Fas-deficient mice have impaired alveolar neutrophil recruitment and decreased expression of anti-KC autoantibody:KC complexes in a model of acute lung injury
© Gil et al.; licensee BioMed Central Ltd. 2012
Received: 3 May 2012
Accepted: 1 October 2012
Published: 9 October 2012
Exposure to mechanical ventilation enhances lung injury in response to various stimuli, such as bacterial endotoxin (LPS). The Fas/FasL system is a receptor ligand system that has dual pro-apoptotic and pro-inflammatory functions and has been implicated in the pathogenesis of lung injury. In this study we test the hypothesis that a functioning Fas/FasL system is required for the development of lung injury in mechanically ventilated mice.
C57BL/6 (B6) and Fas-deficient lpr mice were exposed to either intra-tracheal PBS followed by spontaneous breathing or intra-tracheal LPS followed by four hours mechanical ventilation with tidal volumes of 10 mL/kg, respiratory rate of 150 breaths per minute, inspired oxygen 0.21 and positive end expiratory pressure (PEEP) of 3 cm of water.
Compared with the B6 mice, the lpr mice showed attenuation of the neutrophilic response as measured by decreased numbers of BAL neutrophils and lung myeloperoxidase activity. Interestingly, the B6 and lpr mice had similar concentrations of pro-inflammatory cytokines, including CXCL1 (KC), and similar measurements of permeability and apoptosis. However, the B6 mice showed greater deposition of anti-KC:KC immune complexes in the lungs, as compared with the lpr mice.
We conclude that a functioning Fas/FasL system is required for full neutrophilic response to LPS in mechanically ventilated mice.
Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS) remain important clinical problems in the United States, with an incidence rate of 38.3 cases per 100,000 person-years and a mortality rate of 45% . ALI/ARDS is characterized clinically by sudden respiratory failure with impaired oxygenation and non-cardiogenic pulmonary edema . Pathologically ALI/ARDS is associated with an early inflammatory phase with neutrophilic alveolitis and destruction of the alveolar/capillary permeability barrier, followed by a late fibroproliferative phase with abnormal repair and collagen deposition. There are no specific treatments for ARDS and the main supportive treatment, mechanical ventilation, can be harmful to the lungs when delivered at high tidal volumes .
A growing body of experimental evidence suggests that in addition to the injury caused by high tidal volumes, even moderate or low tidal volumes markedly enhance injury when the lungs are exposed to pathogens or their products [4–6]. For example, mechanical ventilation synergistically enhances lung injury in response to low doses of bacterial lipopolysaccharide (LPS) and this is associated with expression of specific sets of genes that aren’t expressed with LPS or ventilation alone [4, 5, 7]. A computational analysis has mapped the biological processes that are activated by the combination of mechanical ventilation and LPS . One of these biological processes is apoptosis, and a known mediator of apoptosis in injured lungs is the Fas/FasL system.
The Fas/FasL system is composed of the membrane surface receptor Fas and its cognate ligand, FasL. FasL exists in a membrane-bound form, and also in a soluble form that is present in the lungs during acute lung injury . Binding of Fas to sFasL in alveolar epithelial cells independently activates apoptotic and inflammatory pathways that result in death of the cells but also in release of pro-inflammatory cytokines . Although the Fas/FasL system is better known for its pro-apoptotic function, the pro-inflammatory function is also important in the development of lung injury, and mice deficient in Fas (lpr) have an impaired neutrophil recruitment in response to LPS installation and bacterial infections .
Several lines of evidence suggest that the Fas/FasL system plays a role in ALI/ARDS. First, bioactive sFasL is present in the lungs of patients with ARDS, and this is associated with increased mortality [9, 12]. Second, genetic variations in the Fas gene are associated with increased risk for ALI/ARDS in humans . Third, activation of the Fas/FasL system in mammals leads to acute inflammatory injury followed by fibrosis [14–17]. And finally, mice lacking Fas are protected in a number of models of lung injury [11, 18–20]. Thus, the apoptotic and inflammatory responses induced by Fas activation in the lungs are one important factor in the development of ALI/ARDS.
