell interactions may be direct, ie via contact of the cell membranes, or indirect, ie mediated via secreted and diffusible signals (see Supplementary Table 2).

Interaction with resident cells

First of all, the AE2 cell is in direct contact with AE1 cells and during proliferation with AE2 cell neighbours as well. These lateral cell–cell contacts within the alveolar epithelium are maintained by a cell junction complex that includes gap junctions [142]. The basal cell membrane is in close proximity to fibroblasts, in particular during the canalicular phase of lung morphogenesis, while modelling of the alveolar septum results in an increase in the spatial relationship of the AE2 cells with capillary endothelial cells of the adult lung [143].

Alveolar epithelial cells

The in situ study of Ashino and co-workers [64] presented strong evidence of a direct interaction of AE1 and AE2 cells. Mechanical stimulation of AE1 cells is thought to result in [Ca2+]i-oscillations (see above), which are transmitted via interepithelial gap junctions to AE2 cells and modulate exocytosis rate of lamellar bodies [64]. Direct inhibitory interactions between AE1 and AE2 cells have been postulated to suppress AE2 cell proliferation [144]. Loss of AE1 cells during lung injury might then be the trigger to release AE2 cells from growth inhibition. Although E-cadherin, a candidate mediator of contact inhibition [145], has been localised to the basolateral membrane of adult human AE2 cells [146], experimental evidence for contact inhibition of AE2 cell proliferation by AE1 cells still remains to be presented.

The most intensely studied example of an indirect AE2–AE2 cell interaction is probably the negative feedback loop by which SP-A, released into the alveolar space, inhibits surfactant exocytosis in vitro [69]. Although AE2 cells are equipped with membrane receptors for SPA [70], the in vivo relevance of this autocrine mechanism by which AE2 cells may regulate their own action is still not convincing (as pointed out recently [52]). Since mice that are deficient for SP-A did not show any defect in surfactant secretion nor any respiratory deficiency [147], there must be some alternative mechanism compensating for the loss of a SP-A feedback loop, if present at all.

Another potential feedback mechanism that has been postulated is the inhibition of AE2 cell proliferation via AE2-cell-derived transforming growth factor (TGF)-β in bleomycin-induced experimental lung fibrosis [148]. A number of growth factors are released by AE2 cells, which might act in an autocrine way via the corresponding receptors expressed by AE2 cells (see Supplementary Table 2).

Fibroblasts

The interaction of AE2 cells with fibroblasts is probably the best studied reciprocal cell–cell relationship which is relevant to the modelling of alveoles during lung morphogenesis (for review see, eg, [149]) as well as during remodelling associated with alveolar repair following lung injury (for review see, eg, [123,150]). Both direct and indirect cell–cell interactions have been reported, in most instances from studies of cells grown in culture. The supernatant of fibroblast cultures can increase the proliferation rate of rat AE2 cells, while the AE2 cells have been reported to secrete a factor that inhibits fibroblast proliferation [151]. In contrast, however, an increase in fibroblast proliferation was seen if both cell populations grown in co-culture were able to establish direct cell–cell contacts [151]. In addition, AE2-cell-derived factors may affect extracellular matrix formation by fibroblasts, such as stimulation of collagen type I secretion by AE2-cell-derived insulin-like growth factor (IGF) type 1 [152]. On the contrary, surfactant lipids may reduce collagen type I synthesis, and provoke fibroblast apoptosis, an effect partially reversed by SP-A [153].

Transmission electron microscopy has demonstrated the existence of cell membrane protrusions termed foot processes that traverse the epithelial basal membrane and are likely to represent the structural basis for direct contacts with fibroblasts and/or extracellular matrix [154]. Immuno-electron microscopy indicated that CD44v6 (Fig. 2b) is localised at the tips of these foot processes [123]. The CD44 molecules constitute a family of integral membrane glycoproteins that act as receptors of hyaluronan and osteopontin, for example, and are well established as being involved in epithelial cell migration and differentiation [155].

Endothelial cell

Little is known about the interaction of alveolar epithelial and capillary endothelial cells. Pulmonary endothelial cell conditioned medium was reported to stimulate foetal lung epithelial cell growth [156]. Freshly isolated rat AE2 cells grown on lung vascular endothelial cell-synthesised matrix showed an increased rate of proliferation and a more rapid transformation into an AE1-like phenotype than cells grown on plastic or matrigel [157]. Since no other cell-derived matrices were studied, the specificity of this effect remains to be shown.

Endothelin-1 was observed to increase AE2 cell surfactant secretion in vitro via a protein kinase C and Ca2+-mediated pathway [158]. As a source of endothelin-1, endothelial cells are therefore principally competent to act in a paracrine manner on AE2 epithelial cells, which were reported to express the endothelin receptor A [159]. One has to take into account that AE2 cells themselves may synthesise endothelin-1 and stimulate endogenous prostaglandin E2 synthesis in an autocrine fashion [159].

Recently, a very special mechanism of indirect intercellular communication between AE2 cells and endothelial cells has been suggested based on in situ fluorescence imaging studies in alveoli of isolated perfused lungs [160]. Stimulation of alveolar epithelial cells with tumour necrosis factor (TNF)-α was reported to increase epithelial [Ca2+]i and to activate epithelial cytoplasmic phospholipase A2, and results in basolateral release of arachidonic acid. Free arachidonic acid is thought to increase endothelial [Ca2+]i and expression of P-selectin [160], which is known to be crucial for initiation of leukocyte adherence. Thus, AE2 cells may act as transducers of an inflammatory signal from the alveolus to the capillary bed to recruit granulocytes to the site of inflammation.

Interaction with mobile cells

Alveolar macrophages

Among the multitude of secretory products synthesised and released by alveolar macrophages (for reviews, see [123,161]) there are some factors that act as mitogens for AE2 cells, such as hepatocyte growth factor [162] and heparin-binding epidermal growth factor-like protein [163]. Conversely, AE2 cells were shown to express the chemokines RANTES and MCP-1, which chemotactically attract macrophages [164], as well as GM-CSF [165,166], which in turn may stimulate macrophage growth [167]. Furthermore, SP-A released from AE2 cells may modulate macrophage functions such as, oxygen radical release [168], and nitric oxide production [169]. One has to take into account, however, that there may be species-specific differences [162,163].

Leukocytes

Interactions of AE2 cells with leukocytes have just come into focus. AE2 cells may synthesise some cytokines affecting leukocytes, such as interleukin (IL)-6 or IL-8 (see Supplementary Table 2). Via these cytokines, AE2 cells might be involved in the induction of differentiation of basophil, eosinophil, and neutrophil granulocytes and maintenance of inflammatory reactions. Recent data support the idea that AE2 cells have an accessory function in T-lymphocyte activation [170]. This has been suggested on the basis of the finding that the cells bear receptors of MHC class II [171].

AE2 cells were reported to inhibit lymphocyte proliferation in vitro without altering their activation state [172]. AE2-cell-derived TGF-β [170] may indirectly inhibit T-cell proliferation via blockade of activating factors, such as IL-2. In contrast, GM-CSF released at the basolateral surface of AE2 cells may increase the potential of dendritic cells to induce T-cell proliferation [166].

Isolated human AE2 cells as well as the A549 cell lines can be stimulated by TNF-α to secrete MCP-1 and RANTES at their apical membrane and showed increased expression of ICAM-1 and VCAM-1 [173]. These AE2 cell reactions were associated with increased transepithelial migration of monocytes in baso-apical direction. Direct interaction of pneumocytes with migrating monocytes was reported to be mediated by β2-integrins CD11b/CD18 and β1-integrins as well as by CD47 [173]. Adhesion of stimulated neutrophils has been reported to result in oxidant-independent death of AE2 cells [174], while in turn one may speculate that AE2 cells may be involved in initiating apoptosis of neutrophils, an important mechanism for the resolution of inflammation [175].

Conclusion: the AE2 cell under pathological conditions

The concept of the "defender of the alveolus" implies that severe damage to or loss of AE2 cells results in a considerable vulnerability of the alveolus. The impairment of pulmonary surfactant as a source of alveolar compromise is probably the best-documented example of AE2-cell-related pulmonary dysfunction (for a comprehensive review, see [90]). Because intra-alveolar surfactant is highly susceptible to inactivation by serum proteins or reactive oxygen species (for review, see [176]), very few studies presented data indicating that the primary effect resulting in respiratory dysfunction was indeed a defect in AE2 cells [177].

It is still a matter of debate if hyperplastic AE2 cells, which are frequently observed in pathologic states (for reviews, see [144,178]) and which show altered expression patterns of many components and products [123], are beneficial or harmful to the alveolus. There are several indications that hyperplasia of AE2 cells may be a cause of pulmonary fibrosis (for review, see [179]). Unlike normal human AE2 cells, hyperplastic AE2 cells of fibrotic human lungs were reported to produce TGF-β1 [180,181], platelet-derived growth factor (PDGF) [182] as well as TNF-α [180], major profibrotic factors. These findings are diametrically opposed to the concept of AE2 cells as the defender of the alveolus. On the contrary, AE2 cell hyperplasia induced in rats in vivo by instillation of recombinant KGF protein or by transfer of the gene encoding KGF did not result in fibrosis [106,107,183]. Moreover, experimental induction of AE2 cell apoptosis was shown to result in pulmonary fibrosis [184]. Notably, apoptotic AE2 cells were enriched in areas of active lesions in close proximity to myofibroblasts in fibrotic human lung [185]. This again supports the notion implicated by the defender concept that loss of AE2 cells has a detrimental effect for the alveolus.

Many studies have confirmed the beneficial effect of the AE2 cell for the maintenance of a functional alveolar unit in many aspects. Our knowledge of the cell–cell interactions of AE2 cells still remains to be expanded. Even less is known about the significance of AE2 cell apoptosis and of AE2-cell-induced apoptosis of other cell types, and the relationship to repair and/or pathogenesis. Although most of the data collected to date support the concept of the AE2 cell as a defender of the alveolus, the controversy about the character of hyperplastic AE2 cells, however, proscribes drawing a definite conclusion.

