RAPID COMMUNICATION
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Abstract |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The cell surface molecule Fas (CD95) is a member of the tumor necrosis factor receptor family. Ligation
of the Fas receptor can lead to induction of apoptosis in inflammatory cells. It has been suggested that expression of the Fas receptor and its ligand (FasL) in airway epithelium may modulate the inflammatory response commonly found in asthmatic lungs. We examined Fas and FasL expression on primary human tissues, on bronchial epithelial cells in primary culture, and on the immortalized human airway epithelial cell line, 1HAEo
. Receptor and ligand expression were demonstrated using multiple antibodies and multiple
techniques, including immunohistochemistry, flow cytometry, Western blots, and reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining demonstrated that both columnar
and basal cells of intact human lung tissues expressed cell surface Fas and FasL. In addition, both primary cultured and immortalized 1HAEo cells expressed cell surface Fas and FasL, as demonstrated by flow cytometry; expression of Fas and FasL was confirmed at the transcription level using RT-PCR and, for additional confirmation of FasL, using Western blots. We demonstrate that both Fas and FasL are expressed by
human airway epithelial cell subtypes. Expression of these molecules may play an important role in regulation of the inflammatory response.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In 1989, two groups independently reported monoclonal
antibodies with the capacity to induce apoptosis or programmed cell death in various human cell lines (1, 2).
Characterization of one of the antibodies revealed the tumor necrosis factor-
receptor family member Fas (CD95)
and demonstrated its role as a cell surface receptor for a
corresponding ligand, FasL (CD95L). Crosslinking of the
Fas receptor with antibody or binding of FasL can induce
apoptosis in inflammatory cells such as eosinophils and
lymphocytes (3). Other studies of Fas/FasL interactions have demonstrated a role for this receptor in immune cell
homeostasis (4), and it has been hypothesized that dysregulation of the Fas apoptotic pathway contributes to several
autoimmune diseases (5). However, little is known about
the role of these apoptotic molecules in epithelial cells.
Even less is understood regarding the specific roles of Fas/
FasL interactions in acute or chronic inflammatory states
and cell damage or epithelial shedding, such as that seen in
asthma. Because inflammatory cells are commonly seen in
the airway mucosa in asthma, the expression of these apoptotic molecules in the airway epithelium may modulate
the inflammatory state. Whereas inflammatory cells such
as eosinophils express Fas on their surface (6), no study
has examined constitutive cells of the airway. We have
generated data that demonstrate that both Fas and FasL
are expressed on the cell surface of human airway epithelial cells both in situ and in monolayer culture. Our data suggest possible roles for Fas and FasL as modulators of
epithelial inflammation.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Preparation of Human Lung Tissue
Approval for the use of human tissues was granted by the University of Chicago Institutional Review Board. Normal bronchial segments collected from subjects undergoing lung resection were isolated and removed from the fresh lung blocks. Bronchial lumens were flushed with phosphate-buffered saline (PBS) to remove debris, and segments were cleaned of extraneous tissue. Segments were fixed in 4% paraformaldehyde for 1 h, transferred to containers containing PBS at 4°C, and shipped on ice. On arrival, segments were cleaned, sectioned, and embedded in paraffin for preparation of 5-µm tissue sections. Some sections were used for staining with hematoxylin and eosin (H&E) per standard methods, and others for immunohistochemistry as described.
Culture of Primary Human Bronchial Epithelial Cells
Primary human bronchial epithelial cells (1° HBEC) were derived from collected bronchial tissues but shipped on ice in PBS containing 0.1% protease and penicillin/streptomycin solution. On arrival, bronchi were filleted and epithelial cells were collected with a rubber spatula. Cells were plated in F12 supplemented with 10 µg/ml insulin, 5 ng/ml epidermal growth factor, 0.5 µg/ml transferrin, 0.4 µg/ml hydrocortisone, 2 µg/ml triiodothyrinine, 100 µg/ml penicillin, and 5% fetal calf serum (FCS) into collagen-coated six-well plates or two-chamber covered slides and incubated at 37°C in 5% CO2 until confluent.
