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-Induced Resolution of Allergen- Induced Mucus Cell Metaplasia1
* Lovelace Respiratory Research Institute, Albuquerque, NM 87108;
Respiratory Research Group, University of Calgary, Calgary, Alberta, Canada; and
Aventis Pharmaceutical, Bridgewater, NH 08870
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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levels were increased earlier in
-/- compared with +/+ mice. MCM levels were decreased 4-fold at 7
days of allergen exposure in -/- mice and at 15 days in +/+ mice. The
percentage of Bax-expressing mucus cells increased significantly at 7
days in -/- mice and at 10 days in +/+ mice. The Bax-positive mucus
cells exhibited caspase-specific cleavage of cytokeratin 18. IFN-
caused Bax expression in IL-13-induced MCM in microdissected airway
cultures. MCM remained significantly elevated in Bax -/- mice
following 15 days of allergen exposure compared with +/+ mice, while
the number of eosinophils was reduced in both Bax +/+ and -/- mice at
15 days. Together, these data demonstrate that reduced IL-13 levels
were sufficient to elicit maximum MCM, that IFN- induces Bax in
metaplastic mucus cells, and that Bax plays a critical role in the
resolution of MCM, but not in the resolution of
eosinophils. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In airway epithelia, pre-existing and proliferating epithelial cells can differentiate into mucin-producing cells and establish mucus cell metaplasia (MCM)3 following inflammatory responses (3). MCM resolves during the recovery process, and the original proportions of cell types in the airway epithelium are restored (3). Resolution of MCM involves down-regulation of mucin biosynthesis and reduction of cell numbers (4). Therefore, disruption of the mechanisms involved in the reduction of mucus cells may at least in part be responsible for the pathological conditions in asthma and chronic bronchitis, in which MCM persists and contributes to increased mucus secretions and airway obstruction (5).
In rats, exposure to LPS or allergen causes MCM in airway epithelia (6, 7), and 20–30% of the resulting metaplastic mucus cells express Bcl-2, an inhibitor of the cell death program (8). The reduction of Bcl-2 expression precedes the resolution of MCM, thus indicating an antiapoptotic role for Bcl-2 in this system (8, 9). Bcl-2 and related cytoplasmic proteins are key regulators of the cell suicide program (10).
Bcl-2 is the founding member of a family of proteins characterized by at least one of four conserved motifs known as Bcl-2 homology domains BH1 to BH4 (11). This family is subdivided into the BH4 proteins that contain all four homology regions and the BH3 domain-only-containing proteins. Bax is a proapoptotic protein that contains all BH4 domains and can heterodimerize with Bcl-2 or other antiapoptotic family members to register diverse forms of intracellular damage, gauge whether a positive or negative death stimulus is present, and determine the progression or inhibition of the suicide program (11, 12, 13).
P-selectin is both necessary and sufficient for the recruitment of eosinophils, because this protein is critical for the interaction of leukocytes and endothelial cells (14) before the migration through the vasculature to the site of inflammation (15). Previous studies have shown that allergic airway responses are reduced in sensitized and allergen-challenged P-selectin-deficient (-/-) mice (16). The purpose of the current study was to investigate whether reduced inflammation affects the development and resolution of MCM during prolonged exposure of mice to allergen and whether regulators of apoptosis may play a role in the resolution process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male pathogen-free, wild-type (+/+) C57BL/6J mice and P-selectin-deficient (-/-) mice on C57BL/6 background were purchased from The Jackson Laboratory (Bar Harbor, ME). Dr. S. J. Korsmeyer (Dana-Farber Institute, Boston, MA) provided Bax +/- C57BL/6 mice, and we bred and genotyped by PCR the Bax -/- and +/+ littermates, as described previously (17). Mice, 6–8 wk of age, were housed in isolated cages under specific pathogen-free conditions. Mice were acclimatized for 12 days after arrival, then entered into the experimental protocol at 8–10 wk of age. Mice were sensitized by i.p. injection with 1 µg OVA/100 µg Al(OH)3 (grade III; Sigma-Aldrich, St. Louis, MO) in 0.5 ml of saline. A booster injection was given on day 7, using the identical reagents. Seven days later, mice were exposed 5 h/day to OVA aerosol at a concentration of 2.3 mg/m3. Mice were exposed to allergen for 5, 7, 10, or 15 consecutive days and euthanized immediately after the end of the last exposure.
