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,
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Medical Research Service, Seattle Veterans Affairs Medical Center, Seattle, WA 98108;
Section of Pulmonary and Critical Care Medicine, Harborview Medical Center, Seattle, WA 98104; Divisions of
Pulmonary and Critical Care Medicine and of
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Infectious Diseases, Department of Medicine, and
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Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195; and
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Department of Immunology and Inflammation, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We investigated the hypothesis that Fas ligand (FasL) shed into the alveolar fluid of patients with ARDS induces Fas-dependent apoptosis of epithelial cells in the alveoli and distal airways. The Fas/FasL system plays an important role in the regulation of cell life and death. This system is comprised of the cell membrane surface receptor Fas (CD95) and its natural ligand (FasL) (4). Fas is a 45-kDa type I membrane protein member of the TNF family of surface receptors (5). The natural ligand of Fas is Fas ligand (FasL), a 37-kDa type II protein (6). FasL exists as membrane-bound and soluble forms (7). Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity, clonal deletion of alloreactive T cells, and activation-induced suicide of T cells (8, 9, 10). The soluble form (sFasL) results from cleavage of membrane FasL by metalloproteinases (11) and induces apoptosis in susceptible cells (7).
Several lines of evidence suggest that sFasL may be involved in the pathogenesis of tissue injury. Circulating sFasL is elevated in the serum of patients with leukemia (12), lymphoma (12, 13), and inflammatory diseases (14). Blockade of Fas (CD95) in humans with toxic epidermal necrolysis stops the progression of disease (15). Administration of sFasL to mice pretreated with bacteria produces death from hepatic failure (16), and mutant mice deficient in either FasL (gld mice) or Fas (lpr mice) show decreased endothelial damage in response to the administration of IL-2 (17). Recent studies, however, suggest that sFasL is relatively ineffective in inducing apoptosis, and that the release of sFasL may actually down-regulate the apoptotic activity of membrane-bound Fas (11, 18). Thus, the role of sFasL in vivo is controversial.
The role of the Fas/FasL system in humans with acute lung injury has not been studied. Subsets of alveolar epithelial cells express Fas on their surface and undergo apoptosis in response to Fas ligation (19). Monocytes release sFasL in vitro when activated by phytohemagglutinin, immune complexes, or superantigen (20), raising the possibility that activated macrophages in the lungs might also release sFasL. Thus, FasL on the cell surface or released as sFasL by activated macrophages might induce apoptosis of lung epithelial cells, resulting in the epithelial injury and permeability changes characteristic of ARDS.
We investigated whether sFasL accumulates in alveolar fluids during the course of ARDS, whether sFasL can be released by cells in the airspaces, and whether lung fluids from patients with ARDS can cause Fas-dependent apoptosis of lung epithelial cells in vitro. The results suggest that the Fas/FasL system is likely to be of fundamental importance in mediating injury to the lung epithelium in humans with ARDS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Abs used for sFasL detection by ELISA were monoclonal anti-human sFasL mAb, as capture Ab (Clone 4H9; MBL, Nagoya, Japan), and biotinylated anti-human sFasL mAb for detection (Clone 4A5; MBL). For flow cytometric detection of Fas expression, we used anti-Fas R-PE-conjugated mouse monoclonal IgG1 (clone DX2), and a PE-conjugated monoclonal mouse IgG1 as an isotype control Ab (clone MOPC-21) (both Abs from PharMingen, San Diego CA). The sFasL and the fusion protein Fas-Ig were prepared and purified as described previously (21). Anti-Fas mAb (IgG1, mouse, clone ZB4) and anti-FasL mAb (IgG, hamster, clone 4H9) were purchased from Coulter/Immunotech (Miami, FL). Anti HCG IgG1 (Pierce Chemical, Rockford IL) was used as an irrelevant control.
Distal lung epithelial cell culture
Frozen primary cultures of human distal lung epithelial cells (DLEC) were purchased from Clonetics (San Diego, CA) and cultured in complete growth media (SAGM; Clonetics) according to the manufacturer’s protocol. These cells were isolated from distal small airways (less than 1 mm in diameter) immediately postmortem from humans who were free of known respiratory diseases. These cells grow in monolayers, and by electron microscopy show evidence of lamellar-like bodies and absence of cilia and neurosecretory granules.
The cells were seeded in 75-cm2 flasks at a density of 1 x 104 cells/cm2 and incubated at 37°C and 5% CO2. The cells were subcultured when they reached 60–80% confluency. Cells were used for the experiments after the first or second subculture. In these culture conditions, the cells form monolayers and do not differentiate into ciliated cells.
Patient population and bronchoalveolar lavage protocol
All patients admitted to the intensive care units of Harborview Medical Center (Seattle, WA) between 2/14/94 and 3/12/97 were prospectively evaluated and enrolled if they met predetermined criteria either for being at risk for ARDS following sepsis or acute trauma, or for having established ARDS. Specific criteria for sepsis and trauma risks and for ARDS have been described (22). All patients with ARDS met the American European Consensus Conference definition of ARDS (23). The patients at risk for ARDS underwent fiberoptic bronchoscopy and bronchoalveolar lavage (BAL) within 24 h of the onset of risk for ARDS, then again 48 h later if they had not developed ARDS. Patients with established ARDS underwent fiberoptic bronchoscopy and BAL within 24 h of the onset of ARDS (day 1), and then again on days 3, 7, 14, and 21. Fiberoptic bronchoscopy and BAL were also performed on healthy volunteers who were free of lung disease. The BAL were performed by instilling five separate 30 ml aliquots of 0.9% NaCl at 21°C into the right middle lung lobe or the lingula. The BAL aliquots were transported immediately to the laboratory for processing. The fluid was pooled and poured through gauze moistened with 0.9% NaCl to remove mucus. The lavage fluid was spun at 200 x g for 30 min, and the supernatant was removed aseptically and stored at -70°C as individual aliquots in polypropylene tubes (22). Informed consent was obtained from the patient or a surrogate. The protocol was approved by the Human Subjects Review Committee of the University of Washington.