References

  1. Macklin CC: The pulmonary alveolar mucoid film and the pneumonocytes. Lancet. 1954, 29: 1099-1104.

    Google Scholar 

  2. Mason RJ, Williams MC: Type II alveolar cell: defender of the alveolus. Am Rev Respir Dis. 1977, 115: 81-91.

    Google Scholar 

  3. Von Neergaard K: New opinions about the fundamentals of respiratory mechanics. The retraction force of the lung in relationship to the surface tension within the alveoles [in German]. Z ges exp Med. 1929, 66: 373-394.

    Google Scholar 

  4. Pattle R: Properties, function and origin of the alveolar lining layer. Nature. 1955, 175: 1125-1126.

    Google Scholar 

  5. Clements JA: Surface tension of lung extracts. Proc Soc Exp Biol Med. 1957, 95: 170-172.

    Google Scholar 

  6. Tierney DF: Lung surfactant: some historical perspectives leading to its cellular and molecular biology. Am J Physiol. 1989, 257: L1-L12.

    Google Scholar 

  7. Griese M: Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J. 1999, 13: 1455-1476. 10.1034/j.1399-3003.1999.13f36.x.

    Google Scholar 

  8. Van Golde LMG, Batenburg JJ, Robertson B: The pulmonary surfactant system. News in Physiol Sciences. 1994, 9: 13-20.

    Google Scholar 

  9. Weaver TE, Whitsett JA: Function and regulation of pulmonary surfactant-associated proteins. Biochem J. 1991, 273: 249-264.

    Google Scholar 

  10. Possmayer F: A proposed nomenclature for pulmonary surfactant-associated proteins. Am Rev Respir Dis. 1988, 138: 990-998.

    Google Scholar 

  11. Rooney SA: Lung surfactant: cellular and molecular processing. Austin, Texas, RG Landes Company,. 1998

    Google Scholar 

  12. Nogee LM: Genetics of the hydrophobic surfactant proteins. Biochim Biophys Acta. 1998, 1408: 323-333.

    Google Scholar 

  13. Guo X, Lin HM, Lin Z, Montano M, Sansores R, Wang G, DiAngelo S, Pardo A, Selman M, Floros J: Polymorphisms of surfactant protein gene A, B, D, and of SP-B-linked microsatellite markers in COPD of a Mexican population. Chest. 2000, 117: 249S-250S.

    Google Scholar 

  14. Lin Z, Pearson C, Chinchilli V, Pietschmann SM, Luo J, Pison U, Floros J: Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS. Clin Genet. 2000, 58: 181-191. 10.1034/j.1399-0004.2000.580305.x.

    Google Scholar 

  15. Lin Z, deMello DE, Batanian JR, Khammash HM, DiAngelo S, Luo J, Floros J: Aberrant SP-B mRNA in lung tissue of patients with congenital alveolar proteinosis (CAP). Clin Genet. 2000, 57: 359-369. 10.1034/j.1399-0004.2000.570506.x.

    Google Scholar 

  16. Bastacky J, Lee CY, Goerke J, Koushafar H, Yager D, Kenaga L, Speed TP, Chen Y, Clements JA: Alveolar lining layer is thin and continuous: low-temperature scanning electron microscopy of rat lung. J Appl Physiol. 1995, 79: 1615-1628.

    Google Scholar 

  17. Ochs M, Nenadic I, Fehrenbach A, Albes JM, Wahlers T, Richter J, Fehrenbach H: Ultrastructural alterations in intraalveolar surfactant subtypes after experimental ischemia and reperfusion. Am J Respir Crit Care Med. 1999, 160: 718-724.

    Google Scholar 

  18. Daniels CB, Lopatko OV, Orgeig S: Evolution of surface activity related functions of vertebrate pulmonary surfactant. Clin Exp Pharmacol Physiol. 1998, 25: 716-721.

    Google Scholar 

  19. Hills BA: An alternative view of the role(s) of surfactant and the alveolar model. J Appl Physiol. 1999, 87: 1567-1583.

    Google Scholar 

  20. Sullivan LC, Daniels CB, Phillips ID, Orgeig S, Whitsett JA: Conservation of surfactant protein A: evidence for a single origin for vertebrate pulmonary surfactant. J Mol Evol. 1998, 46: 131-138.

    Google Scholar 

  21. Daniels CB, Orgeig S: The comparative biology of pulmonary surfactant: past, present and future. Comp Biochem Physiol -Part A. 2001

    Google Scholar 

  22. Power JH, Doyle IR, Davidson K, Nicholas TE: Ultrastructural and protein analysis of surfactant in the Australian lungfish Neoceratodus forsteri : evidence for conservation of composition for 300 million years. J Exp Biol. 1999, 202: 2543-2550.

    Google Scholar 

  23. Daniels CB, Wood PG, Lopatko OV, Codd JR, Johnston SD, Orgeig S: Surfactant in the gas mantle of the snail Helix aspersa. Physiol Biochem Zool. 1999, 72: 691-698.

    Google Scholar 

  24. Nicholas TE: Pulmonary surfactant: no mere paint on the alveolar wall. Respirology. 1996, 1: 247-257.

    Google Scholar 

  25. Bachofen H, Wilson TA: Micromechanics of the acinus and alveolar walls. In The Lung. Scientific Foundations. Edited by Crystal RG, West JB, Barnes PJ, et al. Philadelphia - New York; Lippincott - Raven Publishers,. 1997, 1159-1167.

    Google Scholar 

  26. Nieman GF, Bredenberg CE, Clark WR, West NR: Alveolar function following surfactant deactivation. J Appl Physiol. 1981, 51: 895-904.

    Google Scholar 

  27. Clements JA: Pulmonary edema and permeability of alveolar membranes. Arch Environ Health. 1961, 2: 104-107.

    Google Scholar 

  28. Lubman RL, Kim K-J, Crandall ED: Alveolar epithelial barrier properties. In The Lung. Scientific Foundations. Edited by Crystal RG, West JB, Barnes PJ, et al. Philadelphia — New York; Lippin-cott — Raven Publishers,. 1997, 585-602.

    Google Scholar 

  29. Stephens RH, Benjamin AR, Walters DV: Volume and protein concentration of epithelial lining liquid in perfused in situ postnatal sheep lungs. J Appl Physiol. 1996, 80: 1911-1920.

    Google Scholar 

  30. Lubman RL, Danto SI, Crandall ED: Evidence for active H+ secretion by rat alveolar epithelial cells. Am J Physiol. 1989, 257: L438-445.

    Google Scholar 

  31. Eckenhoff RG, Somlyo AP: Rat lung type II cell and lamellar body: elemental composition in situ. Am J Physiol. 1988, 254: C614-C620.

    Google Scholar 

  32. Pison U, Max M, Neuendank A, Weissbach S, Pietschmann S: Host defence capacities of pulmonary surfactant: evidence for 'non- surfactant' functions of the surfactant system. Eur J Clin Invest. 1994, 24: 586-599.

    Google Scholar 

  33. Wright JR: Host defense functions of surfactant. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas; R. G. Landes Company,. 1998, 191-214.

    Google Scholar 

  34. Crouch EC: Surfactant protein-D and pulmonary host defense. Respiratory Research. 2000, 1: 93-108.

    Google Scholar 

  35. Singh G, Katyal SL, Brown WE, Collins DL, Mason RJ: Pulmonary lysozyme: a secretory protein of type II pneumocytes in the rat. Am Rev Respir Dis. 1988, 138: 1261-1267.

    Google Scholar 

  36. Haller EM, Shelley SA, Montgomery MR, Balis JU: Immunocytochemical localization of lysozyme and surfactant protein A in rat type II cells and extracellular surfactant forms. J Histochem Cytochem. 1992, 40: 1491-1500.

    Google Scholar 

  37. Kalina M, Mason RJ, Shannon JM: Surfactant protein C is expressed in alveolar type II cells but not in Clara cells of rat lung. Am J Respir Cell Mol Biol. 1992, 6: 594-600.

    Google Scholar 

  38. Voorhout WF, Veenendaal T, Kuroki Y, Ogasawara Y, van Golde LM, Geuze HJ: Immunocytochemical localization of surfactant protein D (SP-D) in type II cells, Clara cells, and alveolar macrophages of rat lung. J Histochem Cytochem. 1992, 40: 1589-1597.

    Google Scholar 

  39. Phelps DS, Floros J: Localization of pulmonary surfactant proteins using immunohistochemistry and tissue in situ hybridization. Exp Lung Res. 1991, 17: 985-995.

    Google Scholar 

  40. Beers MF, Kim CY, Dodia C, Fisher AB: Localization, synthesis, and processing of surfactant protein SP-C in rat lung analyzed by epitope-specific antipeptide antibodies. J Biol Chem. 1994, 269: 20318-20328.

    Google Scholar 

  41. Kikkawa Y, Motoyama EK, Gluck L: Study of the lungs of fetal and newborn rabbits. Morphologic, biochemical, and surface physical development. Am J Pathol. 1968, 52: 177-210.

    Google Scholar 

  42. Askin FB, Kuhn C: The cellular origin of pulmonary surfactant. Lab Invest. 1971, 25: 260-268.

    Google Scholar 

  43. Baritussio AG, Magoon MW, Goerke J, Clements JA: Precursor-product relationship between rabbit type II cell lamellar bodies and alveolar surface-active material. Surfactant turnover time. Biochim Biophys Acta. 1981, 666: 382-393.

    Google Scholar 

  44. Wasano K, Hirakawa Y: Lamellar bodies of rat alveolar type 2 cells have late endosomal marker proteins on their limiting membranes. Histochemistry. 1994, 102: 329-335.

    Google Scholar 

  45. Zen K, Notarfrancesco K, Oorschot V, Slot JW, Fisher AB, Shuman H: Generation and characterization of monoclonal antibodies to alveolar type II cell lamellar body membrane. Am J Physiol. 1998, 275: L172-183.

    Google Scholar 

  46. Wadsworth SJ, Chander A: H+- and K+-dependence of Ca2+ uptake in lung lamellar bodies. J Membr Biol. 2000, 174: 41-51.