One of the most important neutrophil chemoattractants in mice is the chemokine KC (CXCL1), which is the murine functional homologue of the human chemokine IL8 (CXCL8). Activation of Fas in alveolar epithelial cells is followed by a marked increase in KC expression . Interestingly, recent studies suggest that in injured lungs, IL8 in humans and KC in mice form immune complexes with autoantibodies, and these immune complexes can in turn bind Fc receptors such as FcγRIIa and FcγRIII that amplify the inflammatory response [21, 22]. These studies suggest that, in addition to the absolute levels of chemokines, the formation of autoimmune complexes and their association with Fc receptors is important for the development of inflammatory responses in the lungs.
In this study, we ask whether the Fas/FasL system plays a role in the amplification of inflammatory responses that occur early in the course of mechanical ventilation. The specific hypothesis to be tested is that the Fas/FasL system is required for the development of lung injury in mechanically ventilated mice exposed to LPS. To test this hypothesis, we investigate whether the combination of a non-injurious mechanical ventilation strategy with a minimal dose of intratracheal LPS results in an acute lung injury, and whether this injury is attenuated in Fas-deficient lpr mice. We further investigate whether the development of injury is associated with formation and deposition of anti-KC:KC immune complexes.
Materials and methods
All of the animal experiments were approved by the institutional animal research committee of the University of Washington. Mice were housed in a pathogen-free environment according to University of Washington animal use guidelines. Male C57BL/6 mice (“B6”) and mice carrying a spontaneous mutation in the Fas gene that impairs Fas signaling (B6. MRL-Fas lpr /J, “lpr”) were obtained from the Jackson Laboratories and studied at 7-13 weeks of age. Briefly, the mice were anesthetized with 5% inhaled isoflurane and then intubated endotracheally with a 20-gauge angiocatheter. Placement of the catheter in the trachea was verified by visualizing the movement of a 100 μl bubble of water in response to respiratory efforts. After confirming intubation, the trachea was instilled with either E. coli LPS, 15 ng/kg or PBS. The instillate was suspended in 2.5% colloidal carbon to allow later confirmation of the extent and distribution of the instillation macro and microscopically. After the installations some of the mice were extubated, returned to their cages, and allowed free access to food and water; other mice where kept intubated and subjected to mechanical ventilation with the following settings: tidal volume (Tv) 10 ml/kg; respiratory rate (RR) 150 breaths/minute; fraction of inspired oxygen (FiO2) 0.21; and positive end-expiratory pressure (PEEP) of 3 cm H2O. The heart rate, airway pressures, rectal temperatures and EtCO2 were monitored continuously using a computerized monitoring system (Chart 4, AD Instruments, Colorado Springs, CO). The RR was adjusted to maintain the EtCO2 between 30 – 40 mmHg. The body temperature was maintained between 37 and 38°C with external heating. The mice were hydrated with a continuous intraperitoneal infusion of lactated ringer solution at 500 μl/hour. Muscle relaxation was attained with pancuronium bromide, 1 μg/g i.p followed by 0.5 μg/g i.p. every hour. After four hours of mechanical ventilation the mice were euthanized with 0.30 ml/kg i.p. of Beuthanasia-D (Schering-Plough Animal Health, Union, NJ). The thorax was rapidly opened and the mouse was exsanguinated by direct cardiac puncture. The left lung was removed and flash-frozen in liquid nitrogen. The right lung was lavaged with 0.6 mM EDTA in PBS; an aliquot of the bronchoalveolar lavage fluid (BALF) was removed for cell counts and differentials, the remaining fluid was spun at 1200 x g, and the supernatants stored at -80°C in individual aliquots. Following the BAL, the right lung was fixed in 4% buffered paraformaldehyde at an inflation pressure of 15 cm H2O for histological evaluation.
We studied four groups of mice. Two groups consisted of B6 and lpr mice instilled with PBS and allowed to breathe spontaneously (“SB”) (n = 7 for B6 mice, 4 for lpr). The other two groups consisted of B6 and lpr mice instilled with LPS and exposed mechanical ventilation (MV + LPS) (n = 10 for B6 mice, 6 for lpr). The main experimental comparison was between the B6 and lpr mice instilled with LPS and exposed to ventilation.