Culture of Cell Lines
1HAEo cells, a generous gift of Dr. Dieter Gruenert
(University of California San Francisco), are human airway epithelial cells transformed with SV40 and characterized previously (10, 11). Cells were grown on matrix-coated flasks, two-chamber covered slides, or plates, in
Eagle's modified essential medium containing 10% FCS,
2 mM L-glutamine, 100 µg/ml streptomycin, and 100 U/ml penicillin G, and incubated at 37°C in 5% CO2. Cells were
passaged when ~ 75% confluent. Jurkat is a human T-cell
tumor line grown in RPMI-1640 media, incubated at 37°C
in 5% CO2 and maintained per standard techniques.
Flow Cytometry
Flow cytometric analyses were performed by standard techniques using murine immunoglobulin G (IgG) isotype controls (PharMingen, San Diego, CA), specific anti-Fas (clones ZB4; PanVera, Madison, WI), and anti-FasL (clones G247 and NOK1; PharMingen) as primary antibodies. Live cells were primary labeled with 2 µg/5 × 105 cells using either ZB4, G247, or NOK1. Following primary staining, cells were incubated with fluorescein isothiocyanate-conjugated goat antimouse immunoglobulin (Becton-Dickinson, San Jose, CA) using the recommended dilution. The cells were analyzed on a Becton-Dickinson FACScan cytometer, and dead cells were excluded by positive propidium iodide staining.
Immunoperoxidase Staining
Cultured primary bronchial cells and the cell line 1HAEo
were grown to confluence in two-chamber covered slides,
fixed in 4% paraformaldehyde for 2 h, and then air-dried.
Paraffin was removed from the tissue slides with xylene.
Fixed monolayers and tissue slides were then rehydrated
in sequential alcohol baths (100% to 30%). Slides were
blocked in N-2-hydroxyethylpiperazine-N'-ethane sulfonic acid (Hepes) buffer containing 0.1% bovine serum
albumin (BSA) and incubated with the following primary
antibodies: anti-Fas (clones UB2, PanVera at 10 µg/ml;
and CH-11, PharMingen at 5 µg/ml) and anti-FasL (clone
D042-3, PanVera at 20 µg/ml; and polyclonal FasL N-20,
Santa Cruz Biotechnology, Inc. [Santa Cruz, CA], at 5 µg/
ml). Incubations with UB2, D042-3, and FasL N-20 were
for 60 min at room temperature. Slides were rinsed in
Hepes buffer with BSA and then incubated in 1:100 goat
antimouse IgG horseradish peroxidase (HRP) (Sigma, St.
Louis, MO) for 20 min at room temperature prior to slide
development with diaminobenzidine augmented with nickel plus 1:1,000 of 30% H2O2 (Pierce, Rockford, IL) by
incubation for 6 min, followed by rinsing in Hepes buffer.
For the clone CH-11, incubation was overnight at 4°C;
slides were then rinsed prior to the application of 1:100 biotinylated antimouse IgM (Amersham Life Sciences, Arlington Heights, IL) for 4 h at room temperature. This
was followed by incubation with 1:100 streptavidin-HRP
(Dako, Carpenteria, CA) for 20 min at room temperature
and then developed with diaminobenzidine augmented
with nickel plus 1:1,000 of 30% H2O2 (Pierce) as for the
other samples. Slides were counterstained with hematoxylin, rinsed in tap water, and mounted for viewing. With this
method positive (brown) cells were identified.
Controls were performed on identically prepared tissues and slides using the appropriately matched isotype (either mouse IgG or IgM) at the same or greater concentration as the test primary antibody. Subsequent processing of the control slides was as above. For the polyclonal FasL antibody from Santa Cruz Biotechnology, the control reaction included an initial incubation of the antibody with the immunizing peptide. The incubation contained 20 µg/ml of antibody at room temperature for 30 min using a 3:1 molar ratio of peptide/antibody. This incubation mixture was then applied to the samples as the primary antibody, and the processing was completed as above.