    Google Scholar 

  47. Chevalier G, Collet AJ: In vivo incorporation of choline-3H, leucine-3H and galactose-3H in alveolar type II pneumocytes in relation to surfactant. Anat Rec. 1972, 174: 289-310.

    Google Scholar 

  48. Voorhout WF, Weaver TE, Haagsman HP, Geuze HJ, Van Golde LM: Biosynthetic routing of pulmonary surfactant proteins in alveolar type II cells. Microsc Res Tech. 1993, 26: 366-373.

    Google Scholar 

  49. Vorbroker DK, Voorhout WF, Weaver TE, Whitsett JA: Posttranslational processing of surfactant protein C in rat type II cells. Am J Physiol. 1995, 269: L727-733.

    Google Scholar 

  50. Brasch F, Ten Brinke A, Kapp N, Johnen G, Ochs M, Fehrenbach H, Müller K-M, Richter J, Ansorge S, Beers MF, Batenburg JJ, Bühling F: Cathepsin H is a possible candidate for processing of SP-C [abstract]. Am J Respir Crit Care Med. 2000, 161: A44-

    Google Scholar 

  51. Herbein JF, Savov J, Wright JR: Binding and uptake of surfactant protein D by freshly isolated rat alveolar type II cells. Am J Physiol. 2000, 278: L830-839.

    Google Scholar 

  52. Rooney SA: Regulation of surfactant secretion. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas; RG Landes Company,. 1998, 139-163.

    Google Scholar 

  53. Young SL, Ho YS, Silbajoris RA: Surfactant apoprotein in adult rat lung compartments is increased by dexamethasone. Am J Physiol. 1991, 260: L161-167.

    Google Scholar 

  54. Alcorn JL, Mendelson CR: Trafficking of surfactant protein A in fetal rabbit lung in organ culture. Am J Physiol. 1993, 264: L27-35.

    Google Scholar 

  55. Froh D, Ballard PL, Williams MC, Gonzales J, Goerke J, Odom MW, Gonzales LW: Lamellar bodies of cultured human fetal lung: content of surfactant protein A (SP-A), surface film formation and structural transformation in vitro. Biochim Biophys Acta. 1990, 1052: 78-89.

    Google Scholar 

  56. Oosterlaken-Dijksterhuis MA, van EM, van B-B, van G-L, Haagsman HP: Surfactant protein composition of lamellar bodies isolated from rat lung. Biochem J. 1991, 274: 115-119.

    Google Scholar 

  57. Osanai K, Mason RJ, Voelker DR: Trafficking of newly synthesized surfactant protein A in isolated rat alveolar type II cells. Am J Respir Cell Mol Biol. 1998, 19: 929-935.

    Google Scholar 

  58. Young SL, Fram EK, Larson E, Wright JR: Recycling of surfactant lipid and apoprotein-A studied by electron microscopic autoradiography. Am J Physiol. 1993, 265: L19-L26.

    Google Scholar 

  59. Rooney SA, Young SL, Mendelson CR: Molecular and cellular processing of lung surfactant. FASEB J. 1994, 8: 957-967.

    Google Scholar 

  60. Wissel H, Zastrow S, Richter E, Stevens PA: Internalized SP-A and lipid are differentially resecreted by type II pneumocytes. Am J Physiol Lung Cell Mol Physiol. 2000, 278: L580-L590.

    Google Scholar 

  61. Nicholas TE, Power JHT, Barr HA: The pulmonary consequences of a deep breath. Respir Physiol. 1982, 49: 315-324.

    Google Scholar 

  62. Massaro GD, Massaro D: Morphological evidence that large inflations of the lung stimulate secretion of surfactant. Am Rev Respir Dis. 1983, 127: 235-236.

    Google Scholar 

  63. Wirtz HR, Dobbs LG: Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science. 1990, 250: 1266-1269.

    Google Scholar 

  64. Ashino Y, Ying X, Dobbs LG, Bhattacharya J: [Ca2+]i oscillations regulate type II cell exocytosis in the pulmonary alveolus. Am J Physiol Lung Cell Mol Physiol. 2000, 279: L5-13.

    Google Scholar 

  65. Brown LA, Pasquale SM, Longmore WJ: Role of microtubules in surfactant secretion. J Appl Physiol. 1985, 58: 1866-1873.

    Google Scholar 

  66. Tsilibary EC, Williams MC: Actin and secretion of surfactant. J Histochem Cytochem. 1983, 31: 1298-1304.

    Google Scholar 

  67. Liu L: Calcium-dependent self-association of annexin II: a possible implication in exocytosis. Cell Signal. 1999, 11: 317-324.

    Google Scholar 

  68. Haller T, Auktor K, Frick M, Mair N, Dietl P: Threshold calcium levels for lamellar body exocytosis in type II pneumocytes. Am J Physiol. 1999, 277: L893-900.

    Google Scholar 

  69. Dobbs LG, Wright JR, Hawgood S, Gonzalez R, Venstrom K, Nel-lenbogen J: Pulmonary surfactant and its components inhibit secretion of phosphatidylcholine from cultured rat alveolar type II cells. Proc Natl Acad Sci U S A. 1987, 84: 1010-1014.

    Google Scholar 

  70. Strayer DS, Pinder R, Chander A: Receptor-mediated regulation of pulmonary surfactant secretion. Exp Cell Res. 1996, 226: 90-97. 10.1006/excr.1996.0206.

    Google Scholar 

  71. Keough KMW: Surfactant composition and extracellular transformation. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas; RG Landes Company,. 1998, 1-27.

    Google Scholar 

  72. Williams MC: Freeze-fracture studies of tubular myelin and lamellar bodies in fetal and adult rat lungs. J Ultrastruct Res. 1978, 64: 352-361.

    Google Scholar 

  73. Young SL, Fram EK, Craig BL: Three-dimensional reconstruction and qualitative analysis of rat lung type II cells: a computer-based study. Am J Anat. 1985, 174: 1-14.

    Google Scholar 

  74. Gross NJ, Narine KR: Surfactant subtypes in mice: characterization and quantitation. J Appl Physiol. 1989, 66: 342-349.

    Google Scholar 

  75. Magoon MW, Wright JR, Baritussio A, Williams MC, Goerke J, Benson BJ, Hamilton RL, Clements JA: Subfractionation of lung surfactant. Implications for metabolism and surface activity. Biochim Biophys Acta. 1983, 750: 18-31.

    Google Scholar 

  76. Gross NJ, Kellam M, Young J, Krishnasamy S, Dhand R: Separation of alveolar surfactant into subtypes. A comparison of methods. Am J Respir Crit Care Med. 2000, 162: 617-622.

    Google Scholar 

  77. Suzuki Y, Fujita Y, Kogishi K: Reconstitution of tubular myelin from synthetic lipids and proteins associated with pig pulmonary surfactant. Am Rev Respir Dis. 1989, 140: 75-81.

    Google Scholar 

  78. Ueda T, Ikegami M, Jobe A: Surfactant subtypes. In vitro conversion, in vivo function, and effects of serum proteins. Am J Respir Crit Care Med. 1994, 149: 1254-1259.

    Google Scholar 

  79. Putman E, Creuwels LA, van Golde LMG, Haagsman HP: Surface properties, morphology and protein composition of pulmonary surfactant subtypes. Biochem J. 1996, 320: 599-605.

    Google Scholar 

  80. Davies RJ, Genghini M, Walters DV, Morley CJ: The behavior of lung surfactant in electrolyte solutions. Biochim Biophys Acta. 1986, 878: 135-145.

    Google Scholar 

  81. Benson BJ, Williams MC, Sueishi K, Goerke J, Sargeant T: Role of calcium ions in the structure and function of pulmonary surfactant. Biochim Biophys Acta. 1984, 793: 18-27.

    Google Scholar 

  82. Haddad IY, Holm BA, Hlavaty I, Matalon S: Dependence of surfactant function on extracellular pH: mechanisms and modifications. J Appl Physiol. 1994, 76: 657-662.

    Google Scholar 

  83. Yu SH, Possmayer F: Effect of pulmonary surfactant protein A (SP-A) and calcium on the adsorption of cholesterol and film stability. Biochim Biophys Acta. 1994, 1211: 350-358.

    Google Scholar 

  84. Meyboom A, Maretzki D, Stevens PA, Hofmann KP: Reversible calcium-dependent interaction of liposomes with pulmonary surfactant protein A. Analysis by resonant mirror technique and near-infrared light scattering. J Biol Chem. 1997, 272: 14600-14605.

    Google Scholar 

  85. Voorhout WF, Veenendaal T, Haagsman HP, Verkleij AJ, van Golde LM, Geuze HJ: Surfactant protein A is localized at the corners of the pulmonary tubular myelin lattice. J Histochem Cytochem. 1991, 39: 1331-1336.

    Google Scholar 

  86. Beers MF: Molecular processing and cellular metabolism of surfactant protein C. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas; RG Landes Company,. 1998, 93-124.

    Google Scholar 

  87. Nag K, Munro JG, Inchley K, Schurch S, Petersen NO, Possmayer F: SP-B refining of pulmonary surfactant phospholipid films. Am J Physiol. 1999, 277: L1179-1189.

    Google Scholar 

  88. Krishnasamy S, Teng AL, Dhand R, Schultz RM, Gross NJ: Molecular cloning, characterization, and differential expression pattern of mouse lung surfactant convertase. Am J Physiol. 1998, 275: L969-975.

    Google Scholar 

  89. Oulton M, Edwards E, Handa K: Convertase activity in alveolar surfactant and lamellar bodies in fetal, newborn, and adult rabbits. J Appl Physiol. 1999, 86: 71-77.

    Google Scholar 

  90. Lewis JF, Novick RJ, Veldhuizen RAW: Surfactant in lung injury and lung transplantation. New York; Springer,. 1997

    Google Scholar 

  91. Savov J, Silbajoris R, Young SL: Mechanical ventilation of rat lung: effect on surfactant forms. Am J Physiol. 1999, 277: L320-326.