sFasL release by BAL cells
The ARDS BAL cell pellet was resuspended at 1 x 106 cells/ml in RPMI 1640 (Life Technologies, Grand Island, NY) containing L-glutamine (292 µg/ml), penicillin (100 U/ml), and streptomycin (100 µg/ml), and incubated for 24 h at 37°C and 5% CO2 in the following conditions: media only; media with 10% heat-inactivated human AB serum (Sigma, St. Louis, MO); media with 100 ng/ml of Escherichia coli 0111:B4 LPS (List Laboratories, Campbell, CA); and media with 100 ng/ml LPS with 10% heat-inactivated human AB serum. After incubation, the supernatants were removed and stored as individual aliquots at -70°C. sFasL was measured by immunoassay as described below.
FasL measurements
sFasL was measured with a modification of a sandwich immunoassay (24). Briefly, 96-well plates (Costar, Cambridge, MA) were coated overnight at 4°C with the capture Ab at 1.0 µg/ml. After incubation, the wells were washed three times with PBS containing 0.05% Tween-20 (Sigma; PBS-T) and blocked for 1 h at 37°C with 10% nonfat milk in PBS. After washing three times with PBS-T, the standards and samples were added to the wells, and the plate was incubated 1 h at 37°C. After washing three times with PBS-T, the detection Ab was added at 0.1 µg/ml, and the plate was incubated for 1 h at 37°C. The plate was washed three times with PBS-T, and AP-streptavidin (Zymed, San Francisco, CA) was added at a 1:2000 dilution, followed by 1 h incubation at 37°C. After incubation, the wells were washed three times with PBS-T and twice with 0.9% NaCl, then the Attophos fluorescence reagent (JBL Scientific, San Luis Obispo, CA), 200 µL/well was added to the wells, and the plate was incubated for 1 h at room temperature in the dark. After incubation, fluorescence was read on a Cytofluor II microtiter plate fluorometer (PerSeptive Biosystems, Framingham MA) using 430-nm excitation and 560-nm emission wavelengths. The assay was sensitive to an sFasL concentration of 4.0 pg/ml.
Determination of Fas expression by flow cytometry
Briefly, DLEC were cultured in complete media (SAGM; Clonetics) until reaching 70–90% confluence, detached with 0.025% trypsin containing 0.26 mM EDTA (Life Technologies), and washed with PBS. The cell pellet was resuspended at 4 x 106 cells/ml in PBS with 10% FCS (HyClone, Logan UT), and incubated 45 min at 4°C in the dark with 10 µL of either anti-Fas PE-conjugated mAb or control mAb (0.5 mg/ml) for each 106 cells. After incubation, the cells were washed twice and resuspended in 250 µL PBS, then analyzed by flow cytometry using a FACScan instrument (Becton Dickinson, San Jose, CA).
Determination of apoptosis
Apoptotic target cells (DLEC) were identified by three different methods: 1) alamar Blue reduction, 2) acridine orange staining, and 3) DNA end nick labeling assay. The alamar Blue assay is an assay of cell viability; the acridine orange stain and the DNA end nick labeling assay were used to show that the mechanism of cell death was apoptosis.
Alamar Blue assay. Alamar Blue (Biosource, Camarillo CA) is an oxidation/reduction indicator that fluoresces red when it accepts electrons generated during cellular metabolism. The DLEC were grown on 96-well tissue culture plates (Costar). After reaching 60–80% confluence, the experimental media were added to a total volume of 200 µl/well, and the cells were incubated for 24 h at 37°C, 5% CO2. Following incubation, alamar Blue (25 µL) was added to the wells, and the plate was incubated for 1 h at 37°C, 5% CO2. Fluorescence was measured on a Cytofluor II fluorometer using a 530-nm excitation filter and 590-nm emission filter.
Acridine orange staining. The DLEC were grown on 1.8-cm2 chamber slides (Lab-Tek-8; Nunc, Naperville, IL). After reaching 60–80% confluence, the experimental media were added, and the cells were incubated for 24 h at 37°C, 5% CO2. Following incubation, the chambers were removed, and the cell monolayers were labeled with 0.27-M acridine orange in PBS (Sigma) and examined by fluorescence microscopy. Cells were considered apoptotic if they showed condensation of the cytoplasm, and condensation of nuclear chromatin and/or nuclear fragmentation. The total number of cells and the number of apoptotic cells were counted in two low power fields (x160). The results are expressed as the percentage of total cells that were apoptotic.
