| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Department of Pathology,*
University ofMichigan Medical School, Ann Arbor, Michigan; the Laboratory ofMolecular Tumor Biology,
Division of Cellularand Gene Therapies, Center for Biologics Evaluation and Research, Foodand Drug Administration, Bethesda, Maryland; and the Department ofMicrobiology and Immunology,
Walther OncologyCenter, Indiana University School of Medicine, Indianapolis, Indiana
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
Thus, the aim of the present study was to examine the role of Stat6 during chronic allergic airway disease induced by the fungus Aspergillus fumigatus.14 This murine model recapitulates many of the features of clinical fungal asthma including chronic airway inflammation, airway hyperreactivity, and goblet cell hyperplasia.15 In addition, these airway features persist for several weeks in A. fumigatus-sensitized mice that receive a single intrapulmonary challenge with A. fumigatus conidia.16,17 Given that levels of IL-4 and IL-13 are markedly increased during the course of this model14 and both contribute to the development of chronic fungal asthma in mice,18 we examined the role of Stat6 in the airway inflammatory and remodeling events during the development of chronic fungal asthma.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
The generation of Stat6-/- mice has been previously described in detail.5 Stat6-/- were back-crossed 10 generations onto a BALB/c genetic background and were bred as homozygotes in the Indiana University Laboratory Animal Resource Center. Wild-type BALB/c (Stat6+/+) mice were purchased from Harlan Bioproducts (Indianapolis, IN).
A Chronic Model of A. fumigatus-Induced Allergic Asthma
We have previously described a model of chronic allergic airway disease induced by A. fumigatus conidia that is characterized by airway hyperreactivity, lung inflammation, eosinophilia, mucus hypersecretion, goblet cell hyperplasia, and subepithelial fibrosis.14,16,17 Stat6+/+ or Stat6-/- mice were similarly sensitized to a commercially available preparation of soluble A. fumigatus antigens. Seven days after the third intranasal challenge, each mouse received 5.0 x 106 A. fumigatus conidia suspended in 30 µl of PBS Tween 80 (0.1%; v/v) via the intratracheal route.14
To determine the role of IL-4 and IL-13 in the development of fungus-induced allergic airway disease in the absence of Stat6, IL-13-PE38QQR (IL13-PE) was used to target IL-13 receptor-expressing cells. IL13-PE is a recombinant chimeric fusion protein comprised of human IL-13 and a mutated Pseudomonas exotoxin, and it has been previously used to target IL-13 receptor-expressing tumor cells.19,20 Based on preliminary observations, a group of 10 A. fumigatus-sensitized Stat6-/- mice received 200 ng of IL13-PE dissolved in 20 µl of phosphate-buffered saline (PBS) containing 0.25% human serum albumin (HSA-PBS) via an intranasal bolus once daily. IL-13 receptor-positive cells were targeted with IL13-PE from days 37 to 44 after conidia challenge. Another group of ten A. fumigatus-sensitized Stat6-/- mice received 20 µl of IL13-PE vehicle alone once daily via the same route beginning at day 37 and concluding at day 44 after conidia.
Measurement of Bronchial Hyperresponsiveness
Immediately before and at days 21, 30, 38, and 44 after an intratracheal A. fumigatus conidia challenge, bronchial hyperresponsiveness was assessed in a Buxco plethysmograph (Buxco, Troy, NY) as previously described.14 Sodium pentobarbital (Butler Co., Columbus, OH; 0.04 mg/g mouse body weight) was used to anesthetize mice before their intubation and ventilation was carried out with a Harvard pump ventilator (Harvard Apparatus, Reno, NV). Once baseline airway resistance was established, 5 µg of methacholine was introduced into each mouse via a cannulated tail vein, and airway hyperresponsiveness was monitored for approximately 3 minutes. The peak increase in airway resistance was then recorded. After the assessment of airway hyperresponsiveness, approximately 500 µl of blood was removed from each mouse via ocular bleed and centrifuged at 15,000 x g for 10 minutes to yield serum. A bronchoalveolar lavage (BAL) was then performed using 1 ml of filter-sterilized normal saline. Finally, whole lungs were dissected from each mouse and snap frozen in liquid N2 or fixed in 10% formalin for histological analysis (see below).