    Google Scholar 

  92. Fehrenbach H, Brasch F, Uhlig S, Weisser M, Stamme C, Wendel A, Richter J: Early alterations in intracellular and alveolar surfactant of the rat lung in response to endotoxin. Am J Respir Crit Care Med. 1998, 157: 1630-1639.

    Google Scholar 

  93. Bachofen H, Schürch S, Michel RP, Weibel ER: Experimental hydrostatic pulmonary edema in rabbit lungs. Morphology. Am Rev Respir Dis. 1993, 147: 989-996.

    Google Scholar 

  94. deMello DE, Heyman S, Phelps DS, Floros J: Immunogold localization of SP-A in lungs of infants dying from respiratory distress syndrome. Am J Pathol. 1993, 142: 1631-1640.

    Google Scholar 

  95. Korfhagen TR, LeVine AM, Whitsett JA: Surfactant protein A (SP-A) gene targeted mice. Biochim Biophys Acta. 1998, 1408: 296-302.

    Google Scholar 

  96. Breslin JS, Weaver TE: Binding, uptake, and localization of surfactant protein B in isolated rat alveolar type II cells. Am J Physiol. 1992, 262: L699-707.

    Google Scholar 

  97. Pinto RA, Wright JR, Lesikar D, Benson BJ, Clements JA: Uptake of pulmonary surfactant protein C into adult rat lung lamellar bodies. J Appl Physiol. 1993, 74: 1005-1011.

    Google Scholar 

  98. Kuroki Y, Mason RJ, Voelker DR: Alveolar type II cells express a high affinity receptor for surfactant protein A. Proc Natl Acad Sci USA. 1988, 85: 5566-5570.

    Google Scholar 

  99. Horowitz AD, Moussavian B, Whitsett JA: Roles of SP-A, SP-B, and SP-C in modulation of lipid uptake by pulmonary epithelial cells in vitro. Am J Physiol. 1996, 270: L69-L79.

    Google Scholar 

  100. Baritussio A, Alberti A, Armanini D, Meloni F, Bruttomesso D: Different pathways of degradation of SP-A and saturated phosphatidylcholine by alveolar macrophages. Am J Physiol. 2000, 279: L91-L99.

    Google Scholar 

  101. Reed JA, Whitsett JA: Granulocyte-macrophage colony-stimulating factor and pulmonary surfactant homeostasis. Proc Assoc Am Physicians. 1998, 110: 321-332.

    Google Scholar 

  102. Kauffman SL: Cell proliferation in the mammalian lung. Int Rev Exp Pathol. 1980, 22: 131-191.

    Google Scholar 

  103. Uhal BD: Cell cycle kinetics in the alveolar epithelium. Am J Physiol. 1997, 272: L1031-1045.

    Google Scholar 

  104. Bowden DH: Cell turnover in the lung. Am Rev Respir Dis. 1983, 128: S46-S48.

    Google Scholar 

  105. Adamson IYR, Bowden DH: The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. Lab Invest. 1974, 30: 35-42.

    Google Scholar 

  106. Ulich TR, Yi ES, Longmuir K, Yin S, Biltz R, Morris CF, Housley RM, Pierce GF: Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. J Clin Invest. 1994, 93: 562-572.

    Google Scholar 

  107. Fehrenbach H, Kasper M, Tschernig T, Tan P, Schuh D, Shannon JM, Müller M, Mason RJ: Keratinocyte growth factor-induced hyperplasia of rat alveolar type II cell in vivo is resolved by differentiation into type I cells and by apoptosis. Eur Respir J. 1999, 14: 534-544. 10.1183/09031936.99.14353499.

    Google Scholar 

  108. Kapanci Y, Weibel ER, Kaplan HP, Robinson FR: Pathogenesis and reversibility of the pulmonary lesions of oxygen toxicity in monkeys. II. Ultrastructural and morphometric studies. Lab Invest. 1969, 20: 101-117.

    Google Scholar 

  109. Wuenschell CW, Sunday ME, Singh G, Minoo P, Slavkin HC, Warburton D: Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages. J Histochem Cytochem. 1996, 44: 113-123.

    Google Scholar 

  110. Chiarugi V, Magnelli L, Cinelli M, Basi G: Apoptosis and the cell cycle. Cell Mol Biol Res. 1994, 40: 603-612.

    Google Scholar 

  111. Kauffman SL: Alterations in cell proliferation in mouse lung following urethane exposure. 3. Effects of chronic exposure on type 2 alveolar epithelial cell. Am J Pathol. 1972, 68: 317-326.

    Google Scholar 

  112. Evans MJ, Cabral LJ, Stephens RJ, Freeman G: Transformation of alveolar type 2 cells to type 1 cells following exposure to NO2. Exp Mol Pathol. 1975, 22: 142-150.

    Google Scholar 

  113. Kauffman SL: Kinetics of alveolar epithelial hyperplasia in lungs of mice exposed to urethane. I. Quantitative analysis of cell populations. Lab Invest. 1974, 30: 170-175.

    Google Scholar 

  114. Kalina M, Riklis S, Blau H: Pulmonary epithelial cell proliferation in primary culture of alveolar type II cells. Exp Lung Res. 1993, 19: 153-175.

    Google Scholar 

  115. Witschi H: Proliferation of type II alveolar cells: a review of common responses in toxic lung injury. Toxicology. 1976, 5: 267-277.

    Google Scholar 

  116. Bitterman PB, Polunovsky VA, Ingbar DH: Repair after acute lung injury. Chest. 1994, 105: 118S-121S.

    Google Scholar 

  117. Evans MJ, Cabral LJ, Stephens RJ, Freeman G: Renewal of alveolar epithelium in the rat following exposure to NO2. Am J Pathol. 1973, 70: 175-198.

    Google Scholar 

  118. Dobbs LG, Geppert EF, Williams MC, Greenleaf RD, Mason RJ: Metabolic properties and ultrastructure of alveolar type II cells isolated with elastase. Biochim Biophys Acta. 1980, 618: 510-523.

    Google Scholar 

  119. Mason RJ, Shannon JM: Alveolar type II cells. In The Lung. Scientific Foundations. Edited by Crystal RG, West JB, Barnes PJ, et al. Philadelphia - New York; Lippincott - Raven Publishers,. 1997, 543-555.

    Google Scholar 

  120. Mason RJ, Walker SR, Shields BA, Henson JE, Williams MC: Identification of rat alveolar type II epithelial cells with tannic acid and polychrome stain. Am Rev Respir Dis. 1985, 131: 786-788.

    Google Scholar 

  121. Kasper M, Singh G: Epithelial lung cell marker: current tools for cell typing. Histol Histopathol. 1995, 10: 155-169.

    Google Scholar 

  122. Joyce-Brady MF, Brody JS: Ontogeny of pulmonary alveolar epithelial markers of differentiation. Dev Biol. 1990, 137: 331-348.

    Google Scholar 

  123. Kasper M, Haroske G: Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol Histopathol. 1996, 11: 463-483.

    Google Scholar 

  124. Woodcock-Mitchell J, Rannels SR, Mitchell J, Rannels DE, Low RB: Modulation of keratin expression in type II pneumocytes by the extracellular matrix. Am Rev Respir Dis. 1989, 139: 343-351.

    Google Scholar 

  125. Danto SI, Shannon JM, Borok Z, Zabski SM, Crandall ED: Reversible transdifferentiation of alveolar epithelial cells. Am J Respir Cell Mol Biol. 1995, 12: 497-502.

    Google Scholar 

  126. Campbell L, Hollins AJ, Al-Eid A, Newman GR, von Ruhland C, Gumbleton M: Caveolin-1 expression and caveolae biogenesis during cell transdifferentiation in lung alveolar epithelial primary cultures. Biochem Biophys Res Commun. 1999, 262: 744-751. 10.1006/bbrc.1999.1280.

    Google Scholar 

  127. Brody JS, Williams MC: Pulmonary alveolar epithelial cell differentiation. Annu Rev Physiol. 1992, 54: 351-371.

    Google Scholar 

  128. Borok Z, Danto SI, Lubman RL, Cao Y, Williams MC, Crandall ED: Modulation of T1 alpha expression with alveolar epithelial cell phenotype in vitro. Am J Physiol. 1998, 275: L155-164.

    Google Scholar 

  129. Gräper L: A new point of view regarding the physiological elimination of cells [in German]. Arch Zellforsch. 1914, 12: 373-394.

    Google Scholar 

  130. Rich T, Watson CJ, Wyllie A: Apoptosis: the germs of death. Nat Cell Biol. 1999, 1: E69-71. 10.1038/11038.

    Google Scholar 

  131. Huppertz B, Frank HG, Kaufmann P: The apoptosis cascade: morphological and immunohistochemical methods for its visualization. Anat Embryol (Berl). 1999, 200: 1-18.

    Google Scholar 

  132. Behnia M, Robertson KA, Martin WJ: Lung infections: role of apoptosis in host defense and pathogenesis of disease. Chest. 2000, 117: 1771-1777.

    Google Scholar 

  133. Fine A, Janssen-Heininger Y, Soultanakis RP, Swisher SG, Uhal BD: Apoptosis in lung pathophysiology. Am J Physiol Lung Cell Mol Physiol. 2000, 279: L423-L427.

    Google Scholar 

  134. Fine A, Anderson NL, Rothstein TL, Williams MC, Gochuico BR: Fas expression in pulmonary alveolar type II cells. Am J Physiol. 1997, 273: L64-71.

    Google Scholar 

  135. Scavo LM, Ertsey R, Chapin CJ, Allen L, Kitterman JA: Apoptosis in the development of rat and human fetal lungs. Am J Respir Cell Mol Biol. 1998, 18: 21-31.

    Google Scholar 

  136. Schittny JC, Djonov V, Fine A, Burri PH: Programmed cell death contributes to postnatal lung development. Am J Respir Cell Mol Biol. 1998, 18: 786-793.

    Google Scholar 

  137. Bardales RH, Xie SS, Schaefer RF, Hsu SM: Apoptosis is a major pathway responsible for the resolution of type II pneumocytes in acute lung injury. Am J Pathol. 1996, 149: 845-852.