DNA end nick labeling assay. For the DNA end nick labeling assays, the DLEC were grown in chamber slides as described above. The slides were submerged in 10% neutral buffered formalin for 10 min, followed by 70% ethanol for 5 min. The slides were rehydrated for 10 min in PBS and treated with 0.002% proteinase K (Sigma) in distilled water for 5 to 15 min at room temperature. Endogenous peroxidase was removed by placing the slides in 2% hydrogen peroxide in distilled water for 5 min. For equilibration, the slides were treated in 1x Klenow labeling buffer (TACS In situ Apoptosis Detection Kit; Trevigen, Gaithersburg, MD) for at least 1 min and then incubated for 60 min at 37°C with Klenow enzyme and Klenow dNTP mix in 1x Klenow labeling buffer (all reagents from Trevigen) prepared according to instructions from the manufacturer. As a negative control, slides were incubated with the labeling mixture without the Klenow enzyme. After incubation, the slides were completely submerged in 1x Klenow Stop buffer (Trevigen) for 5 min at room temperature and rinsed in 1x PBS for 2 min. The samples were then treated for 15 min with streptavidin-HRP detection solution (Trevigen), washed twice for 2 min in PBS, and incubated in diaminobenzidine (DAB) (Trevigen) for 7 min at room temperature. The samples were then rinsed twice in distilled water and stained with 1% methyl green in 0.1 M sodium acetate (pH 4.0) for 5 min, quickly dehydrated in 95% and 100% ethanol, cleared in xylene and mounted with Permount (Fisher Scientific, Pittsburgh, PA).
Statistical Analysis
For normally distributed data, the two-tailed Student t test was used for comparisons between two groups. One-way ANOVA was used to compare multiple groups. When data were not normally distributed, the Wilcoxon rank sums test was used for comparisons between two groups. For comparisons between multiple groups, a Kruskal-Wallis one-way analysis of variance was used. If the Kruskal-Wallis reached statistical significance, ANOVA with Fischer’s post hoc analysis was performed on log10-transformed data.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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sFasL was measured by immunoassay in the BAL fluid of 20 patients
at risk for ARDS and 45 patients with ARDS who were intubated and
mechanically ventilated. Patients at risk for ARDS underwent BAL as
soon as the risk factor for ARDS was defined. Patients with ARDS were
studied on days 1, 3, 7, 14, and 21 after onset of ARDS. The main
characteristics of the patient population are shown in Table I
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). In contrast, in BAL fluid from normal
volunteers (n = 4), sFasL was undetectable in three
individuals and present at 18 pg/ml in one individual. The median
concentration of sFasL was elevated in the patients at risk for ARDS
(128 pg/ml). In patients with ARDS, the median concentration of sFasL
was elevated at the onset of ARDS (135 pg/ml) and varied with time
during the course of the disease. At each time, more than 50% of the
patients had detectable concentrations of sFasL in their BAL fluid.
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To determine whether sFasL can be released by cells present in the
airspaces of patients with ARDS, cells were isolated by centrifugation
from the BAL fluid of seven patients with early ARDS and incubated
overnight in the following conditions: media only, media with 10%
serum, media with 100 ng/ml LPS, and media with 100 ng/ml LPS and 10%
serum. After 24 h, the supernatants were collected and assayed for
sFasL (Fig. 2). Cells incubated in media
released small amounts of sFasL (466 ± 162 pg/ml). The
supernatants from cells stimulated with LPS contained increased amounts
of sFasL (1096 ± 474 pg/ml). Serum did not enhance the effect
of LPS.
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Primary human DLEC expressed membrane Fas (CD95) as detected by
flow cytometry (Fig. 3A). To
determine sensitivity to sFasL, the DLEC were grown in 96-well tissue
culture plates until reaching 80% confluency. The cells were exposed
to serial dilutions of sFasL ranging from 15.62 ng/ml to 500 ng/ml for
18 h at 37°C, 5% CO2, and the cells were
analyzed with alamar Blue. Exposure of DLEC to sFasL caused a linear
decrease in fluorescence over sFasL concentrations ranging from 62.5 to
500 ng/ml (Fig. 3B).
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, a and b) or
medium containing 500 ng/ml of sFasL plus either an irrelevant mAb
(Fig. 4, c and d), inhibitory anti-FasL mAb
(4H9) (Fig. 4e), inhibitory anti-Fas mAb (ZB4) (Fig. 4f), or Fas-Ig fusion protein, which acts as a soluble
receptor for FasL (Fig. 4g) (21). The cells
exposed to sFasL and the control Ab became apoptotic, whereas the cells
exposed to sFasL with either anti-FasL mAb, anti-Fas mAb, or
Fas-Ig did not develop morphologic features of apoptosis. The total
number of cells, the number of apoptotic cells, and the percentage of
apoptotic cells that appear in each panel of Fig. 4 are shown in Table II.
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To determine whether the lung fluids from patients with ARDS caused Fas-dependent apoptosis of these target cells, we first incubated DLEC in medium supplemented at a 50% concentration with either BAL fluid from normal healthy volunteers, with BAL fluid from five patients on the first day of meeting criteria for risk of ARDS, or with BAL fluid from five patients on day 1 of ARDS. All of these lavage fluids had detectable concentrations of sFasL. The BAL fluids were tested under the following conditions: isotype-matched mAb control, inhibitory anti-FasL mAb (4H9), anti-Fas mAb (ZB4), or Fas-Ig fusion protein.
After 18 h incubation, the percentage of apoptotic cells in the
wells exposed to BAL fluid from patients with ARDS was significantly
higher than in the wells exposed to BAL from normal volunteers
(p < .05) (Fig. 5). Inhibition of the Fas pathway with
either anti-Fas mAb, anti-FasL mAb, or Fas-Ig fusion protein
blocked the proapoptotic effect of every ARDS BAL fluid. In comparison,
the BAL fluid from patients at risk for ARDS did not cause a
significant increase in apoptosis of the target cells, as compared with
normal BAL fluid. The morphologic characteristics of apoptosis and the
disruption of the monolayer following incubation with ARDS BAL fluid
are shown in Fig. 6. The DNA end nick
labeling assays supported the interpretation that the mechanism of
death was apoptosis (Fig. 7).