Morphometric Analysis of Leukocyte Accumulation in BAL Samples
Macrophages, eosinophils, neutrophils, and T cells were quantified in BAL samples cytospun (Shandon Scientific, Runcorn, UK) onto coded microscope slides. Each slide was stained with a Wright-Giemsa differential stain, and the average number of each cell type was determined after counting a total of 300 cells in 10 to 20 high-powered fields (HPF; x1000) per slide. A total of 1 x 106 BAL cells were cytospun onto each slide to compensate for differences in cell retrieval.
ELISA, IgE, and Collagen Analysis
Murine IL-4, IL-13, transforming growth factor-ß (TGF-ß), macrophage chemoattractant protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES), and eotaxin protein levels were determined in 50-µl samples from whole lung homogenates using a standardized sandwich enzyme-linked immunosorbent assay (ELISA) technique previously described in detail.21 Total IgE levels were measured in serum samples using a specific ELISA. All ELISAs were screened to ensure the specificity of each antibody used. Nunc-immuno ELISA plates (MaxiSorp) were coated with the appropriate polyclonal capture antibody (R&D Systems, Minneapolis, MN) at a dilution of 1 to 5 µg/ml coating buffer (in M: 0.6 NaCl; 0.26 H3BO4; 0.08 NaOH; pH 9.6) overnight at 4°C. The unbound capture antibody was washed away, and each plate was blocked with 2% BSA-PBS for 1 hour at 37°C. Each ELISA plate was then washed three times with PBS Tween 20 (0.05%; v/v), and 50 µl of undiluted or diluted (1:10) whole lung homogenate were added to duplicate wells and incubated for 1 hour at 37°C. Following the incubation period, the ELISA plates were thoroughly washed, and the appropriate biotinylated polyclonal detection antibody (3.5 µg/ml) was added. After washing the plates 45 minutes later, streptavidin-peroxidase (1:5000 dilution, Bio-Rad Laboratories, Richmond, CA) was added to each well, incubated for 30 minutes, and then thoroughly washed again. A chromagen substrate solution (Bio-Rad Laboratories) was added, and optical readings at 492 nm were obtained using an ELISA plate scanner. Recombinant murine cytokines and chemokines (R&D Systems, Rochester, MN) were used to generate the standard curves from which the sample concentrations were derived. The limit of ELISA detection for each cytokine was consistently above 50 pg/ml. The Sircol collagen assay (Biocolor Ltd., Belfast, Ireland) was used to measure the soluble forms of collagen present in the same lung homogenates. This assay was developed from the Sirius Red-based histochemical procedure. The cytokine and collagen levels in each sample were normalized to total protein levels measured using the Bradford assay.
Whole Lung Histological Analysis
Whole lungs from A. fumigatus-sensitized Stat6+/+ and Stat6-/- mice before and at various times after A. fumigatus conidia challenge were fully inflated with 10% formalin, dissected, and placed in fresh 10% formalin for 24 hours. Routine histological techniques were used to embed the entire lung with paraffin, and 5-µm sections of whole lung were stained with periodic acid-Schiff reagent (PAS) or Masson trichrome. Morphological evaluations of inflammatory infiltrates and structural alterations were determined around blood vessels and airways using light microscopy at a magnification of x1000.
Statistical Analysis
All results are expressed as means ± SEM (SE). A Student’s t-test or analysis of variance and a Student-Newman-Keuls Multiple Comparison test were used to determine statistical significance between Stat6+/+ and Stat6-/- mice at various times after the conidia challenge; P < 0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Consistent with previous studies, Stat6-/- mice failed to show
the generation of serum IgE at any time in the chronic fungal model.
Total IgE levels in Stat6+/+ mice exceeded 5 µg/ml serum at days 21
to 44 after conidia, whereas total IgE levels in Stat6-/- mice were
below the limit of ELISA detection at these same times (data not
shown). Pronounced goblet cell hyperplasia and peribronchial
inflammation are characteristically found in the airways following the
induction of fungus-induced asthma.14
PAS staining of
whole lung sections from A. fumigatus-sensitized Stat6+/+
mice revealed a significant increase in goblet cells and mucus, as
indicated by magenta staining 30 (A), 38 (C), and 44 (E) days after
conidia challenge (Figure 1,A, C, and E)
.