Histological evaluation
Mice were euthanized by i.p. injection of 15 mg sodium pentobarbital (Abbott Laboratories, Chicago, IL) and exsanguinated via the renal artery. The thoracic contents were exposed, and the lungs were perfused by cardiac puncture with 0.9% saline (w/v; McGaw, Irvine, CA). The trachea was cannulated with a 23-gauge blunt needle tipped with surgical tubing, the lungs were lavaged three times with 0.5 ml ice-cold PBS containing 1% FBS, and the bronchoalveolar lavage fluid (BALF) was collected. For histopathological examinations, lungs from another set of mice were inflated with 10% zinc Formalin (Stephens Scientific, Riverdale, NJ) at a constant pressure of 25 cm for 3 h and immersed in a large volume of the same fixative for 2–3 days, as described previously (18).
A stratified, random-sampling scheme was used to cut the fixed lung
lobes into cross-sectional slices, each 
0.3 cm thick. Depending on
the size of the lung, five or six slices were prepared, embedded in
paraffin, and sectioned at 5 µm thickness. Sections were used for
Alcian blue (AB) or immunohistochemical staining. The number of
AB-positive cells/mm basal lamina was quantified using a Zeiss
microscope equipped with the morphometry software system from
Intelligent Imaging (Denver, CO).
Tissue sections were stained with H&E and scored for eosinophils in the periarterial, perivenular, and peribronchial regions. The scores for the three regions were summed to show the total lung score. The scores of each lung slice were averaged to produce one score for each lung. An immunologist who was blinded to their identity scored each slide by grading from 0 (0% area involved) to 4 (>50% are involved).
Quantification of macrophages, eosinophils, lymphocytes, and neutrophils
The cells recovered by lavage were enumerated using a hemacytometer. Cytological preparations were made and stained with Wright Giemsa stain (American Scientific Products, McGraw Park, IL) to determine the different types of cells present in the BALF. At least 400 cells were counted from each slide, and the distribution of macrophages, neutrophils, eosinophils, and lymphocytes was determined.
Cytokine detection
Lungs of mice were lavaged three times with 0.5 ml of PBS via
the tracheal tube, and BALF was stored at -80°C until use. IL-4,
IL-5, IL-13, and IFN- were measured using Quantikine M Murine (R&D
Systems, Minneapolis, MN). A total of 35 µl of BALF was added to each
anticytokine-coated plate and incubated at 4°C overnight. The
cytokine concentrations in the BALF were determined by standard ELISA
techniques, as described in the manufacturer’s manual. Detection
limits were 3.9 pg/ml for IL-4 and IL-13, 4.7 pg/ml for IFN-, and
7.8 pg/ml for IL-5.
Immunohistochemistry
Endogenous peroxidase activity was blocked by incubating sections in 2% hydrogen peroxide/methanol for 1 min. Slides were washed in deionized water, and all subsequent washes consisted of 0.05% Brij/Dulbecco’s PBS (pH 7.4). Proteins were unmasked by incubating tissue sections with a trypsin solution (Zymed, San Francisco, CA) at 37°C for 10 min, as described by the manufacturer. Slides were first incubated for blocking in 1% normal goat serum in 2% BSA/0.1% Triton X-100 before the primary Ab (polyclonal rabbit anti-mouse Bax, Bcl-2, Bcl-x, Bak, or normal rabbit serum; BD PharMingen, San Diego, CA; at 1/500 dilution) was applied. After an overnight incubation at room temperature, the immunoreaction was visualized using biotinylated goat anti-rabbit Ab, VECTASTAIN ABC reagent, and the peroxidase substrate diaminobenzidine (DAB; Vector Laboratories, Burlingame, CA), as described by the manufacturer. The following procedures verified the specificity of the Bax Ab reaction: the immunohistochemical reactions using rabbit nonimmune IgG showed no staining; the reaction of the Bax Ab was inhibited when the antigenic peptide (19) was added to the reaction. Positive immunoreaction of Abs to Bcl-2, Bcl-x, and Bak was tested on lung tissues from mice and rats instilled with LPS. Epithelial cells with mucosubstances were detected by counterstaining tissue sections with AB (20). The percentage of Bax-positive mucus cells was determined by counting all AB-positive cells throughout the airway epithelia of the lung sections (from 400 to 700 AB-positive cells/mouse).
