Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-β
© Ogawa et al.; licensee BioMed Central Ltd. 2014
Received: 7 April 2014
Accepted: 1 November 2014
Published: 29 November 2014
Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease.
C57BL/6 wild-type (WT) and SP-D−/− mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-β were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D.
Dp-challenged SP-D−/− mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-β1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-β1 and IL-13 positive eosinophils in SP-D−/− mice. Purified eosinophils stimulated with Dp produced TGF-β1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D−/− mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D−/− mice and neutralization of TGF-β1 reduced sub-epithelial fibrosis in Dp-challenged SP-D−/− mice.
These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-β.
Surfactant is a lipoprotein complex that resides at the air-liquid interface of the lungs and is most commonly known for its role in reducing surface tension. Surfactant is produced by alveolar type II cells and airway Clara cells  and is composed of approximately 10% proteins, which includes surfactant protein (SP)-A, SP-B, SP-C and SP-D. SP-A and SP-D are members of collectin family of proteins and can modulate innate immunity. Previous reports have shown that SP-D can enhanced pulmonary clearance of pathogens including; Pseudomonous aerginosa , Klebsiella pneumonia , respiratory syncytial virus (RSV)  and Influenza virus . Furthermore, SP-D has also been shown to modify allergic responses in the lungs and can bind to several common allergens, including house dust mite (Dermatophagoides pteronyssinus, Dp) , Aspergillus fumigatus, (Af)  and pollen granules . Additionally SP-D reduce airway hyperresponsiveness (AHR) and eosinophilia in either ovalbumin (OVA)  or in Af  murine models of allergic airways disease and SP-D administration after antigen challenge can attenuate eosinophila and Th2 cytokine production in Dp-sensitized mice -. While SP-D can attenuate AHR and eosinophilia in these allergic models, the role of SP-D in remodeling of the airways remains unexplored.
Airway remodeling is central to the pathogenesis of asthma and can include sub-epithelial fibrosis, mucus cell hyperplasia and smooth muscle hypertrophy/hyperplasia. A better understanding of the factors that regulate the pathogenesis of sub-epithelial fibrosis may provide an opportunity for novel interventions in chronic bronchial asthma. Previous work demonstrated that both SP-A and SP-D can mitigate pulmonary fibrosis in mouse models of lung injury. For example, SP-A-deficient and SP-D-deficient mice are susceptible to bleomycin-induced lung injury and display increased cellular inflammation, more severe lung fibrosis, and reduced survival ,. Studies using the bleomycin lung fibrosis model support that SP-D attenuate pulmonary fibrosis through both regulation of TGF-β1 and PDGF-AA production, as well as, limiting fibrocyte migration into the lung . Clinical relevance of these findings is supported by the association between serum levels of either SP-A or SP-D and mortality in patients with pulmonary fibrosis ,.
Based on these previous observations, we used a model of chronic exposure to Dp to test the hypothesis that SP-D would attenuate the development of sub-epithelial fibrosis in an allergic airways disease. Present findings here suggest that SP-D plays a protective role in allergic airways by reducing the development of sub-epithelial fibrosis.
Materials and methods
Detailed methods are described in the supporting information.
Preparation of antigen
House-dust mite antigen (Dermatophagoides pteronyssinus, Dp) was purchased from Cosmobio Ltd (Tokyo, Japan). Endotoxin levels were reduced using endotoxin removal solution (Sigma-Aldrich, Japan) to <0.02 EU/mg.
All mouse studies were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Institute of Animal Care and Use Committee (IACUC) at Duke University. All surgery was performed under Ketamine (50 mg/kg)/Xylazine (5 mg/kg) anesthesia and all efforts were made to minimize suffering.
Exogenous SP-D administration in vivo
Recombinant SP-D was isolated from Chinese hamster ovary cells expressing rat SP-D protein as described previously . Recombinant SP-D (3 μg in 50 μl PBS) or 50 μl PBS as control was administered into Dp-challenged SP-D−/− mouse by oropharyngeal aspiration as described previously , twice weekly from days 13 to 38 (Figure 1).