Total cell counts in the BALF were performed with a hemacytometer. Differential counts were performed on cytospin preparations using the Diff-quick method (Fisher Scientific Company L.L.C., Kalamazoo, MI). BALF total protein was measured with the bicinchoninic acid method (BCA assay, Pierce, Rockford, IL). BALF IgM (Bethyl Laboratories, Montgomery, TX) and α-macroglobulin (Life Diagnostics, West Chester, PA) were measured with immunoassays. Lung homogenate TNF-α, KC, IL1β, and IL6 were measured using a multiplex fluorescent bead assay (R&D Systems, Minneapolis, MN).
As a measurement of the total content of PMN in the lungs we measured myeloperoxidase (MPO) activity in lung homogenates prepared in 50 mM K2HPO4, pH 6.0 with 5% CH3(CH2)15 N(Br)(CH3)3, 5 mM EDTA. Active caspase-3 and Poly ADP ribose polymerase (PARP) activity were measured in lung homogenates prepared on a 1:20 ratio of a lysis buffer (0.5% Triton-X-100, 150 mM NaCl, 15 mM Tris, 1 mM CaCl, and 1 mM MgCl, pH7.4). The lung homogenate was spun at 10,000 x g for 20 min at 4°C and the supernatant used for measurements of active caspase-3 and PARP using the CPP32/Caspase-3-Fluorometric Protease Assay Kit (BioVision, Mountain View, CA) and a PARP activity kit (Cell Signaling, Boston MA). Serum Creatinine, ALT and bilirubin were measured at a commercial laboratory. Anti-KC autoantibody:KC immune complexes were measured in BAL fluids using an ELISA assay according to a previously described protocol . Briefly, 96-well microtiter plates were coated with antibody against KC (Peprotech). After blocking, the plates were incubated with BAL fluid samples obtained from mice. Then, the plates were washed and incubated with biotinylated horse antibody against mouse immunoglobulins (Vector Laboratories) followed by HRP-conjugated streptavidin and the substrate tetramethyl benzidine (Sigma).
Measurement of murine neutrophil chemotaxis in vitro
C57BL/6 and lpr mice were euthanized by exposure to CO2 followed by cervical dislocation. The femur and tibia of both hind legs were isolated and freed of all soft tissue, and then the ends of both bones were removed. The femur and tibia were placed proximal end down in a 0.6 mL Eppendorf tube, which had been punctured at its lower tip with an 18-gauge needle and placed inside a 1.5 mL Eppendorf tube. The tubes were spun at 2000 X g for 30 seconds and neutrophils were isolated as previously described . After isolation, neutrophils were labeled with calcein-AM (5 μg/ml; Molecular Probes, Eugene, OR) for 30 minutes at 37°C, washed two times in PBS and resuspended at a concentration of 1 x 106/mL.
Neutrophil chemotaxis was assessed using the Neuro Probe ChemoTx® Disposable Chemotaxis system (Neuro Probe Inc. Gaithersburg, MD). The wells of the 96-well plate were filled with various concentrations of KC. A polycarbonate filter (8 μm pores) with a hydrophobic ring around the area over each well was placed on the 96-well plate and calcein-labelled neutrophils were added to each ring. The chemotaxis chamber, consisting of the polycarbonate filter and 96-well plate, was incubated for 30 min at 37°C in 5% CO2 and then non-migrating neutrophils were removed from the upper side of the filter. The chemotaxis chamber was placed in a multi-well fluorescent plate reader (Synergy 4, BioTek, Winooski, VT) and the migrated cells were measured using the calcein fluorescence signal (excitation - 485 nm, emission - 530 nm). Neutrophil migration was expressed as a percent of the total number of neutrophils that were placed on the topside of the filter (% Total).
Histology and immunohistochemistry
Lung sections were embedded in paraffin, cut into 4 μm sections, and stained with hematoxylin and eosin.