Detection of caspase cleavage product of cytokeratin 18
Caulin et al. (21) showed that activation of caspases in epithelial cells leads to cleavage of cytokeratins, in particular cytokeratin 18. Cytokeratins 8 and 18 are major intermediate filaments of single-layer epithelial tissues (22), so we investigated their cleavage in mucus cells. M30CytoDEATH (Roche Diagnostic, Indianapolis, IN) recognizes a specific caspase cleavage site within cytokeratin 18 not detectable in native cytokeratin 18 of normal cells (23), and was used essentially as described by the manufacturer, except for the steps described below. The immunoreaction of the Ab was detected using 1.5 mg/ml (1/200 dilution) of the anti-mouse Ig biotin, VECTASTAIN ABC reagent, and DAB (Vector Laboratories, Inc.). The reaction was terminated by extensive rinsing in water, and mucus cells were visualized by staining with AB. Finally, the sections were counterstained with hematoxylin and mounted with Permount (Sigma-Aldrich).
Immunoblot detection of proteins
Protein extracts were prepared from the entire right lung of mice by homogenizing in radioimmunoprecipitation assay buffer (10 mM Tris, pH 7.4, 150 mM NaCl, 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 5 mM EDTA) supplemented with the protease inhibitors PMSF (1 mM), pepstatin (10 µg/ml), aprotinin (2 µg/ml), and benzamidine (2 µg/ml), and analyzed by Western blotting, as described (8). The Bax Ab was either at 1/3000 dilution (Upstate Biotechnology, Lake Placid, NY) or 1/500 dilution (BD PharMingen).
Microdissected airway cultures
Distal airway bronchioles were removed by microdissection,
essentially as described (24). After removal from mice,
lungs were inflated with 1% SeaPlaque low-melting-temperature agarose
(FMC Bioproducts, Rockland, ME) in 2x DMEM (Life Technologies, Grand
Island, NY) and immersed in ice-cold F12 medium. The lung lobes were
isolated, and distal airway branches were dissected starting from the
branch point. Up to 15 bronchioles were obtained from each mouse, and 3
bronchioles were used for each treatment. Bronchioles from at least
three mice were prepared for each treatment to normalize for
mouse-to-mouse variability. Distal airways (3–5/well) were transferred
to 0.4-µm-pore-size Transwell (Costar, Pleasanton, CA) mesh inserts
in 12-well plates. A total of 400 µl of medium was added to the
bottom of the Transwell system and 60 µl to the top chamber with the
bronchioles. They were placed in the center of the mesh inserts, with
the long axis of the cylindrical bronchiole fully extended in the plane
of the insert membrane. Culture medium, previously described
(24), was changed 24 h after placing the organ
cultures and every other day thereafter. Bronchioles were kept in
culture at the air-liquid interface for 7 days, and were treated with
nothing as control. IL-13 (20 ng/ml) or IFN- (50 ng/ml) was added to
the IL-13 treatment for the last 2 days in culture. Experiments with
these treatments were repeated at least three times. The volume density
of mucosubstances was quantified in these tissues in a blinded fashion.
Explants were fixed in zinc Formalin for 1–3 days and pre-embedded in
1% agarose before processing for paraffin embedding. Tissue sections
(5 mm) were then prepared and subjected to AB/periodic acid-Schiff
(PAS)-staining or immunostaining procedures. Mice that showed
mucus cells in control medium without IL-13 were excluded from
analyses.
Statistical analyses
Grouped results from at least four different mice were expressed as mean ± SEM, and differences between groups were assessed for significance by Student’s t test, when data were available in only two groups. When data were available in more than two groups, ANOVA was used to perform pairwise comparisons, and Fisher’s least significant difference test was used to determine differences between groups. A p value of <0.05 was considered to indicate statistical significance.
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Results |
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Overall, P-selectin -/- mice had fewer lymphocytes (Fig. 1
A) and eosinophils (Fig. 1B) in their BALF after 10 days of repeated allergen
exposure. Although the number of lymphocytes was similar in both +/+
and -/- mice after 5 days of exposure, the number of lymphocytes
increased significantly by 2-fold in +/+ mice, while it remained
unchanged in -/- mice at 10 days of allergen exposure (Fig. 1A). The number of eosinphils was 2-fold higher in +/+
mice compared with -/- mice at both 5 and 10 days of allergen
exposure (Fig. 1B). No differences were observed in the
number of macrophages and neutrophils between +/+ and -/- mice at
these time points (data not shown).
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A). IL-5 levels were
decreased to almost undetectable levels after 7 and 10 days in -/-
mice, while their levels were still elevated after 7 days in +/+ mice
and decreased to background levels after 15 days (Fig. 2B).