Anti-TGF-β1 antibody administration in vivo
1.0 mg/kg of Anti-TGF-β1 antibody (R&D Systems, Minneapolis, MN) or 1.0 mg/kg of IgG isotype antibody(R&D Systems) as control was administered intraperitoneally into Dp challenged WT and SP-D−/− mouse twice weekly from days 14 to 37 (Figure 1).
Eosinophil purification and in vitro experiment
Eosinophils were purified from blood of IL-5 transgenic mouse as described previously and purity was determined to be greater than 95% . Eosinophils (4x105) were incubated in 48 well plates in the presence or absence of SP-D for 1 hr. After pre-incubation, eosinophils were stimulated by various concentration of Dp solution for 24 hrs. SP-D was boiled by 100°C for 10 min and was used as heat-inactivated SP-D .
Lung tissue was fixed in 10% formalin and embedded in paraffin. Three-micrometer thick sequential sections were performed. Sections for fibrosis were stained with Gomori’s trichrome stain. Sequential sections were stained with Luna-modified stain and TGF-β1 and IL-13 immunohistochemistry (IHC). Both primary antibodies were purchased from Abcam (Cambridge, UK). IHC were performed as described previously . Morphological analysis was performed quantitatively by Image J (National Institutes of Health).
Measurements of total protein and cytokine concentrations
Harvested lungs were homogenized in lysis buffer (Cell Signaling Technology, Inc. Danvers, MA) containing 1 mM phenylmethanesulfonyl fluoride (PMSF, Sigma-Aldrich) using Savant FastPrep FP120 Homogenizer (Thermo Scientific, Waltham, MA). Protein concentrations were determined by the BCA method (Pierce, Rockford, IL). Cytokines/growth factor were measured with commercial ELISA kits (details were described in Additional file 1). The values graphed for cytokine were adjusted to the total protein concentration of the respective lung samples.
Lungs were homogenized in 0.5 M acetic acid (50 volumes to wet lung weight) containing about 1 mg/ml pepsin (Sigma) using Savant FastPrep FP120 Homogenizer (Thermo Scientific, Waltham, MA). Total lung collagen was determined using the Sircol Collagen Assay kit (Biocolor Ltd., Belfast, Northern Ireland) according to the manufacturer’s instructions. The values graphed for collagen were adjusted to the total protein concentration of the respective lung samples.
The lungs were minced and enzymatically digested (DNAse and Collagenase) for 1 hr at 37°C. Cells were stained by various fluorescence conjugated -antibodies (details were described in Additional file 1). The stained cells were analyzed by FACS using a BD LSRII and BD FACS Canto II (San Diego, CA) for acquisition.
Comparisons between groups were analyzed using one-way ANOVA with post-hoc Tukeys analysis. Some comparisons between groups made with Student T-test without ANOVA (GraphPad Prism, version 5.0; GraphPad Software, Inc., San Diego, CA). Data are presented as mean ± SEM. Differences were considered statistically significant if p values were less than 0.05.
Sub-epithelial airway fibrosis in Dp challenged mice
Cellular inflammation in Dp-challenged mice
TGF-β1 is recognized to be a key cytokine driving fibrotic lung disease . Total TGF-β1 concentration in BALF of Dp challenged SP-D−/− mice was significantly increased when compared to Dp-challenged WT mice and PBS challenged SPD−/− mice (Figure 3B). Active TGF-β1 of lung homogenate in Dp challenged SP-D−/− mice tended to increase when compared to Dp-challenged WT mice although there are no statistically significant differences observed (Figure 3C). These findings suggest that functional TGF-β1 was produced around inflammatory site of lung in SP-D deficient mice.
Several Th2 cytokines, IL-4, IL-5 and IL-13, were undetectable in BALF, but were present in the lung homogenates. While there were no detectable differences in IL-4 and IL-5 between both groups of Dp-challenged mice, SP-D−/− mice had significantly increased IL-13 production when compared to WT after Dp-challenge (Figure 3C).