    Google Scholar 

  138. Fehrenbach H, Kasper M, Koslowski R, Tan P, Schuh D, Müller M, Mason RJ: Alveolar epithelial type II cell apoptosis in vivo during resolution of keratinocyte growth factor-induced hyperplasia in the rat. Histochem Cell Biol. 2000, 114: 49-61.

    Google Scholar 

  139. Weibel ER, Taylor CR: Design and structure of the human lung. In Pulmonary Diseases and Disorders. Edited by Fishman AP. New York; McGraw-Hill Book, Company,. 1988, 11-61.

    Google Scholar 

  140. Crapo JD, Barry BE, Gehr P, Bachofen M, Weibel ER: Cell number and cell characteristics of the normal human lung. Am Rev Respir Dis. 1982, 126: 332-337.

    Google Scholar 

  141. Cruz-Orive LM, Weibel ER: Recent stereological methods for cell biology: a brief survey. Am J Physiol. 1990, 258: L148-L156.

    Google Scholar 

  142. Kasper M, Traub O, Reimann T, Bjermer L, Grossmann H, Müller M, Wenzel KW: Upregulation of gap junction protein connexin43 in alveolar epithelial cells of rats with radiation-induced pulmonary fibrosis. Histochem Cell Biol. 1996, 106: 419-424.

    Google Scholar 

  143. Marin L, Dameron F, Relier JP: Changes in the cellular environment of differentiating type II pneumocytes. Quantitative study in the perinatal rat lung. Biol Neonate. 1982, 41: 172-182.

    Google Scholar 

  144. Mason RJ, McCormack FX: Alveolar type II cell reactions in pathologic states. In Lung surfactant: Basic research in the pathogenesis of lung disorders. Edited by Müller B, von Wichert P. Basel; Karger,. 1994, 194-204.

    Google Scholar 

  145. St Croix B, Sheehan C, Rak JW, Florenes VA, Slingerland JM, Kerbel RS: E-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27(KIP1). J Cell Biol. 1998, 142: 557-571.

    Google Scholar 

  146. Kasper M, Behrens J, Schuh D, Müller M: Distribution of E-cadherin and Ep-CAM in the human lung during development and after injury. Histochem Cell Biol. 1995, 103: 281-286.

    Google Scholar 

  147. Ikegami M, Korfhagen TR, Whitsett JA, Bruno MD, Wert SE, Wada K, Jobe AH: Characteristics of surfactant from SP-A-deficient mice. Am J Physiol. 1998, 275: L247-254.

    Google Scholar 

  148. Khalil N, O'Connor RN, Flanders KC, Shing W, Whitman CI: Regulation of type II alveolar epithelial cell proliferation by TGF-beta during bleomycin-induced lung injury in rats. Am J Physiol. 1994, 267: L498-507.

    Google Scholar 

  149. Shannon JM, Deterding RR: Epithelial-mesenchymal interactions in lung development. In Lung growth and development. Edited by McDonald JA. New York; Marcel Dekker, Inc.,. 1997, 81-118.

    Google Scholar 

  150. O'Reilly MA, Stripp BR, Pryhuber GS: Epithelial-mesenchymal interactions in the alteration of gene expression and morphology following lung injury. Microsc Res Tech. 1997, 38: 473-479. 10.1002/(SICI)1097-0029(19970901)38:5<473::AID-JEMT3>3.3.CO;2-H.

    Google Scholar 

  151. Adamson IYR, Young L, King GM: Reciprocal epithelial: fibroblast interactions in the control of fetal and adult rat lung cells in culture. Exp Lung Res. 1991, 17: 821-835.

    Google Scholar 

  152. Griffin M, Bhandari R, Hamilton G, Chan YC, Powell JT: Alveolar type II cell-fibroblast interactions, synthesis and secretion of surfactant and type I collagen. J Cell Sci. 1993, 105: 423-432.

    Google Scholar 

  153. de Lara LV, Becerril C, Montano M, Ramos C, Maldonado V, Melendez J, Phelps DS, Pardo A, Selman M: Surfactant components modulate fibroblast apoptosis and type I collagen and collagenase-1 expression. Am J Physiol. 2000, 279: L950-798.

    Google Scholar 

  154. Adamson IY, Hedgecock C, Bowden DH: Epithelial cell-fibroblast interactions in lung injury and repair. Am J Pathol. 1990, 137: 385-392.

    Google Scholar 

  155. Bajorath J: Molecular organization, structural features, and ligand binding characteristics of CD44, a highly variable cell surface glycoprotein with multiple functions. Proteins. 2000, 39: 103-111. 10.1002/(SICI)1097-0134(20000501)39:2<103::AID-PROT1>3.3.CO;2-7.

    Google Scholar 

  156. Smith SK, Giannopoulos G: Influence of pulmonary endothelial cells on fetal lung development. Pediatr Pulmonol. 1985, 1: S53-S59.

    Google Scholar 

  157. Adamson IY, Young L: Alveolar type II cell growth on a pulmonary endothelial extracellular matrix. Am J Physiol. 1996, 270: L1017-1022.

    Google Scholar 

  158. Sen N, Grunstein MM, Chander A: Stimulation of lung surfactant secretion by endothelin-1 from rat alveolar type II cells. Am J Physiol. 1994, 266: L255-262.

    Google Scholar 

  159. Markewitz BA, Kohan DE, Michael JR: Endothelin-1 synthesis, receptors, and signal transduction in alveolar epithelium: evidence for an autocrine role. Am J Physiol. 1995, 268: L192-200.

    Google Scholar 

  160. Kuebler WM, Parthasarathi K, Wang PM, Bhattacharya J: A novel signalling mechanism between gas and blood compartments of the lung. J Clin Invest. 2000, 105: 905-913.

    Google Scholar 

  161. Lohmann-Matthes ML, Steinmuller C, Franke-Ullmann G: Pulmonary macrophages. Eur Respir J. 1994, 7: 1678-1689.

    Google Scholar 

  162. Mason RJ, Leslie CC, McCormick-Shannon K, Deterding RR, Nakamura T, Rubin JS, Shannon JM: Hepatocyte growth factor is a growth factor for rat alveolar type II cells. Am J Respir Cell Mol Biol. 1994, 11: 561-567.

    Google Scholar 

  163. Leslie CC, McCormick-Shannon K, Shannon JM, Garrick B, Damm D, Abraham JA, Mason RJ: Heparin-binding EGF-like growth factor is a mitogen for rat alveolar type II cells. Am J Respir Cell Mol Biol. 1997, 16: 379-387.

    Google Scholar 

  164. O'Brien AD, Standiford TJ, Christensen PJ, Wilcoxen SE, Paine R: Chemotaxis of alveolar macrophages in response to signals derived from alveolar epithelial cells. J Lab Clin Med. 1998, 131: 417-424.

    Google Scholar 

  165. Blau H, Riklis S, Kravtsov V, Kalina M: Secretion of cytokines by rat alveolar epithelial cells: possible regulatory role for SP-A. Am J Physiol. 1994, 266: L148-155.

    Google Scholar 

  166. Christensen PJ, Armstrong LR, Fak JJ, Chen GH, McDonald RA, Toews GB, Paine R: Regulation of rat pulmonary dendritic cell immunostimulatory activity by alveolar epithelial cell-derived granulocyte macrophage colony- stimulating factor. Am J Respir Cell Mol Biol. 1995, 13: 426-433.

    Google Scholar 

  167. Worgall S, Singh R, Leopold PL, Kaner RJ, Hackett NR, Topf N, Moore MA, Crystal RG: Selective expansion of alveolar macrophages in vivo by adenovirus-mediated transfer of the murine granulocyte-macrophage colony-stimulating factor cDNA. Blood. 1999, 93: 655-666.

    Google Scholar 

  168. Weissbach S, Neuendank A, Pettersson M, Schaberg T, Pison U: Surfactant protein A modulates release of reactive oxygen species from alveolar macrophages. Am J Physiol. 1994, 267: L660-666.

    Google Scholar 

  169. Stamme C, Walsh E, Wright JR: Surfactant protein A differentially regulates IFN-γ- and LPS-induced nitrite production by rat alveolar macrophages. Am J Respir Cell Mol Biol. 2000, 23: 772-779.

    Google Scholar 

  170. Zissel G, Ernst M, Rabe K, Papadopoulos T, Magnussen H, Schlaak M, Müller-Quernheim J: Human alveolar epithelial cells type II are capable of regulating T-cell activity. J Investig Med. 2000, 48: 66-75.

    Google Scholar 

  171. Schneeberger EE, DeFerrari M, Skoskiewicz MJ, Russell PS, Colvin RB: Induction of MHC-determined antigens in the lung by interferon-gamma. Lab Invest. 1986, 55: 138-144.

    Google Scholar 

  172. Paine R, Mody CH, Chavis A, Spahr MA, Turka LA, Toews GB: Alveolar epithelial cells block lymphocyte proliferation in vitro without inhibiting activation. Am J Respir Cell Mol Biol. 1991, 5: 221-229.

    Google Scholar 

  173. Rosseau S, Selhorst J, Wiechmann K, Leissner K, Maus U, Mayer K, Grimminger F, Seeger W, Lohmeyer J: Monocyte migration through the alveolar epithelial barrier: adhesion molecule mechanisms and impact of chemokines. J Immunol. 2000, 164: 427-435.

    Google Scholar 

  174. Simon RH, DeHart PD, Todd RFd: Neutrophil-induced injury of rat pulmonary alveolar epithelial cells. J Clin Invest. 1986, 78: 1375-1386.

    Google Scholar 

  175. Haslett C: Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am J Respir Crit Care Med. 1999, 160: S5-11.

    Google Scholar 

  176. Putman E, van Golde LM, Haagsman HP: Toxic oxidant species and their impact on the pulmonary surfactant system. Lung. 1997, 175: 75-103.

    Google Scholar 

  177. Uhlig S, Brasch F, Wollin L, Fehrenbach H, Wendel A, Richter J: Functional and fine structural changes in isolated rat lungs challenged with endotoxin ex vivo and in vitro. Am J Pathol. 1995, 146: 1235-1247.