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There was a significant relationship at the onset of ARDS between
sFasL in BAL fluid and survival (Fig. 8).
The patients who subsequently died had significantly higher
concentrations of sFasL (median 344.2 ng/ml, range 4–1328.5 pg/ml) in
the BAL fluid on day 1 of ARDS, as compared with those who lived
(median 70.4 ng/ml, range 4–883.6 pg/ml) (p =
0.04). There was no significant association between the concentration
of sFasL in BAL fluid and either the risk factor for ARDS, total BAL
protein, total neutrophils (PMN), or the number of days on mechanical
ventilation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The alveolar epithelium forms a tight barrier between the airspaces and the vascular compartment (25). In addition, alveolar epithelial cells actively regulate the transport of fluid and electrolytes between the airspaces and the interstitium (3, 26). A characteristic feature of the acute respiratory distress syndrome is widespread destruction of the alveolar epithelium (27) leading to noncardiogenic pulmonary edema. The mechanism of destruction of the alveolar epithelium is unclear. We report here that human DLEC express Fas and that sFasL can induce apoptosis of these target cells by a Fas-dependent mechanism. Furthermore, BAL fluid from patients with ARDS contains sFasL at concentrations sufficient to induce Fas-dependent apoptosis of human DLEC. The findings demonstrate that sFasL is released in vivo during human disease as a biologically active, death-inducing effector molecule capable of inducing apoptosis in Fas-susceptible target cells of the lungs, and suggest that the Fas/FasL system could play a role in the pathogenesis of the epithelial injury seen in ARDS.
The role of sFasL in the pathogenesis of tissue injury has been controversial. Some evidence indicates that sFasL can cause injury in the lungs and other tissues. For example, subsets of murine type II pneumocytes express Fas Ag, and the intratracheal instillation of an activating anti-Fas Ab induces apoptosis of type II cells in vivo (28). However, two separate groups have recently found that sFasL exerted an antiapoptotic effect by competing with membrane-bound FasL for binding to Fas (11, 18). Tanaka et al. found that sFasL in solution was less effective than membrane FasL in inducing apoptosis, and that sFasL inhibited the cytotoxicity mediated by membrane FasL (11). Thus, it was proposed that sFasL might function to protect healthy bystander cells from cells bearing FasL, such as cytotoxic T cells. Schneider et al. found that sFasL is 1000-fold less active that membrane-bound FasL, and that inoculating high doses of sFasL in mice did not cause hepatic failure, providing support for the idea that sFasL is less efficient than membrane FasL in mediating cell death (18).
The data from this study may help clarify the role of sFasL in the
pathogenesis of tissue injury in general and of acute lung injury in
particular. We found that human DLEC are sensitive to Fas ligation, but
that relatively high concentrations of sFasL are required for the
induction of apoptosis in vitro (e.g., >100 ng/ml). These results
appear to confirm those of Tanaka et al. (11). However,
when the cells were incubated in BAL fluid from patients at the onset
of ARDS, they became apoptotic, even though the concentrations of sFasL
in the BAL fluid were less than those required to induce apoptosis of
DLEC in vitro (e.g., <1.0 ng/ml; Fig. 1
). The BAL fluid from patients
at risk for ARDS had no effect on DLEC apoptosis, despite containing
similar concentrations of sFasL as the BAL fluid from patients at the
onset of ARDS. This suggests that a cofactor may be required for the
development of the apoptotic response to sFasL. The need for other
factors that potentiate the effects of sFasL would also explain the
fact that, in the at risk population, the BAL fluid concentrations of
sFasL were unrelated to subsequent development of ARDS and to
mortality, while during early ARDS the BAL fluid concentration of sFasL
was significantly higher in the patients who died. These factors could
include oxidative stress (29, 30), which induces apoptosis
in cell lines (31, 32, 33), inflammatory cytokines, or a
previously undescribed mediator. In preliminary studies, however, we
have found that the DLEC used in these experiments are not sensitive to
TNF-
or IL-1ß, either alone or in conjunction with sFasL (data not
shown). The requirement of a cofactor for the development of a full
apoptotic response to sFasL may explain the apparent discrepancies
between our finding that sFasL can induce apoptosis of target cells and
those of Tanaka et al. (11) and Schneider et al.
(18), which suggest that sFasL is a poor inducer of
apoptosis.
There are several potential sources for the sFasL detected in the lung fluids. The data show that cells recovered from the airspaces of patients with ARDS release FasL, and that the release increases after stimulation with LPS, which is detectable in the BAL fluid of many patients with ARDS (34). Because the cells recovered by BAL are a mixed population of alveolar macrophages and neutrophils, the data do not indicate which cell type is responsible for FasL release. The alveolar macrophage is a possible source, since cells of the human monocyte/macrophage lineage contain FasL and release it when activated by phytohemagglutinin, immune complexes, or superantigen (20). A second possibility is that sFasL increases in the circulation as part of the systemic inflammatory response, and then moves into the airspaces when endothelial and epithelial permeability increase. Indeed, plasma sFasL concentrations are elevated in the serum of patients with inflammatory diseases (14), and we have detected high circulating concentrations of sFasL in the serum of patients with sepsis (data not shown). Thus, it is possible that locally shed sFasL and systemic influx of circulating sFasL account for the increased concentrations that we detected in BAL fluid from patients at risk for and with ARDS.