IL-13 levels were 4-fold higher in +/+ compared with -/- mice at 5
and 7 days of exposure and decreased to background levels in both
groups at 15 days (Fig. 2C). IFN- was only detected in
-/- mice at 5 days of exposure. In +/+ mice, IFN- levels were at
background levels at 5 and 7 days, but were significantly increased at
10 days of allergen exposure compared with -/- mice (Fig. 2D).
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Despite reduced inflammatory cells in -/- mice, the number of
mucus cells/mm basal lamina was increased from essentially 0 in
nonexposed mice to similarly high levels in both +/+ and -/- mice
after 5 days of allergen exposure (Fig. 3). However, while MCM levels remained
high in +/+ mice after 7 and 10 days of exposure, MCM was significantly
decreased in P-selectin -/- mice at 7 and 10 days of allergen
exposure (Fig. 3). In +/+ mice, MCM did not decline until 15 days of
allergen exposure.
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2 to 21% in +/+ mice and to 34% in
-/- mice (Fig. 4A). A higher
percentage of mucus cells was immunopositive for Bax in P-selectin
-/- compared with +/+ mice at 7 days of exposure; the difference
between P-selectin -/- and +/+ mice was statistically not significant
at 10 and 15 days of allergen exposure (Fig. 4A). We
demonstrated immunospecificity for the Bax protein by inhibition with
the antigenic peptide (Fig. 4, B and C).
Furthermore, Abs raised to two different epitopes of the Bax peptide
(aa 1–24 and 43–61) showed similar immunoreaction in mucus cells
(data not shown). Bcl-2, Bcl-x, and Bak were not detected.
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, D and
E). Bax-negative mucus cells showed no immunostaining with
M30CytoDEATH (data not shown). These observations suggested that
overexpression of Bax in mucus cells was involved in the apoptotic
process through activation of caspases.
IFN- reduces MCM and induces Bax expression in microdissected
airway cultures
We had previously shown that IFN- is essential for the
resolution of MCM during prolonged exposure to allergen
(4). To confirm that IFN- acts directly on airway
epithelial cells through a Bax-mediated pathway, microdissected distal
airways were treated for 7 days with IL-13 only, or IFN- was added
for the last 2 days. The number of mucus cells (Fig. 5A) and the volume density of
mucosubstances (data not shown) per mm basal lamina were increased
significantly when IL-13 was present, but not when IFN- was
added for the last 2 days of culture (Fig. 5A). Furthermore,
immunostaining for Bax was only detected in explants treated with
IFN-, but not in explants treated only with IL-13 (Fig. 5, B and C).
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To test the hypothesis that Bax is important for the decrease of
MCM during prolonged and repeated allergen challenge, we immunized and
challenged Bax +/+ and -/- mice with OVA. Expression of Bax in +/+
and -/- mouse lungs was assessed by Western blotting. The 21-kDa Bax
was absent from the Bax -/- mouse lungs, but was detected in +/+ mice
and further confirmed the specificity of the Ab (Fig. 6A). Although nonchallenged
Bax +/+ and -/- mice had little mucus in airway epithelia, MCM was
increased to similar levels in both +/+ and -/- mice following 5 days
of allergen exposure (data not shown). However, after 15 days, Bax
-/- mice still had elevated MCM compared with +/+ mice (Fig. 6B). Furthermore, eosinophils were present in both Bax +/+
and -/- mice at 5 days of allergen challenge, but were essentially
absent in lung tissues of both +/+ and -/- mice at 15 days of
allergen exposure, indicating that Bax was not essential for the
elimination of eosinophils (Fig. 6C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is increased in the BALF of mice during prolonged exposure to
allergen and mediates cell death in metaplastic mucus cells. The
present study demonstrates that the proapoptotic regulator Bax is an
essential component of this resolution process.
The presence of IL-4 in both P-selectin +/+ and -/- mice at 5, 10,
and 15 days of allergen exposure shows that the production of this Th2
cytokine was not inhibited in these mice even after the coincident
appearance of the Th1 cytokine, IFN-. However, IL-5 and IL-13 were
reduced in -/- mice as early as 7 days of allergen exposure, while
the levels of these cytokines had decreased to background levels in +/+
mice only after 10 days of exposure. Whereas P-selectin -/- mice had
low IL-13 and detectable IFN- levels at 5 days of exposure, it took
10 days of exposure to increase IFN- and decrease IL-13 to
undetectable levels in +/+ mice. Thus, the levels of IL-5 and IFN-
were kinetically altered in P-selectin -/- mice over the exposure
period of 10 days. These data suggest that synthesis of IL-13 and
IFN- is inversely correlated; however, this inverse correlation was
not observed between IL-4 and IFN-.