    Google Scholar 

  178. McCormack FX: Role of pulmonary epithelium and surfactant in the pathogenesis of interstitial lung disease. In Interstitial lung disease. Edited by Schwarz MI, King TE. Hamilton; BC Decker Inc.,. 1998, 165-180.

    Google Scholar 

  179. Gauldie J, Sime PJ, Xing Z, Marr B, Tremblay GM: Transforming growth factor-beta gene transfer to the lung induces myofibroblast presence and pulmonary fibrosis. Curr Top Pathol. 1999, 93: 35-45.

    Google Scholar 

  180. Kapanci Y, Desmouliere A, Pache JC, Redard M, Gabbiani G: Cytoskeletal protein modulation in pulmonary alveolar myofibroblasts during idiopathic pulmonary fibrosis. Possible role of transforming growth factor beta and tumor necrosis factor alpha. Am J Respir Crit Care Med. 1995, 152: 2163-2169.

    Google Scholar 

  181. Khalil N, O'Connor RN, Flanders KC, Unruh H: TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immuno-histochemical study. Am J Respir Cell Mol Biol. 1996, 14: 131-138.

    Google Scholar 

  182. Antoniades HN, Bravo MA, Avila RE, Galanopoulos T, Neville-Golden J, Maxwell M, Selman M: Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest. 1990, 86: 1055-1064.

    Google Scholar 

  183. Morikawa O, Walker TA, Nielsen LD, Pan T, Cook JL, Mason RJ: Effect of adenovector-mediated gene transfer of keratinocyte growth factor (KGF) on the proliferation of aveolar type II cells in vitro and in vivo. Am J Respir Cell Mol Biol. 2000, 23: 626-635.

    Google Scholar 

  184. Kuwano K, Hagimoto N, Kawasaki M, Yatomi T, Nakamura N, Nagata S, Suda T, Kunitake R, Maeyama T, Miyazaki H, Hara N: Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest. 1999, 104: 13-19.

    Google Scholar 

  185. Uhal BD, Joshi I, Hughes WF, Ramos C, Pardo A, Selman M: Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am J Physiol. 1998, 275: L1192-L1199.

    Google Scholar 

  186. Rooney SA: Regulation of surfactant phospholipid biosynthesis. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas: R. G. Landes Company,. 1998, 29-45.

    Google Scholar 

  187. Mason RJ, Greene K, Voelker DR: Surfactant protein A and surfactant protein D in health and disease. Am J Physiol. 1998, 275: L1-L13.

    Google Scholar 

  188. Mendelson CR, Young PP, Michael LF, Gao E, Alcorn JL: Surfactant protein A gene and its regulation. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas: R. G. Landes Company,. 1998, 47-74.

    Google Scholar 

  189. Lin S, Weaver TE: Cellular and molecular processing of surfactant protein B. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas: R. G. Landes Company,. 1998, 75-92.

    Google Scholar 

  190. Crouch EC: Biosynthesis and secretion of surfactant protein D. In Lung surfactant: cellular and molecular processing. Edited by Rooney SA. Austin, Texas: R. G. Landes Company,. 1998, 125-138.

    Google Scholar 

  191. Gibson KF, Phadke S: Intracellular distribution of lysozyme in rat alveolar type II epithelial cells. Exp Lung Res. 1994, 20: 595-611.

    Google Scholar 

  192. Rustow B, Kolleck I, Guthmann F, Haupt R, Kunze D, Stevens P: Synthesis and secretion of plasmalogens by type-II pneumocytes. Biochem J. 1994, 302: 665-668.

    Google Scholar 

  193. Ishii Y, Hashizume Y, Watanabe T, Waguri S, Sato N, Yamamoto M, Hasegawa S, Kominami E, Uchiyama Y: Cysteine proteinases in bronchoalveolar epithelial cells and lavage fluid of rat lung. J Histochem Cytochem. 1991, 39: 461-468.

    Google Scholar 

  194. Brasch F, Ochs M, Bühling F, Fehrenbach H, Schmiedl A, Ansorge S, Wahlers T, Müller K-M, Richter J: Cathepsin H and SP-B are colocalized in multivesicular, composite and lamellar bodies of human type II pneumocytes. Am J Respir Crit Care Med. 1999, 159: A182-

    Google Scholar 

  195. Fabisiak JP, Vesell ES, Rannels DE: Interactions of beta adrenergic antagonists with isolated rat alveolar type II pneumocytes. I. Analysis, characterization and regulation of specific beta adrenergic receptors. J Pharmacol Exp Ther. 1987, 241: 722-727.

    Google Scholar 

  196. Ewing CK, Duffy DM, Roberts JM: Characterization of the beta-adrenergic receptor in isolated human fetal lung type II cells. Pediatr Res. 1992, 32: 350-355.

    Google Scholar 

  197. Gilfillan AM, Rooney SA: Functional evidence for adenosine A2 receptor regulation of phosphatidylcholine secretion in cultured type II pneumocytes. J Pharmacol Exp Ther. 1987, 241: 907-914.

    Google Scholar 

  198. Warburton D, Buckley S, Cosico L: P1 and P2 purinergic receptor signal transduction in rat type II pneumocytes. J Appl Physiol. 1989, 66: 901-905.

    Google Scholar 

  199. Rice WR, Burton FM, Fiedeldey DT: Cloning and expression of the alveolar type II cell P2u-purinergic receptor. Am J Respir Cell Mol Biol. 1995, 12: 27-32.

    Google Scholar 

  200. Liu L, Wang M, Fisher AB, Zimmerman UJ: Involvement of annexin II in exocytosis of lamellar bodies from alveolar epithelial type II cells. Am J Physiol. 1996, 270: L668-L676.

    Google Scholar 

  201. Sohma H, Matsushima N, Watanabe T, Hattori A, Kuroki Y, Akino T: Ca(2+)-dependent binding of annexin IV to surfactant protein A and lamellar bodies in alveolar type II cells. Biochem J. 1995, 312: 175-181.

    Google Scholar 

  202. Chander A, Wu RD: In vitro fusion of lung lamellar bodies and plasma membrane is augmented by lung synexin. Biochim Biophys Acta. 1991, 1086: 157-166.

    Google Scholar 

  203. Sen N, Spitzer AR, Chander A: Calcium-dependence of synexin binding may determine aggregation and fusion of lamellar bodies. Biochem J. 1997, 322: 103-109.

    Google Scholar 

  204. Gross NJ, Bublys V, D'Anza J, Brown CL: The role of alpha 1-antitrypsin in the control of extracellular surfactant metabolism. Am J Physiol. 1995, 268: L438-L445.

    Google Scholar 

  205. Barr F, Clark H, Hawgood S: Identification of a putative surfactant convertase in rat lung as a secreted serine carboxylesterase. Am J Physiol. 1998, 274: L404-L410.

    Google Scholar 

  206. Kresch MJ, Christian C, Lu H: Isolation and partial characterization of a receptor to surfactant protein A expressed by rat type II pneumocytes. Am J Respir Cell Mol Biol. 1998, 19: 216-225.

    Google Scholar 

  207. Edelson JD, Shannon JM, Mason RJ: Alkaline phosphatase: a marker of alveolar type II cell differentiation. Am Rev Respir Dis. 1988, 138: 1268-1275.

    Google Scholar 

  208. de Vries AC, Schram AW, Tager JM, Batenburg JJ, van Golde LM: A specific acid alpha-glucosidase in lamellar bodies of the human lung. Biochim Biophys Acta. 1985, 837: 230-238.

    Google Scholar 

  209. Bui KC, Wu F, Buckley S, Wu L, Williams R, Carbonaro-Hall D, Hall FL, Warburton D: Cyclin A expression in normal and transformed alveolar epithelial cells. Am J Respir Cell Mol Biol. 1993, 9: 115-125.

    Google Scholar 

  210. Wu F, Buckley S, Bui KC, Warburton D: Differential expression of cyclin D2 and cdc2 genes in proliferating and nonproliferating alveolar epithelial cells. Am J Respir Cell Mol Biol. 1995, 12: 95-103.

    Google Scholar 

  211. Hastings RH, Summers-Torres D, Yaszay B, LeSueur J, Burton DW, Deftos LJ: Parathyroid hormone-related protein, an autocrine growth inhibitor of alveolar type II cells. Am J Physiol. 1997, 272: L394-L399.

    Google Scholar 

  212. Hill DJ, Wright TC, Andrews ML, Karnowsky MJ: Localization of calmodulin in differentiating pulmonary type II epithelial cells. Lab Invest. 1984, 51: 297-306.

    Google Scholar 

  213. Wang J, Campos B, Kaetzel MA, Dedman JR: Expression of a calmodulin inhibitor peptide in progenitor alveolar type II cells disrupts lung development. Am J Physiol. 1996, 271: L245-L250.

    Google Scholar 

  214. Mouhieddine OB, Cazals V, Maitre B, Le Bouc Y, Chadelat K, Clement A: Insulin-like growth factor-II (IGF-II), type 2 IGF receptor, and IGF- binding protein-2 gene expression in rat lung alveolar epithelial cells: relation to proliferation. Endocrinology. 1994, 135: 83-91.

    Google Scholar 

  215. Grummer MA, Thet LA, Zachman RD: Expression of retinoic acid receptor genes in fetal and newborn rat lung. Pediatr Pulmonol. 1994, 17: 234-238.

    Google Scholar 

  216. Tangada SD, Peterson RD, Funkhouser JD: Regulation of expression of aminopeptidase N in fetal rat lung by dexamethasone and epidermal growth factor. Biochim Biophys Acta. 1995, 1268: 191-199.

    Google Scholar 

  217. Buckley S, Barsky L, Driscoll B, Weinberg K, Anderson KD, Warburton D: Apoptosis and DNA damage in type 2 alveolar epithelial cells cultured from hyperoxic rats. Am J Physiol. 1998, 274: L714-L720.