In earlier studies, we found that BAL fluid from patients with early ARDS (days 1 and 3) inhibits neutrophil apoptosis, and that this effect is mediated primarily by the cytokines G-CSF and GM-CSF (22). We now report that BAL fluid obtained at the same times during the course of ARDS contains sFasL and has the ability to induce apoptosis in primary human lung epithelial cells. These findings indicate that, during ARDS, proapoptotic and antiapoptotic mediators are present in the airspaces and that the biologic effects depend on the specific mediators and cell types. Thus, the inflammatory milieu may be proapoptotic for some cells (e.g., epithelial cells) and antiapoptotic for others (e.g., neutrophils).
The target cells that we used to establish a role for sFasL are
nonciliated pulmonary epithelial cells that are derived from distal
small airways (1–2 mm diameter) of normal lungs. In the culture
conditions that we used, they form monolayers and do not differentiate
into ciliated cells (Fig. 4). Cytokeratin staining indicates that these
cells are of epithelial origin. By electron microscopy, the cells lack
neurosecretory granules and form lamellar-like bodies. We have also
found that they stain positive with two different murine mAb raised
against human surfactant protein A (data not shown). However, they are
not primary alveolar Type I or Type II cells, which are difficult to
isolate from human lungs. Traditional surrogates of alveolar epithelial
cells, such as A549 cells, are not necessarily good targets for
studies of normal apoptosis pathways because they are immortal cells.
The DLEC provide an approximation of the responses of alveolar
epithelial cells, but studies with authentic Type I or Type II alveolar
epithelial cells will be required to confirm these findings. In recent
studies, we have found that the activation of the Fas/FasL system in
the lungs of mice results in apoptosis of cells in the alveolar
epithelium and development of alveolar injury (35).
Further studies in animal models of lung injury, particularly with mice
deficient in Fas (lpr mice) or FasL (gld
mice), could help clarify the role of the Fas/FasL system in the
pathogenesis of the epithelial destruction seen during acute lung
injury.
The results of this study have important implications. The data show that sFasL can induce apoptosis of human lung epithelial cells during acute lung injury. In addition, the data suggest that the permeability changes seen in ARDS could be due at least in part to Fas/FasL-dependent apoptosis of lung epithelial cells. Strategies designed to inhibit the Fas/FasL system might prevent or modify the lung epithelial damage that occurs in humans with acute lung injury.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas R. Martin, Seattle Veterans Affairs Medical Center, 151L, 1660 South Columbian Way, Seattle WA 98108-1597. E-mail address:
3 Abbreviations used in this paper: ARDS, acute respiratory distress syndrome; FasL, Fas ligand; sFasL, soluble FasL; BAL, bronchoalveolar lavage; DLEC, distal lung epithelial cells.
Received for publication February 23, 1999. Accepted for publication June 9, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Fas. Am. J. Physiol. 273:L921.This article has been cited by other articles:
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P. S. Tang, M. Mura, R. Seth, and M. Liu Acute lung injury and cell death: how many ways can cells die? Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L632 - L641. [Abstract] [Full Text] [PDF]
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 G D Perkins, F Gao, and D R Thickett In vivo and in vitro effects of salbutamol on alveolar epithelial repair in acute lung injury Thorax, March 1, 2008; 63(3): 215 - 220. [Abstract] [Full Text] [PDF]
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D. R. Thickett, G. D. Perkins, C. O'Kane, S. McKeown, and D. McAuley Does MMP-12 Play a Role in Human Lung Fibrosis? Am. J. Respir. Cell Mol. Biol., February 1, 2008; 38(2): 247 - 247. [Full Text] [PDF]
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 M. Perl, C.-S. Chung, U. Perl, J. Lomas-Neira, M. de Paepe, W. G. Cioffi, and A. Ayala Fas-induced Pulmonary Apoptosis and Inflammation during Indirect Acute Lung Injury Am. J. Respir. Crit. Care Med., September 15, 2007; 176(6): 591 - 601. [Abstract] [Full Text] [PDF]
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 J. W. Lee, X. Fang, G. Dolganov, R. D. Fremont, J. A. Bastarache, L. B. Ware, and M. A. Matthay Acute Lung Injury Edema Fluid Decreases Net Fluid Transport across Human Alveolar Epithelial Type II Cells J. Biol. Chem., August 17, 2007; 282(33): 24109 - 24119. [Abstract] [Full Text] [PDF]
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G. Matute-Bello, M. M. Wurfel, J. S. Lee, D. R. Park, C. W. Frevert, D. K. Madtes, S. D. Shapiro, and T. R. Martin Essential Role of MMP-12 in Fas-Induced Lung Fibrosis Am. J. Respir. Cell Mol. Biol., August 1, 2007; 37(2): 210 - 221. [Abstract] [Full Text] [PDF]
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 Y. Miyake, H. Kaise, K.-i. Isono, H. Koseki, K. Kohno, and M. Tanaka Protective Role of Macrophages in Noninflammatory Lung Injury Caused by Selective Ablation of Alveolar Epithelial Type II Cells J. Immunol., April 15, 2007; 178(8): 5001 - 5009. [Abstract] [Full Text] [PDF]