The simultaneous presence of IL-4, a cytokine produced by Th2 cells,
and IFN-, a cytokine produced by Th1 cells, suggests that Th2 cells
were not eliminated when IFN--producing Th1 cells were present. Low
IL-13 levels as a result of P-selectin deficiency may have been
responsible for the earlier increase of IFN- levels. The presence of
IFN- at 5 days, but not at later time points in P-selectin -/-
mice suggests that only a transient increase in IFN- is sufficient
to reduce MCM.
No differences were observed in MCM at 5 days of allergen exposure in
P-selectin +/+ and -/- mice despite reduced inflammatory cell numbers
and IL-13 levels in -/- compared with +/+ mice. These data suggest
that maximum levels of MCM were reached by the lower levels of IL-13 in
-/- mice, and increased IL-13 levels in +/+ mice did not further
increase MCM. Our previous studies show that instillation of IL-13,
which induces MCM by directly affecting airway epithelial cells
(26, 27, 28), into mice that were exposed to allergen for 5
days does not further increase MCM (4). These observations
suggest that 60–80 mucus cells/mm basal lamina is the maximum number
of mucus cells that the airway epithelium can accommodate, and that
reduced levels of inflammatory responses are sufficient to cause
maximum MCM. The presence of similar levels of IL-4 in both P-selectin
+/+ and -/- mice at 7 and 10 days of allergen exposure when MCM was
reduced in -/- mice further confirms previous reports that IL-4 or
IL-5 is not crucial for the development of MCM (29).
P-selectin -/- mice exhibited significantly lower numbers of
eosinophils and lymphocytes in BALF after sensitization and challenge
with OVA compared with +/+ mice (16). The earlier decrease
of MCM correlates with the earlier increase of IFN- levels in
P-selectin -/- mice and supports our previous finding that IFN-
decreases MCM by inducing programmed cell death in epithelial mucus
cells (4). In addition, the faster decline of MCM in
P-selectin -/- compared with +/+ mice shows that deletion of
P-selectin has a beneficial role in this regard.
Mucus cells from P-selectin +/+ and -/- mice that were exposed to allergen under a different protocol (16) showed Bax expression at percentages similar to those reported in this study, which indicates that our findings are reproducible under various conditions. Although both P-selectin +/+ and -/- mice exhibited only 1–3% of Bax-positive mucus cells after a 5-day exposure to OVA, this percentage was significantly higher in both +/+ and -/- mice after a 7- to 15-day exposure. These data suggested that Bax was involved in the decrease of MCM.
The difference in the percentage of Bax-positive mucus cells between P-selectin -/- and +/+ mice was evident at 7 days of allergen exposure, when MCM was decreased in -/- mice, but persisted until 15 days of exposure in +/+ mice. Although the percentage of Bax-positive mucus cells was increased in +/+ mice at 10 days of allergen exposure, MCM was still elevated in these mice at this time point. This observation suggests that MCM may have decreased in P-selectin +/+ mice at an earlier time point than at 15 days. The detection of caspase activity in these cells and the presence of higher MCM levels in Bax -/- mice compared with +/+ mice after 15 days of allergen exposure further suggest that the resolution of MCM occurs by mechanisms involving Bax.
Results from our previous study show that IFN- induces cell death in
metaplastic mucus cells, as detected by TUNEL positivity
(4). These findings were reconfirmed in the present study
using microdissected airway cultures. Treatment of microdissected
airway tissue cultures with IL-13 induced MCM, and the addition of
IFN- reduced MCM levels and caused expression of Bax in mucus cells.
These observations suggest that IFN- may have reduced MCM by
inducing the proapoptotic Bax, but the mechanisms remain unknown.
Whether IFN- directly causes induction of Bax expression is being
investigated.
We have reported on Bcl-2 expression in metaplastic mucus cells during
the resolution of MCM after a single intratracheal instillation of rats
with LPS (8). Approximately 20–30% of mucus cells
transiently expressed Bcl-2 before MCM was decreased to background
levels 2 days later (8). The facts that Bcl-2 expression
is associated with the appearance of LPS-induced MCM and Bcl-2 is not
detected in allergen-induced MCM in mice suggest that the mechanisms of
resolution in these two experimental systems are different.