    Google Scholar 

  218. Effros RM, Darin C, Jacobs ER, Rogers RA, Krenz G, Schneeberger EE: Water transport and the distribution of aquaporin-1 in pulmonary air spaces. J Appl Physiol. 1997, 83: 1002-1016.

    Google Scholar 

  219. King LS, Agre P: Pathophysiology of the aquaporin water channels. Annu Rev Physiol. 1996, 58: 619-648.

    Google Scholar 

  220. Folkesson HG, Matthay MA, Hasegawa H, Kheradmand F, Verkman AS: Transcellular water transport in lung alveolar epithelium through mercury-sensitive water channels. Proc Natl Acad Sci U S A. 1994, 91: 4970-4974.

    Google Scholar 

  221. Schneeberger EE: Alveolar type I cells. In The Lung. Scientific Foundations, 2nd ed. Edited by Crystal RG, West JB, Barnes PJ, et al. Philadelphia, New York: Lippincott-Raven Publishers,. 1997, 535-542.

    Google Scholar 

  222. DeCoursey TE: Hydrogen ion currents in rat alveolar epithelial cells. Biophys J. 1991, 60: 1243-1253.

    Google Scholar 

  223. Borok Z, Danto SI, Dimen LL, Zhang XL, Lubman RL: Na+-K+-ATPase expression in alveolar epithelial cells: upregulation of active ion transport by KGF. Am J Physiol. 1998, 274: L149-L158.

    Google Scholar 

  224. Schneider GT, Cook DI, Gage PW, Young JA: Voltage sensitive, high-conductance chloride channels in the luminal membrane of cultured pulmonary alveolar (type II) cells. Pflugers Arch. 1985, 404: 354-357.

    Google Scholar 

  225. Lubman RL, Danto SI, Chao DC, Fricks CE, Crandall ED: Cl(-)-HCO3- exchanger isoform AE2 is restricted to the basolateral surface of alveolar epithelial cell monolayers. Am J Respir Cell Mol Biol. 1995, 12: 211-219.

    Google Scholar 

  226. Nord EP, Brown SE, Crandall ED: Characterization of Na+-H+ antiport in type II alveolar epithelial cells. Am J Physiol. 1987, 252: C490-C498.

    Google Scholar 

  227. Schneeberger EE, McCarthy KM: Cytochemical localization of Na+-K+-ATPase in rat type II pneumocytes. J Appl Physiol. 1986, 60: 1584-1589.

    Google Scholar 

  228. Ridge KM, Rutschman DH, Factor P, Katz AI, Bertorello AM, Sznajder JL: Differential expression of Na-K-ATPase isoforms in rat alveolar epithelial cells. Am J Physiol. 1997, 273: L246-L255.

    Google Scholar 

  229. Folkesson HG, Matthay MA, Westrom BR, Kim KJ, Karlsson BW, Hastings RH: Alveolar epithelial clearance of protein. J Appl Physiol. 1996, 80: 1431-1445.

    Google Scholar 

  230. Fleming RE, Moxley MA, Waheed A, Crouch EC, Sly WS, Longmore WJ: Carbonic anhydrase II expression in rat type II pneumocytes. Am J Respir Cell Mol Biol. 1994, 10: 499-505.

    Google Scholar 

  231. Komatsu T, Yamamoto M, Shimokata K, Nagura H: Phenotypic characterization of alveolar capillary endothelial cells, alveolar epithelial cells and alveolar macrophages in patients with pulmonary fibrosis, with special reference to MHC class II antigens. Virchows Arch A Pathol Anat Histopathol. 1989, 415: 79-90.

    Google Scholar 

  232. Peters U, Papadopoulos T, Müller-Hermelink HK: MHC class II antigens on lung epithelial of human fetuses and neonates. Ontogeny and expression in lungs with histologic evidence of infection. Lab Invest. 1990, 63: 38-43.

    Google Scholar 

  233. Ronni T, Matikainen S, Sareneva T, Melen K, Pirhonen J, Keskinen P, Julkunen I: Regulation of IFN-alpha/beta, MxA, 2',5'-oligoadenylate synthetase, and HLA gene expression in influenza A-infected human lung epithelial cells. J Immunol. 1997, 158: 2363-2374.

    Google Scholar 

  234. Salik E, Tyorkin M, Mohan S, George I, Becker K, Oei E, Kalb T, Sperber K: Antigen trafficking and accessory cell function in respiratory epithelial cells. Am J Respir Cell Mol Biol. 1999, 21: 365-379.

    Google Scholar 

  235. Strunk RC, Eidlen DM, Mason RJ: Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways. J Clin Invest. 1988, 81: 1419-1426.

    Google Scholar 

  236. Venembre P, Boutten A, Seta N, Dehoux MS, Crestani B, Aubier M, Durand G: Secretion of alpha 1-antitrypsin by alveolar epithelial cells. FEBS Lett. 1994, 346: 171-174.

    Google Scholar 

  237. Boutten A, Venembre P, Seta N, Hamelin J, Aubier M, Durand G, Dehoux MS: Oncostatin M is a potent stimulator of alpha1-antitrypsin secretion in lung epithelial cells: modulation by transforming growth factor-beta and interferon-gamma. Am J Respir Cell Mol Biol. 1998, 18: 511-520.

    Google Scholar 

  238. Sallenave JM, Silva A, Marsden ME, Ryle AP: Secretion of mucus proteinase inhibitor and elafin by Clara cell and type II pneumocyte cell lines. Am J Respir Cell Mol Biol. 1993, 8: 126-133.

    Google Scholar 

  239. Hayashi T, Stetler Stevenson WG, Fleming MV, Fishback N, Koss MN, Liotta LA, Ferrans VJ, Travis WD: Immunohistochemical study of metalloproteinases and their tissue inhibitors in the lungs of patients with diffuse alveolar damage and idiopathic pulmonary fibrosis. Am J Pathol. 1996, 149: 1241-1256.

    Google Scholar 

  240. van Klaveren RJ, Roelant C, Boogaerts M, Demedts M, Nemery B: Involvement of an NAD(P)H oxidase-like enzyme in superoxide anion and hydrogen peroxide generation by rat type II cells. Thorax. 1997, 52: 465-471.

    Google Scholar 

  241. Holguin F, Moss I, Brown LAS, Guidot DM: Chronic ethanol ingestion impairs alveolar type II cell glutathione homeostasis and function and predisposes to endotoxin-mediated acute edematous lung injury in rats. J Clin Invest. 1998, 101: 761-768.

    Google Scholar 

  242. Joyce-Brady M, Takahashi Y, Oakes SM, Rishi AK, Levine RA, Kinlough CL, Hughey RP: Synthesis and release of amphipathic gamma-glutamyl transferase by the pulmonary alveolar type 2 cell. Its redistribution throughout the gas exchange portion of the lung indicates a new role for surfactant. J Biol Chem. 1994, 269: 14219-14226.

    Google Scholar 

  243. Vincent R, Chang LY, Slot JW, Crapo JD: Quantitative immunocytochemical analysis of Mn SOD in alveolar type II cells of the hyperoxic rat. Am J Physiol. 1994, 267: L475-L481.

    Google Scholar 

  244. Jackson RM, Parish G, Ho YS: Effects of hypoxia on expression of superoxide dismutases in cultured ATII cells and lung fibroblasts. Am J Physiol. 1996, 271: L955-L962.

    Google Scholar 

  245. Jones KG, Holland JF, Foureman GL, Bend JR, Fouts JR: Xenobiotic metabolism in Clara cells and alveolar type II cells isolated from lungs of rats treated with beta-naphthoflavone. J Pharmacol Exp Ther. 1983, 225: 316-319.

    Google Scholar 

  246. Guadiz G, Sporn LA, Goss RA, Lawrence SO, Marder VJ, Simpson Haidaris PJ: Polarized secretion of fibrinogen by lung epithelial cells. Am J Respir Cell Mol Biol. 1997, 17: 60-69.

    Google Scholar 

  247. Simon RH, Gross TJ, Edwards JA, Sitrin RG: Fibrin degradation by rat pulmonary alveolar epithelial cells. Am J Physiol. 1992, 262: L482-L488.

    Google Scholar 

  248. Hasegawa T, Sorensen L, Dohi M, Rao NV, Hoidal JR, Marshall BC: Induction of urokinase-type plasminogen activator receptor by IL-1 beta. Am J Respir Cell Mol Biol. 1997, 16: 683-692.

    Google Scholar 

  249. Kotani I, Sato A, Hayakawa H, Urano T, Takada Y, Takada A: Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis. Thromb Res. 1995, 77: 493-504.

    Google Scholar 

  250. Olman MA, Mackman N, Gladson CL, Moser KM, Loskutoff DJ: Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse. J Clin Invest. 1995, 96: 1621-1630.

    Google Scholar 

  251. Panos RJ: Cytokines and alveolar type II cells. In Cytokines of the Lung. Edited by Kelley J. New York: Marcel Dekker, Inc.,. 1993, 417-456.

    Google Scholar 

  252. Finkelstein JN, Johnston C, Barrett T, Oberdorster G: Particulate-cell interactions and pulmonary cytokine expression. Environ Health Perspect. 1997, 5: 1179-1182.

    Google Scholar 

  253. Wallace WA, Howie SE: Immunoreactive interleukin 4 and interferon-gamma expression by type II alveolar epithelial cells in interstitial lung disease. J Pathol. 1999, 187: 475-480. 10.1002/(SICI)1096-9896(199903)187:4<475::AID-PATH268>3.3.CO;2-E.

    Google Scholar 

  254. Standiford TJ, Kunkel SL, Basha MA, Chensue SW, Lynch JPd, Toews GB, Westwick J, Strieter RM: Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung. J Clin Invest. 1990, 86: 1945-1953.

    Google Scholar 

  255. Kunkel SL, Standiford T, Kasahara K, Strieter RM: Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung. Exp Lung Res. 1991, 17: 17-23.

    Google Scholar 

  256. Vlahakis NE, Schroeder MA, Limper AH, Hubmayr RD: Stretch induces cytokine release by alveolar epithelial cells in vitro. Am J Physiol. 1999, 277: L167-L173.