Reverse Transcription-Polymerase Chain Reaction
Total RNA from samples of cultured cells was isolated using a commercially available kit (RNA STAT-60TM; Tel-Test "B," Inc., Friendswood, TX). First-strand synthesis was performed with 1 µg total RNA, 2.5 µM random hexamers, 1 mM nucleotides, and 2.5 U/µl MuLV reverse transcriptase. Amplification of strands with 2.5 U/100 µl AmpliTaq DNA polymerase, 0.2 mM nucleotides (Perkin-Elmer, Foster City, CA), and sequence-specific primers was done for 40 cycles using standard parameters. PCR primers used in reverse transcriptase-polymerase chain reaction (RT-PCR) analyses for Fas and FasL were from published sequences (3, 12) and spanned multiple exons to exclude amplification of any contaminating genomic DNA. An additional control for specificity of RNA amplification was the use of parallel samples that were analyzed omitting reverse. Amplified PCR products were analyzed on a 1.5% agarose/Tris (0.045 M)/borate (0.045 M)/EDTA (0.001 M) (TBE) gel containing 0.25 µg/ml EtBr prior to photography.
Western Blot Analysis
Primary cells and the cell line were grown to confluence in six-well chambers. Cell were harvested by scraping and then collected by centrifugation. The pellet was lysed by boiling for 5 min in lysis buffer (1% sodium dodecyl sulfate [SDS], 1 mM sodium vanadate, 10 mM Tris-HCl at pH 7.4). Total protein cell extracts were separated by SDS gel-electrophoresis and transferred to nylon-nitrocellulose membranes (Sigma; 0.2-µm pore size) using standard techniques. Western was probed for FasL using clone 33 (Transduction Laboratory, Lexington, KY) and bands were visualized using enhanced chemiluminescence reagents (Dako) by the manufacturer's suggested method.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Fas and FasL Expression in Human Lung Tissues
Immunohistochemical analyses of human lung tissues reveals the expression of both Fas and FasL in situ (Figure 1). Expression is noted for both Fas and FasL throughout the epithelial layer and is significant compared with the isotype-matched IgG controls in four of four tissues. By visual determination, Fas expression appears to be similar between basal and all forms of columnar cells. The anti-FasL N-20 antibody demonstrates that FasL expression may be significantly greater in the columnar cells.
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Fas and FasL Expression on Cultured Airway Epithelial Cells
As an additional test to assess epithelial cell surface expression for Fas and FasL, we examined 1° HBEC and
1HAEo using flow cytometry. Both Fas and FasL are expressed on 1° HBEC and 1HAEo cells, as demonstrated
in representative flow analyses (Figure 2). Fluorescence of
primary cells is 130.2 ± 75.4 for Fas and 15.5 ± 4.3 for
FasL versus 8.3 ± 0.7 for IgG control (n = 3). In 1HAEo
cells, mean fluorescence is 26.9 ± 1.9 for Fas and 13.6 ± 3.3 for FasL versus 5.2 ± 0.7 for IgG control (P < 0.001 for
IgG control versus Fas and P < 0.04 versus FasL, n = 5).
Similar levels of cell surface expression were obtained for
FasL using the NOK1 monoclonal antibody (mAb) (data
not shown).
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To visualize surface expression on 1° HBEC and
1HAEo, we examined Fas and FasL using the immunoperoxidase method on fixed monolayers. Both receptor
and ligand were demonstrated on the 1° HBEC (Figure 3).
The staining pattern produced by FasL N-20 on the
1HAEo cells (Figure 4) demonstrated that the majority of
these basal-like cells expressed FasL. However, the anti-Fas
mAb UB2 weakly identified a subset of the monolayer cells.
Additional confirmation of the presence of Fas on these cultured human airway cells was performed using the mAb
clone CH-11. This antibody demonstrates a universal membrane staining pattern (Figure 4). Similar CH-11 mAb
staining of the primary cultured human airway epithelial
cells was noted (data not shown).
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Fas and FasL Transcription in Cultured Epithelial Cells
To determine expression of the apoptotic molecules Fas
and FasL at the transcriptional level, RT-PCR was utilized
on total RNA isolated from 1° HBEC and 1HAEo cells.