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C. M. Alvira, A. Abate, G. Yang, P. A. Dennery, and M. Rabinovitch Nuclear Factor-{kappa}B Activation in Neonatal Mouse Lung Protects against Lipopolysaccharide-induced Inflammation Am. J. Respir. Crit. Care Med., April 15, 2007; 175(8): 805 - 815. [Abstract] [Full Text] [PDF]
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S. Bao and D. L. Knoell Zinc modulates cytokine-induced lung epithelial cell barrier permeability Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1132 - L1141. [Abstract] [Full Text] [PDF]
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L. M. Schnapp, S. Donohoe, J. Chen, D. A. Sunde, P. M. Kelly, J. Ruzinski, T. Martin, and D. R. Goodlett Mining the Acute Respiratory Distress Syndrome Proteome: Identification of the Insulin-Like Growth Factor (IGF)/IGF-Binding Protein-3 Pathway in Acute Lung Injury Am. J. Pathol., July 1, 2006; 169(1): 86 - 95. [Abstract] [Full Text] [PDF]
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S. Cuzzocrea, G. Nocentini, R. Di Paola, M. Agostini, E. Mazzon, S. Ronchetti, C. Crisafulli, E. Esposito, A. P. Caputi, and C. Riccardi Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation J. Immunol., July 1, 2006; 177(1): 631 - 641. [Abstract] [Full Text] [PDF]
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M. Perl, C.-S. Chung, J. Lomas-Neira, T.-M. Rachel, W. L. Biffl, W. G. Cioffi, and A. Ayala Silencing of Fas, but Not Caspase-8, in Lung Epithelial Cells Ameliorates Pulmonary Apoptosis, Inflammation, and Neutrophil Influx after Hemorrhagic Shock and Sepsis Am. J. Pathol., December 1, 2005; 167(6): 1545 - 1559. [Abstract] [Full Text] [PDF]
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T. R. Martin, N. Hagimoto, M. Nakamura, and G. Matute-Bello Apoptosis and Epithelial Injury in the Lungs Proceedings of the ATS, October 1, 2005; 2(3): 214 - 220. [Abstract] [Full Text] [PDF]
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M. E. De Paepe, Q. Mao, Y. Chao, J. L. Powell, L. P. Rubin, and S. Sharma Hyperoxia-induced apoptosis and Fas/FasL expression in lung epithelial cells Am J Physiol Lung Cell Mol Physiol, October 1, 2005; 289(4): L647 - L659. [Abstract] [Full Text] [PDF]
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G. Matute-Bello, J. S. Lee, W. C. Liles, C. W. Frevert, S. Mongovin, V. Wong, K. Ballman, S. Sutlief, and T. R. Martin Fas-Mediated Acute Lung Injury Requires Fas Expression on Nonmyeloid Cells of the Lung J. Immunol., September 15, 2005; 175(6): 4069 - 4075. [Abstract] [Full Text] [PDF]
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T. Suzuki, T. J. Moraes, E. Vachon, H. H. Ginzberg, T.-T. Huang, M. A. Matthay, M. D. Hollenberg, J. Marshall, C. A. G. McCulloch, M. T. H. Abreu, et al. Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells Am. J. Respir. Cell Mol. Biol., September 1, 2005; 33(3): 231 - 247. [Abstract] [Full Text] [PDF]
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T. A. Neff, R.-F. Guo, S. B. Neff, J. V. Sarma, C. L. Speyer, H. Gao, K. D. Bernacki, M. Huber-Lang, S. McGuire, L. M. Hoesel, et al. Relationship of Acute Lung Inflammatory Injury to Fas/FasL System Am. J. Pathol., March 1, 2005; 166(3): 685 - 694. [Abstract] [Full Text] [PDF]
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H. Kida, M. Yoshida, S. Hoshino, K. Inoue, Y. Yano, M. Yanagita, T. Kumagai, T. Osaki, I. Tachibana, Y. Saeki, et al. Protective effect of IL-6 on alveolar epithelial cell death induced by hydrogen peroxide Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L342 - L349. [Abstract] [Full Text] [PDF]
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S. Bao, Y. Wang, P. Sweeney, A. Chaudhuri, A. I. Doseff, C. B. Marsh, and D. L. Knoell Keratinocyte growth factor induces Akt kinase activity and inhibits Fas-mediated apoptosis in A549 lung epithelial cells Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L36 - L42. [Abstract] [Full Text] [PDF]
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 X. Li, R. Shu, G. Filippatos, and B. D. Uhal Apoptosis in lung injury and remodeling J Appl Physiol, October 1, 2004; 97(4): 1535 - 1542. [Abstract] [Full Text] [PDF]
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M. E. De Paepe, Q. Mao, M. Embree-Ku, L. P. Rubin, and F. I. Luks Fas/FasL-mediated apoptosis in perinatal murine lungs Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L730 - L742. [Abstract] [Full Text] [PDF]
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 F. Tamura, R. Nakagawa, T. Akuta, S. Okamoto, S. Hamada, H. Maeda, S. Kawabata, and T. Akaike Proapoptotic Effect of Proteolytic Activation of Matrix Metalloproteinases by Streptococcus pyogenes Thiol Proteinase (Streptococcus Pyrogenic Exotoxin B) Infect. Immun., August 1, 2004; 72(8): 4836 - 4847. [Abstract] [Full Text] [PDF]
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T. Geiser, M. Ishigaki, C. van Leer, M. A. Matthay, and V. C. Broaddus H2O2 inhibits alveolar epithelial wound repair in vitro by induction of apoptosis Am J Physiol Lung Cell Mol Physiol, August 1, 2004; 287(2): L448 - L453. [Abstract] [Full Text] [PDF]
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M. Nakamura, G. Matute-Bello, W. C. Liles, S. Hayashi, O. Kajikawa, S.-M. Lin, C. W. Frevert, and T. R. Martin Differential Response of Human Lung Epithelial Cells to Fas-Induced Apoptosis Am. J. Pathol., June 1, 2004; 164(6): 1949 - 1958. [Abstract] [Full Text] [PDF]