Double labeling for Terminal transferase dUTP nick end labeling (TUNEL) staining and cytokeratin
Lung tissue sections were deparaffinized, washed in xylene, rehydrated, permeabilized with proteinase K, and incubated with the TUNEL reaction mixture according to manufacturer instructions (In Situ Cell Death Detection kit, AP, Roche Applied Science, Indianapolis, IN). Negative controls were treated with labeling solution without terminal transferase. Immediately after TUNEL labeling the slides were washed three times in PBS, blocked with Protein Block (Dako, Carpinteria CA) and incubated for 2 hr in the dark at 37°C with the mouse monoclonal pan-cytokeratin antibody C11 (Abcam, Cambridge, UK) previously labeled with Alexa Fluor 555 (Invitrogen, Eugene, OR). Negative control slides were incubated with an isotype control mouse IgG1k labeled with Alexa Fluor 555 (BD Pharmingen, San Diego, CA). The slides were washed and immediately visualized with a fluorescent microscope.
Detection of anti-KC:KC immune complexes
Lung tissue sections from B6 and lpr mice exposed to MV + LPS were processed as previously described . The sections were incubated with anti-KC antibody (Peprotech, Rocky Hill, NJ) followed by chicken anti-rabbit secondary antibody (Alexa 647, pseudocolor red) (Invitrogen), and then with anti-FcγRIII antibody (R&D Systems) followed by chicken anti-rat secondary antibody (Alexa 488, green), and finally with biotynylated anti-Ly-6 G antibody (eBioscience, San Diego, CA), used as a neutrophil marker, followed by streptavidin (Alexa 568, pseudocolor magenta). Lung tissues were counter-stained with Hoechst 33342 (Calbiochem, Gibbstown, NJ). The slides were evaluated using a PerkinElmer Ultra VIEW LCI confocal imaging system with Nikon TE2000-S fluorescence microscope using PlanApox20 objective and PlanApox60 or x100 immersion oil objective (numerical aperture [NA] 1.4) at room temperature. Ultra VIEW Imaging Suite software (version 22.214.171.124) was used for image processing.
Statistical analysis was performed using two-factor ANOVA followed by the Bonferroni post-hoc analysis. One factor was “treatment” (SB or MV + LPS) and the other factor was “strain” (B6 or lpr). The analysis was designed to determine the overall effect of each of the factors, the presence of an interaction effect, and the comparison of “strain” for each level of “treatment”. Data was generated using GraphPad Prism. A p value of less than 0.05 was considered significant.
The neutrophil response to MV + LPS was attenuated in the lprmice
Other parameters of lung injury were similar in B6 and lprmice
The differences in BAL neutrophils are not explained by differences in B6 and lprneutrophil chemotaxis
Anti-KC autoantibody:KC immune complex deposition
The goal of this study was to determine whether Fas deficiency is protective in mechanically ventilated mice exposed to intratracheal LPS. The main finding was that Fas-deficient lpr mice showed decreased neutrophil recruitment in response to combined mechanical ventilation and LPS, even though the cytokine, permeability, and apoptotic responses were similar to those of B6 mice. Interestingly, despite the presence of similar concentrations of KC in the BAL of lpr and B6 mice, only the B6 mice showed extensive KC deposition in the lungs, and this was associated with the presence of anti-KC:KC complexes in the BALF and lung tissue.
In this study, we focused on the initial events of the injury response by studying mice four hours after the initiation of injury, which was induced by combining a very low dose of endotoxin with mechanical ventilation. The main finding was that a functional Fas/FasL system was required for neutrophil migration into the airspaces of the lungs of mechanically ventilated mice exposed to LPS. The changes in BAL neutrophils seen in this study were associated with changes in lung myeloperoxidase (MPO) activity, and because lung MPO activity is a measurement of the total content of neutrophils in the lungs, the data suggests that the Fas/FasL system is required for both neutrophil migration into the airspaces and for neutrophil recruitment into the lungs. This observation confirms other studies that suggest a key role for the Fas/FasL system in neutrophil migration into the airspaces; for example, activation of Fas in the lungs of mice and rabbits results in a neutrophilic alveolitis (1, 2), whereas pharmacologic blockade of the Fas/FasL system attenuates the neutrophilic response to bacteria and bacterial products (3-6).