Th2/Th1 cell population and cytokines in Dp-challenged mice
Treatment with exogenous SP-D in Dp-challenged mice
TGF-β1 and IL-13 positive eosinophil infiltration in lungs of Dp-challenged mice
Histological data of eosinophils and epithelial cells by IHC
TGF + Eo
% of TGF + Eo
IL13 + Eo
% of IL13 + Eo
% of TGF + epithelial cells
7.67 ± 1.90
42.34 ± 3.71
8.41 ± 1.79
41.83 ± 3.87
88.35 ± 5.14
14.51 ± 1.92*
41.91 ± 3.90
15.32 ± 2.59*
41.58 ± 4.31
91.65 ± 3.68
9.06 ± 1.45†
40.38 ± 4.29
8.65 ± 1.32†
37.34 ± 2.43
97.07 ± 1.31
SP-D regulates eosinophil-derived TGF-β1 and IL-13
TGF-β blockade inhibits sub-epithelial fibrosis in the SP-D deficient animal
Sub-epithelial fibrosis is a major complication of chronic allergic airways disease and can result in fixed air-flow obstruction. Current understanding of the fundamental molecular mechanisms resulting in sub-epithelial fibrosis and effective therapeutic interventions remains limited. Utilizing a mouse model of chronic challenge to clinically relevant house dust mite, we demonstrate a central role of SP-D in the development of sub-epithelial fibrosis. Our new findings support that SP-D regulates the number of tissue eosinophils and the level of eosinophil-derived TGF-β1 and IL-13. Together our findings provide novel evidence supporting that functional SP-D can protect allergic airways from the development of sub-epithelial fibrosis.
TGF-β is known as a key cytokine of collagen production in fibrotic disease including airway remodeling in asthma ,. TGF-β can induce differentiation of fibroblasts to myofibroblasts, which can contribute to collagen deposition  and production of growth factors ,. Previous reports demonstrated anti TGF-β1 or smad3 neutralizing antibody treatment reduced airway remodeling in OVA chronic exposure model ,. In our findings, TGF-β1 production was increased in SP-D−/− mice, contributing to enhance sub-epithelial fibrosis. Interestingly, SP-D can bind to allergens including Dp . Therefore, if functional SP-D is absent, unbound Dp antigen may be a trigger that leads to enhanced TGF-β1production and sub-epithelial fibrosis as observed in SP-D−/− mice.
Previous work has suggested that sub-epithelial fibrosis after chronic challenge to house dust mite antigen was independent of either eosinophils or TGF-β1 ,. In that context, our observation that anti-TGF-β1 antibody treatment reduced sub-epithelial fibrosis and collagen production in the Dp-challenged SP-D deficient mice was quite unexpected. One explanation is that the previous studies used mice that were sufficient in SP-D and the involvement of eosinophils and/or TGF-β1 may not be appreciated until SP-D is absent or dysfunctional.
Alternatively, IL-13 is recognized as a Th2 cytokine that can contribute to sub-epithelial fibrosis and a pro-fibrotic cytokine in lung diseases . IL-13 depletion can reduce sub-epithelial fibrosis and epithelial hypertrophy in chronic asthma model ,. Fattouh et al. demonstrated that IL-13 was important for airway fibrosis independent of TGF-β signaling in Th2 associated disease ,. Our findings demonstrated that IL-13 production was increased in Dp-challenged SPD−/− mice and SP-D rescue decrease these responses similar to previous observations . In addition, our findings demonstrate that anti-TGF-β1 antibody treatment decreased IL-13 production in lung homogenate in SPD−/− mice (Figure 9), which suggests a potential synergistic role between TGF-β1 and IL-13 in airway remodeling when SP-D is absent. A previous study found that administration of a soluble TGF-β receptor-Fc molecule ameliorated IL-13-induced fibrosis , supporting this paradigm. Recent reports also showed that inhibition of TGF-β1/smad3 signaling can lead to decrease IL-13 production in lung diseases ,. Similar mechanism seems to occur in the lung of SP-D−/− mice, which warrant further study.