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J. C. Rudkowski, E. Barreiro, R. Harfouche, P. Goldberg, O. Kishta, P. D'Orleans-Juste, J. Labonte, O. Lesur, and S. N. A. Hussain Roles of iNOS and nNOS in sepsis-induced pulmonary apoptosis Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L793 - L800. [Abstract] [Full Text] [PDF]
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 G. Matute-Bello, R. K. Winn, T. R. Martin, and W. C. Liles Sustained Lipopolysaccharide-Induced Lung Inflammation in Mice Is Attenuated by Functional Deficiency of the Fas/Fas Ligand System Clin. Vaccine Immunol., March 1, 2004; 11(2): 358 - 361. [Abstract] [Full Text] [PDF]
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T. M. O'Connor and C. P. Bredin Interferon-{gamma} Toxicity in Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 428 - 428. [Full Text]
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O. Lesur, M. Brisebois, A. Thibodeau, F. Chagnon, D. Lane, and T. Fullop Role of IFN-{gamma} and IL-2 in rat lung epithelial cell migration and apoptosis after oxidant injury Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L4 - L14. [Abstract] [Full Text] [PDF]
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R. H. Hastings, R. A. Quintana, R. Sandoval, D. Duey, Y. Rascon, D. W. Burton, and L. J. Deftos Proapoptotic Effects of Parathyroid Hormone-Related Protein in Type II Pneumocytes Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 733 - 742. [Abstract] [Full Text] [PDF]
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V. E. Kagan, G. G. Borisenko, B. F. Serinkan, Y. Y. Tyurina, V. A. Tyurin, J. Jiang, S. X. Liu, A. A. Shvedova, J. P. Fabisiak, W. Uthaisang, et al. Appetizing rancidity of apoptotic cells for macrophages: oxidation, externalization, and recognition of phosphatidylserine Am J Physiol Lung Cell Mol Physiol, July 1, 2003; 285(1): L1 - L17. [Abstract] [Full Text] [PDF]
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D. R. Park, A. R. Thomsen, C. W. Frevert, U. Pham, S. J. Skerrett, P. A. Kiener, and W. C. Liles Fas (CD95) Induces Proinflammatory Cytokine Responses by Human Monocytes and Monocyte-Derived Macrophages J. Immunol., June 15, 2003; 170(12): 6209 - 6216. [Abstract] [Full Text] [PDF]
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T. O. Yarovinsky, M. M. Monick, and G. W. Hunninghake Integrin Receptors Are Crucial for the Restimulation of Activated T Lymphocytes Am. J. Respir. Cell Mol. Biol., May 1, 2003; 28(5): 607 - 615. [Abstract] [Full Text] [PDF]
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 Y. Imai, J. Parodo, O. Kajikawa, M. de Perrot, S. Fischer, V. Edwards, E. Cutz, M. Liu, S. Keshavjee, T. R. Martin, et al. Injurious Mechanical Ventilation and End-Organ Epithelial Cell Apoptosis and Organ Dysfunction in an Experimental Model of Acute Respiratory Distress Syndrome JAMA, April 23, 2003; 289(16): 2104 - 2112. [Abstract] [Full Text] [PDF]
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T. Fujita, M. Maruyama, J. Araya, K. Sassa, Y. Kawagishi, R. Hayashi, S. Matsui, T. Kashii, N. Yamashita, E. Sugiyama, et al. Hydrogen Peroxide Induces Upregulation of Fas in Human Airway Epithelial Cells via the Activation of PARP-p53 Pathway Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 542 - 552. [Abstract] [Full Text] [PDF]
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K. H. Albertine, M. F. Soulier, Z. Wang, A. Ishizaka, S. Hashimoto, G. A. Zimmerman, M. A. Matthay, and L. B. Ware Fas and Fas Ligand Are Up-Regulated in Pulmonary Edema Fluid and Lung Tissue of Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome Am. J. Pathol., November 1, 2002; 161(5): 1783 - 1796. [Abstract] [Full Text] [PDF]
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J. Araya, M. Maruyama, A. Inoue, T. Fujita, J. Kawahara, K. Sassa, R. Hayashi, Y. Kawagishi, N. Yamashita, E. Sugiyama, et al. Inhibition of proteasome activity is involved in cobalt-induced apoptosis of human alveolar macrophages Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L849 - L858. [Abstract] [Full Text] [PDF]
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J. Hamacher, R. Lucas, H. R. Lijnen, S. Buschke, Y. Dunant, A. Wendel, G. E. Grau, P. M. Suter, and B. Ricou Tumor Necrosis Factor-{alpha} and Angiostatin Are Mediators of Endothelial Cytotoxicity in Bronchoalveolar Lavages of Patients with Acute Respiratory Distress Syndrome Am. J. Respir. Crit. Care Med., September 1, 2002; 166(5): 651 - 656. [Abstract] [Full Text] [PDF]
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N. Hagimoto, K. Kuwano, I. Inoshima, M. Yoshimi, N. Nakamura, M. Fujita, T. Maeyama, and N. Hara TGF-{beta}1 as an Enhancer of Fas-Mediated Apoptosis of Lung Epithelial Cells J. Immunol., June 15, 2002; 168(12): 6470 - 6478. [Abstract] [Full Text] [PDF]
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J. Sanchez-Esteban, Y. Wang, L. A. Cicchiello, and L. P. Rubin Pre- and Postnatal Lung Development, Maturation, and Plasticity: Cyclic mechanical stretch inhibits cell proliferation and induces apoptosis in fetal rat lung fibroblasts Am J Physiol Lung Cell Mol Physiol, March 1, 2002; 282(3): L448 - L456. [Abstract] [Full Text] [PDF]