As noted in Figures 5 and 6, both cultured cells express both genes when grown in standard serum-containing media. Figure 5 demonstrates the transcription of Fas in two
independent primary human airway epithelial cultures and
1HAEo. The expression is comparable with that observed in control Jurkat cells, and the molecular weight of
the resultant amplified fragments is of the expected size
for RNA-amplification with no detected signal in the reverse transcriptase negative lanes. For FasL expression, additional analyses were performed on the primary amplification product of the expected molecular weight to confirm identity (Figure 6). A Southern blot of the amplified
product using an internal sequence as probe and re-amplification of the primary amplification demonstrated that
this product corresponds to expected FasL sequences.
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) were
included to analyze for amplification of contaminating genomic
DNA; all (
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FasL Western Blot Analysis
The surface expression of FasL, as determined by flow cytometry, was less than that identified for Fas. As additional confirmatory data, we identified the presence of
protein from two independent primary cultures and the
1HAEo cell line that corresponds to the expected molecular weight for FasL, as seen for the control Jurkat cells
(Figure 7).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The regulatory role of the Fas-initiated apoptosis cascade in hematopoietic cells is well recognized (13). The expression and role of these molecules in epithelial cells, however, is not well understood. There are a few reports of Fas expression in other human epithelial cells (14) and of FasL only on corneal epithelial cells (15). We demonstrate for the first time both Fas and FasL expression on human airway epithelial cells. Expression was demonstrated by in situ staining, flow cytometry, RT-PCR, and Western analyses. The respective genes were transcribed under standard culture conditions.
Fas and FasL are expressed on the epithelial cell surface of both basal and all forms of columnar cells. This coexpression of receptor and ligand is uncommon for mammalian cells and has been described only for corneal epithelium (15), crypt cells in ulcerative colitis (17), and two hematopoietic cells, neutrophils (18), and T cells (3, 5, 14). These cells are exposed to different environmental stimuli than airway epithelium; consequently, functional roles for Fas/FasL molecules may not be similar to those identified in other tissues. In airway epithelium, the Fas/ FasL-mediated pathway may initiate apoptosis and/or modulate the rate of cell turnover. Modulation of cell turnover has been suggested for the coexpression in embryonic tissues (19) and in mature neutrophils (18). FasL expression and its association to cell turnover generally has been ascribed to tissues with high rates of turnover. Additionally, coexpression of Fas/FasL suggests a possible role for an autocrine or paracrine loop causing self or adjacent-cell death, which should be manifested by a high cell turnover. Airway epithelium, however, has estimated turnover rates of ~ 1% in normal tissue (20), suggesting a basal regulation of the Fas/FasL interaction that prevents apoptosis in these tissues. Forms of regulation may include segregation of the Fas receptor and ligand onto nonadjacent membrane surfaces, state of receptor cluster activation (21), phosphorylation of cluster elements (22), or roles for cell surface metalloproteases regulating the soluble and membrane-bound forms of FasL (23).
Also of interest are the potential separate functional roles for Fas and FasL in airway epithelium. Fas expression appeared to be greater in epithelial regions where some epithelial damage was present (data not shown). Neo-expression of Fas has been demonstrated in a causative role of Hashimoto's thyroiditis (24). It is possible that neo- or overexpression of Fas may be proinflammatory in airway inflammatory states such as asthma and chronic bronchitis and, as a result, may play a role in overall epithelial integrity. Indeed, increased epithelial cell turnover has been documented in chronic bronchitis (20). On the other hand, the expression of FasL may function to prevent infiltration of Fas-bearing inflammatory cells (e.g., eosinophils) into the epithelial layer. A role of Fas/FasL in immune privilege (14, 19, 25) has been suggested for other tissues, including testis (26), brain (27), and placenta (28). One could speculate, therefore, that constitutive, functional expression of FasL represents the basal state of airway epithelium, whereas infiltration of the epithelial layer by inflammatory cells results from "breakdown" of the Fas/FasL barrier of immune privilege. This "breakdown" may include either altered levels of FasL expression or expression of a "weaker" genetic variant of FasL (29) that could predispose these tissues to inflammation. Weakening of the immune barrier by the inheritance of a "weak" form of FasL may predispose airway epithelium to chronic inflammation and individuals to conditions such as asthma. Increased cell survival from immune surveillance, as suggested to occur for lung carcinoma (30), is thought to be FasL-dependent. Here, the expression of FasL is thought to provide a selective advantage by facilitating killing of the responsible immune cells, which express Fas, by the malignant cells expressing FasL. This is difficult to reconcile with the observation here of FasL expression in normal human airway epithelium.