Approximately 25–35% of mucus cells expressed Bax after repeated
exposure to allergen for 15 days. Trifilieff et al. (25)
found that by 3-day postallergen exposure, 30% of epithelial cell
nuclei were BrdU positive, a marker for cells that undergo DNA
synthesis during the cell cycle. Taken together, the observed Bax
positivity in 25–35% of mucus cells during the resolution of MCM
may represent cells that must be eliminated to reconstitute the
original cell number of the repaired epithelium. Further studies are
needed to determine whether only newly formed cells express Bax and
undergo apoptosis during resolution of metaplasia or whether
pre-existing cells also undergo apoptosis during this resolution
process.
The lungs of both Bax +/+ and -/- mice were cleared of eosinophils following exposure to allergen for 15 days, indicating that Bax was not essential for reducing eosinophil numbers. This finding agrees with previous reports that eosinophils are cleared by apoptosis through the Fas/Fas ligand-dependent pathway (30). Ochiai et al. (31) have presented evidence in vitro that IL-5 inhibits eosinophil apoptosis by up-regulating Bcl-2 expression.
In summary, our results demonstrate that a reduced inflammatory
response is sufficient to elicit maximum MCM; immune deviation occurs
earlier in P-selectin -/- mice; and Bax is crucial for the resulting
IFN--induced decrease of MCM by causing apoptosis in metaplastic
mucus cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yohannes Tesfaigzi, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, SE, Albuquerque, NM 87108. E-mail address: ytesfaig{at}lrri.org
3 Abbreviations used in this paper: MCM, mucus cell metaplasia; AB, Alcian blue; BALF, bronchoalveolar lavage fluid; DAB, diaminobenzidine; PAS, periodic acid-Schiff.
Received for publication June 19, 2002. Accepted for publication September 6, 2002.
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References |
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but not Fas mediates reduction of allergen-induced mucous cell metaplasia by inducing apoptosis. J. Immunol. 168:4764.
, but not on eosinophils. J. Immunol. 162:6178. (IFN-) inhibits eosinophil apoptosis by up-regulation of bcl-2 expression. Clin. Exp. Immunol. 107:198.[Medline]This article has been cited by other articles:
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  Y. A. Mebratu, B. F. Dickey, C. Evans, and Y. Tesfaigzi The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFN{gamma}-induced cell death J. Cell Biol., November 3, 2008; 183(3): 429 - 439. [Abstract] [Full Text] [PDF]
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 K. Schwalm, J. F. Stevens, Z. Jiang, M. R. Schuyler, R. Schrader, S. H. Randell, F. H. Y. Green, and Y. Tesfaigzi Expression of the proapoptotic protein Bax is reduced in bronchial mucous cells of asthmatic subjects Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1102 - L1109. [Abstract] [Full Text] [PDF]
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 J. Xiang, J. Rir-Sim-Ah, and Y. Tesfaigzi IL-9 and IL-13 Induce Mucous Cell Metaplasia That Is Reduced by IFN-{gamma} in a Bax-Mediated Pathway Am. J. Respir. Cell Mol. Biol., March 1, 2008; 38(3): 310 - 317. [Abstract] [Full Text] [PDF]
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 B. A. Stout, K. Melendez, J. Seagrave, M. J. Holtzman, B. Wilson, J. Xiang, and Y. Tesfaigzi STAT1 Activation Causes Translocation of Bax to the Endoplasmic Reticulum during the Resolution of Airway Mucous Cell Hyperplasia by IFN-{gamma} J. Immunol., June 15, 2007; 178(12): 8107 - 8116. [Abstract] [Full Text] [PDF]
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J. Pierce, J. Rir-Sima-Ah, I. Estrada, J. Wilder, A. Strasser, and Y. Tesfaigzi Loss of pro-apoptotic Bim promotes accumulation of pulmonary T lymphocytes and enhances allergen-induced goblet cell metaplasia Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L862 - L870. [Abstract] [Full Text] [PDF]
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Y. Tesfaigzi Roles of Apoptosis in Airway Epithelia Am. J. Respir. Cell Mol. Biol., May 1, 2006; 34(5): 537 - 547. [Abstract] [Full Text] [PDF]
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 J. F. Harris, M. J. Fischer, J. R. Hotchkiss, B. P. Monia, S. H. Randell, J. R. Harkema, and Y. Tesfaigzi Bcl-2 Sustains Increased Mucous and Epithelial Cell Numbers in Metaplastic Airway Epithelium Am. J. Respir. Crit. Care Med., April 1, 2005; 171(7): 764 - 772. [Abstract] [Full Text] [PDF]
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