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 M. Shimizu, K. Fukuo, S. Nagata, T. Suhara, M. Okuro, K. Fujii, Y. Higashino, M. Mogi, Y. Hatanaka, and T. Ogihara Increased plasma levels of the soluble form of fas ligand in patients with acute myocardial infarction and unstable angina pectoris J. Am. Coll. Cardiol., February 20, 2002; 39(4): 585 - 590. [Abstract] [Full Text] [PDF]
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K. R. Coulter, A. Doseff, P. Sweeney, Y. Wang, C. B. Marsh, M. D. Wewers, and D. L. Knoell Opposing Effect by Cytokines on Fas-Mediated Apoptosis in A549 Lung Epithelial Cells Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 58 - 66. [Abstract] [Full Text] [PDF]
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 U. Joashi, S. M. Tibby, C. Turner, A. Mayer, C. Austin, D. Anderson, A. Durward, and I. A. Murdoch Soluble Fas may be a proinflammatory marker after cardiopulmonary bypass in children J. Thorac. Cardiovasc. Surg., January 1, 2002; 123(1): 137 - 144. [Abstract] [Full Text] [PDF]
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G. S. Filippatos, N. Gangopadhyay, O. Lalude, N. Parameswaran, S. I. Said, W. Spielman, and B. D. Uhal Regulation of apoptosis by vasoactive peptides Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L749 - L761. [Abstract] [Full Text] [PDF]
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G. Matute-Bello, C. W. Frevert, W. C. Liles, M. Nakamura, J. T. Ruzinski, K. Ballman, V. A. Wong, C. Vathanaprida, and T. R. Martin Fas/Fas Ligand System Mediates Epithelial Injury, but Not Pulmonary Host Defenses, in Response to Inhaled Bacteria Infect. Immun., September 1, 2001; 69(9): 5768 - 5776. [Abstract] [Full Text] [PDF]
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B. D. Uhal Fas and apoptosis in the alveolar epithelium: holes in the dike? Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L326 - L327. [Full Text] [PDF]
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G. Matute-Bello, W. C. Liles, C. W. Frevert, M. Nakamura, K. Ballman, C. Vathanaprida, P. A. Kiener, and T. R. Martin Recombinant human Fas ligand induces alveolar epithelial cell apoptosis and lung injury in rabbits Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L328 - L335. [Abstract] [Full Text] [PDF]
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 C. OBERHOLZER, A. OBERHOLZER, M. CLARE-SALZLER, and L. L. MOLDAWER Apoptosis in sepsis: a new target for therapeutic exploration FASEB J, April 1, 2001; 15(6): 879 - 892. [Abstract] [Full Text] [PDF]
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R. C. Reddy, G. H. Chen, M. W. Newstead, T. Moore, X. Zeng, K. Tateda, and T. J. Standiford Alveolar Macrophage Deactivation in Murine Septic Peritonitis: Role of Interleukin 10 Infect. Immun., March 1, 2001; 69(3): 1394 - 1401. [Abstract] [Full Text] [PDF]
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K. L. Serrao, J. D. Fortenberry, M. L. Owens, F. L. Harris, and L. A. S. Brown Neutrophils induce apoptosis of lung epithelial cells via release of soluble Fas ligand Am J Physiol Lung Cell Mol Physiol, February 1, 2001; 280(2): L298 - L305. [Abstract] [Full Text] [PDF]
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G. Matute-Bello, R. K. Winn, M. Jonas, E. Y. Chi, T. R. Martin, and W. C. Liles Fas (CD95) Induces Alveolar Epithelial Cell Apoptosis in Vivo : Implications for Acute Pulmonary Inflammation Am. J. Pathol., January 1, 2001; 158(1): 153 - 161. [Abstract] [Full Text] [PDF]
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M. E. De Paepe, L. P. Rubin, C. Jude, A. M. Lesieur-Brooks, D. R. Mills, and F. I. Luks Fas ligand expression coincides with alveolar cell apoptosis in late-gestation fetal lung development Am J Physiol Lung Cell Mol Physiol, November 1, 2000; 279(5): L967 - L976. [Abstract] [Full Text] [PDF]
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 T. Imanishi, C. E. Murry, H. Reinecke, T. Hano, I. Nishio, W.C. Liles, L. Hofsta, K. Kim, K. D. O'Brien, S. M. Schwartz, et al. Cellular FLIP is expressed in cardiomyocytes and down-regulated in TUNEL-positive grafted cardiac tissues Cardiovasc Res, October 1, 2000; 48(1): 101 - 110. [Abstract] [Full Text] [PDF]
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A. Fine, Y. Janssen-Heininger, R. P. Soultanakis, S. G. Swisher, and B. D. Uhal Apoptosis in lung pathophysiology Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L423 - L427. [Abstract] [Full Text] [PDF]
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M. Kawasaki, K. Kuwano, N. Hagimoto, T. Matsuba, R. Kunitake, T. Tanaka, T. Maeyama, and N. Hara Protection from Lethal Apoptosis in Lipopolysaccharide-Induced Acute Lung Injury in Mice by a Caspase Inhibitor Am. J. Pathol., August 1, 2000; 157(2): 597 - 603. [Abstract] [Full Text] [PDF]
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 L. B. Ware and M. A. Matthay The Acute Respiratory Distress Syndrome N. Engl. J. Med., May 4, 2000; 342(18): 1334 - 1349. [Full Text] [PDF]
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 M. Hernandez, L. Fuentes, F. J. Fernandez Aviles, M. S. Crespo, and M. L. Nieto Secretory Phospholipase A2 Elicits Proinflammatory Changes and Upregulates the Surface Expression of Fas Ligand in Monocytic Cells: Potential Relevance for Atherogenesis Circ. Res., January 11, 2002; 90(1): 38 - 45. [Abstract] [Full Text] [PDF]
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