    Google Scholar 

  257. Elias JA, Zheng T, Einarsson O, Landry M, Trow T, Rebert N, Panuska J: Epithelial interleukin-11. Regulation by cytokines, respiratory syncytial virus, and retinoic acid. J Biol Chem. 1994, 269: 22261-22268.

    Google Scholar 

  258. Paine R, Rolfe MW, Standiford TJ, Burdick MD, Rollins BJ, Strieter RM: MCP-1 expression by rat type II alveolar epithelial cells in primary culture. J Immunol. 1993, 150: 4561-4570.

    Google Scholar 

  259. Nash JR, McLaughlin PJ, Butcher D, Corrin B: Expression of tumour necrosis factor-alpha in cryptogenic fibrosing alveolitis. Histopathology. 1993, 22: 343-347.

    Google Scholar 

  260. Piguet PF, Ribaux C, Karpuz V, Grau GE, Kapanci Y: Expression and localization of tumor necrosis factor-alpha and its mRNA in idiopathic pulmonary fibrosis. Am J Pathol. 1993, 143: 651-655.

    Google Scholar 

  261. Lesur O, Arsalane K, Berard J, Mukuna JP, de Brum-Fernandes AJ, Lane D, Rola-Pleszczynski M: Functional IL-2 receptors are expressed by rat lung type II epithelial cells. Am J Physiol. 1997, 273: L495-L503.

    Google Scholar 

  262. Nakamura H, Hino T, Kato S, Shibata Y, Takahashi H, Tomoike H: Tumour necrosis factor receptor gene expression and shedding in human whole lung tissue and pulmonary epithelium. Eur Respir J. 1996, 9: 1643-1647.

    Google Scholar 

  263. Boussaud V, Soler P, Moreau J, Goodwin RG, Hance AJ: Expression of three members of the TNF-R family of receptors (4-1BB, lymphotoxin-beta receptor, and Fas) in human lung. Eur Respir J. 1998, 12: 926-931.

    Google Scholar 

  264. Raaberg L, Nexo E, Buckley S, Luo W, Snead ML, Warburton D: Epidermal growth factor transcription, translation, and signal transduction by rat type II pneumocytes in culture. Am J Respir Cell Mol Biol. 1992, 6: 44-49.

    Google Scholar 

  265. Madtes DK, Busby HK, Strandjord TP, Clark JG: Expression of transforming growth factor-alpha and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats. Am J Respir Cell Mol Biol. 1994, 11: 540-551.

    Google Scholar 

  266. Williams AO, Flanders KC, Saffiotti U: Immunohistochemical localization of transforming growth factor-beta 1 in rats with experimental silicosis, alveolar type II hyperplasia, and lung cancer. Am J Pathol. 1993, 142: 1831-1840.

    Google Scholar 

  267. Asakura S, Colby TV, Limper AH: Tissue localization of transforming growth factor-beta1 in pulmonary eosinophilic granuloma. Am J Respir Crit Care Med. 1996, 154: 1525-1530.

    Google Scholar 

  268. Buckley S, Bui KC, Hussain M, Warburton D: Dynamics of TGF-beta 3 peptide activity during rat alveolar epithelial cell proliferative recovery from acute hyperoxia. Am J Physiol. 1996, 271: L54-L60.

    Google Scholar 

  269. Maniscalco WMA, Watkins RH, Finkelstein JN, Campbell MH: Vascular endothelial growth factor mRNA increases in alveolar epithelial cells during recovery from oxygen injury. Am J Respir Cell Mol Biol. 1995, 13: 377-386.

    Google Scholar 

  270. Buch S, Han RN, Liu J, Moore A, Edelson JD, Freeman BA, Post M, Tanswell AK: Basic fibroblast growth factor and growth factor receptor gene expression in 85% O2-exposed rat lung. Am J Physiol. 1995, 268: L455-L464.

    Google Scholar 

  271. Klein JM, Fritz BL, McCarthy TA, Wohlford-Lenane CL, Snyder JM: Localization of epidermal growth factor receptor in alveolar epithelium during human fetal lung development in vitro. Exp Lung Res. 1995, 21: 917-939.

    Google Scholar 

  272. Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L: Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. Embo J. 1994, 13: 3296-3301.

    Google Scholar 

  273. Finch PW, Cunha GR, Rubin JS, Wong J, Ron D: Pattern of keratinocyte growth factor and keratinocyte growth factor receptor expression during mouse fetal development suggests a role in mediating morphogenetic mesenchymal-epithelial interactions. Dev Dyn. 1995, 203: 223-240.

    Google Scholar 

  274. Maitre B, Clement A, Williams MC, Brody JS: Expression of insulin-like growth factor receptors 1 and 2 in the developing lung and their relation to epithelial cell differentiation. Am J Respir Cell Mol Biol. 1995, 13: 262-270.

    Google Scholar 

  275. Kasper M, Günthert U, Dall P, Kayser K, Schuh D, Haroske G, Müller M: Distinct expression patterns of CD44 isoforms during human lung development and in pulmonary fibrosis. Am J Respir Cell Mol Biol. 1995, 13: 648-656.

    Google Scholar 

  276. Kasper ME, Huber O, Grossmann H, Rudolph B, Tränkner C, Müller M: Immunocytochemical distribution of E-cadherin in normal and injured lung tissue of the rat. Histochem Cell Biol. 1995, 104: 383-390.

    Google Scholar 

  277. Kang BH, Manderschied BD, Huang YC, Crapo JD, Chang LY: Contrasting response of lung parenchymal cells to instilled TNF alpha and IFN gamma: the inducibility of specific cell ICAM-1 in vivo. Am J Respir Cell Mol Biol. 1996, 15: 540-550.

    Google Scholar 

  278. Kumar NM, Sigurdson SL, Sheppard D, Lwebuga-Mukasa JS: Differential modulation of integrin receptors and extracellular matrix laminin by transforming growth factor-beta 1 in rat alveolar epithelial cells. Exp Cell Res. 1995, 221: 385-394. 10.1006/excr.1995.1389.

    Google Scholar 

  279. Giaid A, Michel RP, Stewart DJ, Sheppard M, Corrin B, Hamid Q: Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet. 1993, 341: 1550-1554.

    Google Scholar 

  280. Lipchik RJ, Chauncey JB, Paine R, Simon RH, Peters-Golden M: Arachidonate metabolism increases as rat alveolar type II cells differentiate in vitro. Am J Phys Lung Cell Mol Physiol. 1990, 259: L73-L80.

    Google Scholar 

  281. Punjabi CJ, Laskin JD, Pendino KJ, Goller NL, Durham SK, Laskin DL: Production of nitric oxide by rat type II pneumocytes: increased expression of inducible nitric oxide synthase following inhalation of a pulmonary irritant. Am J Respir Cell Mol Biol. 1994, 11: 165-172.

    Google Scholar 

  282. Blau H, Riklis S, Van Iwaarden JF, McCormack FX, Kalina M: Nitric oxide production by rat alveolar macrophages can be modulated in vitro by surfactant protein A. Am J Physiol. 1997, 272: L1198-L1204.

    Google Scholar 

  283. Asano K, Chee CB, Gaston B, Lilly CM, Gerard C, Drazen JM, Stamler JS: Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc Natl Acad Sci U S A. 1994, 91: 10089-10093.

    Google Scholar 

  284. Hoffmann G, Grote J, Friedrich F, Mutz N, Schobersberger W: The pulmonary epithelial cell line L 2 as a new model for an inducible nitric oxide synthase expressing distal airway epithelial cell. Biochem Biophys Res Commun. 1995, 217: 575-583. 10.1006/bbrc.1995.2814.

    Google Scholar 

  285. Senior RM, Griffin GL, Mudd MS, Moxley MA, Longmore WJ, Pierce RA: Entactin expression by rat lung and rat alveolar epithelial cells. Am J Respir Cell Mol Biol. 1996, 14: 239-247.

    Google Scholar 

  286. Crouch E, Longmore W: Collagen-binding proteins secreted by type II pneumocytes in culture. Biochim Biophys Acta. 1987, 924: 81-86.

    Google Scholar 

  287. Maniscalco WM, Sinkin RA, Watkins RH, Campbell MH: Transforming growth factor-beta 1 modulates type II cell fibronectin and surfactant protein C expression. Am J Physiol. 1994, 267: L569-L577.

    Google Scholar 

  288. Koch M, Wehrle-Haller B, Baumgartner S, Spring J, Brubacher D, Chiquet M: Epithelial synthesis of tenascin at tips of growing bronchi and graded accumulation in basement membrane and mesenchyme. Exp Cell Res. 1991, 194: 297-300.

    Google Scholar 

  289. Wallace WA, Howie SE, Lamb D, Salter DM: Tenascin immunoreactivity in cryptogenic fibrosing alveolitis. J Pathol. 1995, 175: 415-420.

    Google Scholar 

  290. Maniscalco WM, Campbell MH: Transforming growth factor-beta induces a chondroitin sulfate/dermatan sulfate proteoglycan in alveolar type II cells. Am J Physiol. 1994, 266: L672-L680.

    Google Scholar 

  291. Sage H, Farin FM, Striker GE, Fisher AB: Granular pneumocytes in primary culture secrete several major components of the extracellular matrix. Biochemistry. 1983, 22: 2148-2155.

    Google Scholar 

  292. Simon RH, Scott MJ, Reza MM, Killen PD: Type IV collagen production by rat pulmonary alveolar epithelial cells. Am J Respir Cell Mol Biol. 1993, 8: 640-646.

    Google Scholar 

Download references

Acknowledgements

Over the last decade I have had the pleasure of working with many colleagues, and of profiting greatly from the stimulating discussions we have had about many aspects of pulmonary research. Many thanks to all of you. This work was supported by the German Bundesministerium für Bildung und Forschung (FKZ 01ZZ5904).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Heinz Fehrenbach.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fehrenbach, H. Alveolar epithelial type II cell: defender of the alveolus revisited. Respir Res 2, 33 (2001). https://doi.org/10.1186/rr36

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/rr36

Keywords