In summary, we have described the expression of both Fas and FasL in normal human airway epithelial cells and an immortalized epithelial cell line. This information leads to additional areas of study of the mechanisms of inflammation in airways diseases such as asthma, and of potential therapeutic interventions for these chronic inflammatory conditions.
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Footnotes |
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Address correspondence to: Kimm J. Hamann, Ph.D., University of Chicago, Section of Pulmonary and Critical Care Medicine, 5841 S. Ellis MC6076, Chicago, IL 60637. E-mail: khamann{at}medicine.bsd.uchicago.edu
(Received in original form July 21, 1997 and in revised form February 23, 1998).
* These authors are to be considered equal contributors and co-first authors.Abbreviations: immortalized human airway epithelial cell line, 1HAEo
;
primary human bronchial epithelial cells, 1° HBEC; N-2- hydroxyethylpiperazine-N'-ethane sulfonic acid, Hepes; horseradish peroxidase,
HRP; immunoglobulin G, IgG; monoclonal antibody, mAb; reverse transcription-polymerase chain reaction, RT-PCR.
Acknowledgments: This work was supported by AI-32654, HL-48696, HL-51853, the American Lung Association, and BMFT 01KE9301 (Germany). One author (A.I.S.) is a fellow of the Parker B. Francis Foundation.
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References |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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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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N. S. Undevia, D. R. Dorscheid, B. A. Marroquin, W. L. Gugliotta, R. Tse, and S. R. White Smad and p38-MAPK signaling mediates apoptotic effects of transforming growth factor-{beta}1 in human airway epithelial cells Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L515 - L524. [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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R. Tse, B. A. Marroquin, D. R. Dorscheid, and S. R. White {beta}-Adrenergic agonists inhibit corticosteroid-induced apoptosis of airway epithelial cells Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L393 - L404. [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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 Z. O-Quan Shi, M. J. Fischer, G. T. De Sanctis, M. R. Schuyler, and Y. Tesfaigzi IFN-{gamma}, But Not Fas, Mediates Reduction of Allergen-Induced Mucous Cell Metaplasia by Inducing Apoptosis J. Immunol., May 1, 2002; 168(9): 4764 - 4771. [Abstract] [Full Text] [PDF]
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 D. R. DORSCHEID, K. R. WOJCIK, S. SUN, B. MARROQUIN, and S. R. WHITE Apoptosis of Airway Epithelial Cells Induced by Corticosteroids Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1939 - 1947. [Abstract] [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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S. R. White, P. Williams, K. R. Wojcik, S. Sun, P. S. Hiemstra, K. F. Rabe, and D. R. Dorscheid Initiation of Apoptosis by Actin Cytoskeletal Derangement in Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., March 1, 2001; 24(3): 282 - 294. [Abstract] [Full Text] [PDF]
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S. R. White, K. R. Wojcik, D. Gruenert, S. Sun, and D. R. Dorscheid Airway Epithelial Cell Wound Repair Mediated by {alpha}-Dystroglycan Am. J. Respir. Cell Mol. Biol., February 1, 2001; 24(2): 179 - 186. [Abstract] [Full Text]
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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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K. J. Hamann, J. E. Vieira, A. J. Halayko, D. Dorscheid, S. R. White, S. M. Forsythe, B. Camoretti-Mercado, K. F. Rabe, and J. Solway Fas cross-linking induces apoptosis in human airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, March 1, 2000; 278(3): L618 - L624. [Abstract] [Full Text] [PDF]
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 I. Durieu, C. Amsellem, C. Paulin, M.-T. Chambe, J. Bienvenu, G. Bellon, and Y Pacheco Fas and Fas ligand expression in cystic fibrosis airway epithelium Thorax, December 1, 1999; 54(12): 1093 - 1098. [Abstract] [Full Text]
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