Major accumulations of leukocytes around these airways were also
observed at all time points (Figure 1, A, C, and E)
. Compared with the
Stat6+/+ group, little mucus and minor peribronchial
accumulations of leukocytes were detected in the lungs of Stat6-/-
mice at 30, 38, or 44 days after conidia challenge in A.
fumigatus-sensitized mice (Figure 1, B, D and F)
. This data
suggested that goblet cell hyperplasia and peribronchial inflammation
during chronic fungal asthma is Stat6-dependent.
|
Previous in vitro studies have shown that Stat6
activation is required for the generation of the CC chemokine eotaxin
by airway epithelial cells22
and endothelial
cells.23
Other studies have shown that the synthesis of CC
chemokines such as macrophage-derived chemokine and T cell activation
gene-3 by primary Th2 cells in culture is also dependent on
Stat6.24
To determine whether Stat6 deficiency affected
the lung levels of eotaxin and other pro-allergic CC chemokines such as
MCP-1 and RANTES during chronic fungal asthma, whole lung samples from
Stat6+/+ and Stat6-/- mice were analyzed at days 21, 30, 38, and 44
after the conidia challenge. As shown in Figure 2
, whole lung levels of MCP-1, RANTES,
and eotaxin were significantly decreased in Stat6-/- mice compared
with Stat6+/+ mice at nearly all times examined after the conidia
challenge. One exception to this trend was noted at day 30 after the
conidia challenge when whole lung levels of eotaxin did not differ
between the two groups of mice (Figure 2C)
. Furthermore, it is
important to note that significantly higher levels of all three CC
chemokines were present in the lungs of Stat6-/- mice at days 30 to
44 after conidia compared with whole lung levels of these chemokines
measured in the day 21 group of Stat6-/- mice. These findings
suggested that Stat6 was necessary, in part, for the full expression of
MCP-1, eotaxin, and RANTES during chronic fungal asthma.
|
Airway hyperresponsiveness is a persistent and complicating
feature of fungus-induced asthma.15
Stat6+/+ mice
sensitized to A. fumigatus antigen exhibited significantly
elevated airway hyperresponsiveness in response to methacholine 21 days
after conidia challenge compared with airway responses to methacholine
measured in these mice before the conidia challenge (Figure 3)
. Furthermore, airway
hyperresponsiveness remained significantly elevated in Stat6+/+ mice at
days 30, 38, and 44 after the conidia challenge. In contrast,
Stat6-/- mice exhibited significantly less airway hyperresponsiveness
at day 21 after the conidia challenge compared with
Stat6+/+ mice at the same time (Figure 3)
. However,
Stat6-/- mice exhibited airway hyperresponsiveness similar to
that measured in Stat6+/+ mice at days 30, 38, and 44 after conidia
(Figure 3)
. Thus, these data suggested that airway hyperresponsiveness
ultimately manifests in Stat6-/- mice during chronic fungal asthma.
|
The infiltration of eosinophils and lymphocytes into the airways
has been shown to play a key role in the development of allergic airway
disease.25
Given that airway hyperresponsiveness and
peribronchial fibrosis were present at day 30, but not at day 21 after
conidia in Stat6-/- mice, we next examined whether the appearance of
these features of allergic disease was associated with increased
leukocyte numbers in the BAL. No significant differences in eosinophil,
neutrophil, or macrophage numbers were measured between Stat6+/+ or
Stat6-/- mice at any time after conidia (data not shown). At day 21
after the conidia challenge in A. fumigatus-sensitized
Stat6+/+ mice, approximately 50% of the cells in the BAL were T cells
(Figure 4)
, whereas T cells comprised
less than 1% of the cells in the BAL from Stat6-/- mice at this
time. However, at day 30 after the conidia challenge, T cells were
prominent in the BAL from both Stat6+/+ and Stat6-/- mice, comprising
greater than 20% of the total cells in the BAL (Figure 4)
. Thus, these
findings suggest that the appearance of airway hyperresponsiveness in
Stat6-/- mice subsequent to day 30 after conidia may be related to
the augmented recruitment of T cells into the airways of these mice.