In either chronic antigen exposure asthma model or gene-modified model, both peribronchial fibrosis and TGF-β production were related to eosinophils ,. In airways of asthmatic patients, 75-80% of TGF-β1 mRNA expression positive cells were eosinophils ,. On the other hand, it is known that bronchial epithelial cells were also source of TGF-β1 in asthma . In OVA challenged model, bronchial epithelium-derived TGF-β1 was enhanced sub-epithelial fibrosis . Therefore, we examined what type of cells that are a potential source of TGF-β1 and as target cells by SP-D in this model. In the present findings, TGF-β1 expressing eosinophils were increased in Dp-challenged SP-D−/− mice. Moreover, we identified that SP-D directly suppress the production of eosinophil derived TGF-β. To our knowledge, this is the first report to demonstrate a direct function of SP-D on eosinophils response to antigen. In contrast, our findings showed that TGF-β1 expression in bronchial epithelial cells of SP-D−/− mice were not significant difference among the 3 groups unlike TGF expression in eosinopils (Figure 7 and Table 1). Based on these results, our findings suggest that a target of SP-D in Dp-induced sub-epithelial fibrosis may be the activated eosinophils that produce TGF-β1. In addition to regulation of eosinophil-derived TGF-β, SP-D also attenuated IL-13 production from Dp stimulated eosinophils. Since we did not identify an increase Th2 cells in the lung tissue from SP-D−/− mice, our findings suggest that eosinophils may be also an important source of IL-13 as reported in other model systems . Taken together, our findings support that functional SP-D regulates both the tissue infiltration and function of eosinophils, resulting in protection of the airways against development of sub-epithelial fibrosis. Our findings extend the functional role of SP-D in allergic airways disease beyond regulation of eotaxin-triggered chemotaxis and degranulation of eosinophils , induction of apoptosis in eosinophils, and enhanced uptake of eosinophils by macrophages .
The molecular mechanism that SP-D inhibited TGF-β1 and IL-13 production by Dp-activated eosinophils also remains unknown. Previous reports have shown that interstitial eosinophils express high levels of signal regulatory protein (SIRP)-α, an inhibitory receptor of SP-D, and that cross-linking of SIRP-α on the surface of eosinophils significantly reduced the amount of eosinophil peroxidase released during stimulation with a calcium ionophore . In macrophages under normal condition, SP-D binds SIRP-α, leading to inhibit p38 activation, which induces cytokine production via Src homology region 2 domain-containing phosphatase (SHP)-1 ,. It remains unknown whether similar events occur in eosinophils during chronic allergic inflammatory conditions. Since Toll-like receptor (TLR) 4 is candidate of receptor of Dp , it is possible that SP-D bind Dp directly in order to block Dp binding to TLR4. Alternatively, SP-D may also interfere with signaling by binding directly to TLR4. Understanding the molecular mechanisms that SP-D regulates eosinophil function will be the focus of future investigations.
In conclusion, we identify that SP-D regulates eosinophil production of both IL-13 and TGF-β after stimulation with Dp, mitigating sub-epithelial fibrosis which is an important component of airway remodeling in chronic allergic airways disease. Appreciation of the functional role of SP-D during allergic airways disease is high clinical significance since a better understanding of how to attenuate the severity of sub-epithelial fibrosis could lead to better treatment options.
We thank the late Dr. Jo Rae Wright for providing the opportunity to study airway remodeling using SP-D−/− mice and for her intellectual contribution during the initial conception of this project. We appreciate Dr. Jeffrey Whitsett for providing the SP-D deficient mice used in this study. We also thank Katherine Evans (Duke University) for the preparation of recombinant rat SP-D, Charles Giamberardino (Duke University) and Julia L. Nugent (Duke University) for the technical support. We thank Mrs Megumi Kume and Miss Hitomi Umemoto (Department of Molecular and Environmental Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School) for preparing histological sections and stains. We appreciate the continued support provided by the NIH (ES016126, AI081672, ES020350, HL111151).
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