One potential explanation for the decreased migration of neutrophils into the airspaces of the Fas-deficient mice is that Fas ligation induces release of neutrophilic cytokines such as KC in macrophages and in lung epithelial cells in vitro (7-9). Thus, we had expected to see lower concentrations of KC in the mechanically ventilated lpr mice exposed to LPS, as compared with the B6 animals. However, this was not the case, and the difference in neutrophil migration was not due to differences in soluble KC concentrations.
Another potential mechanism that would explain differences in neutrophil migration with similar concentrations of soluble KC is a difference in neutrophil chemotaxis of lpr and B6 neutrophils. However, our chemotaxis studied showed that, if anything, neutrophils from lpr mice have slightly increased chemotaxis to KC, strongly suggesting that differences in chemotaxis are not the reason for the attenuation in the neutrophilic response seen in the lpr mice.
Neutrophil recruitment and migration appears to be partly dependent on the formation of anti-KC:KC immune complexes, which can bind Fcγ receptors in local leukocytes, enhancing the inflammatory response . For example, the generation of anti-KC:KC immune complexes in the lungs of mice is followed by acute inflammatory lung injury, and this injury requires the presence of Fcγ receptors . Furthermore, mice lacking γ chains show attenuated injury in response to LPS, suggesting that this process is relevant for inflammation secondary to bacterial products . The human equivalent of anti-KC:KC complexes are anti-IL8:IL8 complexes, and these are present in the lungs of patients with ARDS [25, 26]. In our study, we found that there are less anti-KC:KC complexes in the lungs of the lpr mice, even though the concentrations of KC were similar to those in the B6 mice. Thus, it is possible that the lower numbers of neutrophils seen in the lpr mice were due to decreased formation and deposition of anti-KC:KC complexes in the lungs. Additional studies are necessary to confirm this hypothesis, and it remains possible that differences in other unmeasured chemotactic agents account for the differences in neutrophil recruitment. The mechanism linking the Fas/FasL system with impaired formation and deposition of immune complexes remains unclear. To date, lpr mice, particularly the MRL/lpr strain are known to generate autoantibodies that can result in a lupus-like syndrome .
A surprising finding in the present study was that there was no increase in the markers of permeability or apoptosis in the B6 mice exposed to mechanical ventilation and LPS, as compared to the lpr mice; instead, the injury response was limited to neutrophilic inflammation and cytokine release. One explanation is that neutrophil recruitment precedes the development of tissue injury in our model, in which the mice were studied relatively early, four hours after the onset of ventilation. Less clear is the finding that the lpr mice actually had increased caspase-3 activity and TUNEL positive cells compared with the B6 mice. We do not have a clear explanation for this finding, but they seem to be specific to the LPS + MV model, because in another model using mechanical ventilation in which WT and lpr mice were exposed to pneumonia virus of mice (PVM) prior to four hours of MV, we found a decrease in caspase-3 activity in the lpr mice .
It is important to emphasize that the decrease in neutrophils seen in the lpr mice does not imply “protection”. It is unclear whether the lung neutrophilic response is directly associated with negative outcomes in ALI/ARDS or not. Most studies of lung injury presume that neutrophilia or increased concentrations of cytokine are deleterious, but all of these studies are limited in that they do not effectively reproduce the series of events seen in the clinical setting, where patients with multiple comorbidities are intubated for prolonged periods of time. Our study should be interpreted as knowledge on the mechanisms of that initiate lung injury, but not extrapolated to the ultimate results of that injury.
In summary, we report that in B6 mice, the combination of mechanical ventilation and LPS is associated with recruitment of neutrophils to the lungs and with deposition of anti-KC:KC immune complexes. In comparison, mice deficient in Fas recruited lower numbers of neutrophils, and this was associated with less deposition of immune complexes in the lungs. We conclude that a functioning Fas/FasL system is required for a full neutrophilic response to LPS in mechanically ventilated mice.
This work was supported by NIH grant HL-083044 and HL-081764 (GMB) and the Parker B. Francis foundation (SEG).
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