|
Previous studies have demonstrated a role for Stat6 in the
development of granulomas and collagen deposition;26
therefore, we investigated the role of Stat6 in the development of
peribronchial fibrosis following the induction of chronic fungal
asthma. Total collagen levels measured in whole lung homogenates were
significantly attenuated in Stat6-/- mice compared to Stat6+/+ mice
21 days after conidia challenge. However, total collagen levels in the
lungs of Stat6-/- mice were markedly increased at later time points
after conidia challenge. No significant differences in collagen levels
were detected between Stat6+/+ and Stat6-/- mice 30, 38, or 44 days
after conidia challenge in A. fumigatus-sensitized mice
(Figure 5A)
. Histological analysis of
whole lung sections taken from Stat6+/+ and Stat6-/- mice at 30, 38,
and 44 days after conidia challenge confirmed these findings (not
shown). At day 30 after conidia, the increase in total collagen in
whole lung samples from Stat6-/- mice coincided with a significant
increase in levels of the profibrotic cytokine, TGF-ß (Figure 5B)
.
Thus, the appearance of peribronchial fibrosis was delayed in
Stat6-/- mice compared with Stat6+/+ mice, and changes in total lung
collagen in the former group coincided with an increase in lung levels
of TGF-ß.
|
To determine whether the absence of Stat6 during chronic fungal
asthma influenced levels of Th2 cytokines such as IL-4 and IL-13, whole
lung levels of both cytokines were measured at days 21, 30, 38, and 44
after the conidia challenge in A. fumigatus-sensitized
Stat6+/+ and Stat6-/- mice. Whole lung IL-4 protein levels are shown
in Figure 6A
. It was evident that IL-4
levels increased in a time-dependent manner in both groups. At days 21
and 30 after conidia, IL-4 levels in Stat6-/- mice were significantly
lower than levels measured in Stat6+/+ at the same time points.
However, at days 38 and 44, whole lung IL-4 levels were comparable in
both groups (Figure 6A)
. Whole lung IL-13 levels are shown in Figure 6B
. The greatest levels of IL-13 in Stat6+/+ mice were detected at day
30 after conidia. Whole lung IL-13 levels in Stat6-/- mice were
significantly lower than levels measured in their wild-type
counterparts at the day 21 following the conidia challenge. However, at
all subsequent times examined, IL-13 levels were similar in the two
groups (Figure 6B)
.
|
IL-13 and IL-4 have key roles in the development of airway
hyperresponsiveness in this model of fungus-induced allergic airway
disease.18
We recently began to examine the therapeutic
effect of IL13-PE, a fusion protein that targets and kills IL-4- and
IL-13-responsive cells,19,20
in this chronic fungal asthma
model. Our preliminary findings show that IL13-PE reverses all of the
airway features of chronic fungal asthma when administered from day 14
to 28 after the conidia challenge. In the present study, Stat6-/-
mice were treated for seven consecutive days with IL13-PE, and airway
hyperresponsiveness following methacholine was determined 44 days after
conidia challenge. Airway hyperresponsiveness in Stat6-/- mice
treated with vehicle increased significantly after methacholine
administration (3.8 ± 0.1 to 19.6 ± 4.1 cm
H2O/ml/s; Figure 7
). In contrast, mice treated with
IL13-PE exhibited no significant increase in airway hyperresponsiveness
from basal levels after methacholine administration (Figure 7)
. The
IL13-PE treatment also completely abolished the presence of T cells,
eosinophils, and neutrophils present in BAL samples from Stat6-/-
mice at day 44 after conidia (Figure 8)
.
|
|
. Essentially, IL13-PE therapy from
days 38 to 44 after conidia did not reverse the peribronchial fibrosis
evident at day 44 after conidia (Figure 9)
. These data suggest that the
development of airway hyperresponsiveness, but not peribronchial
fibrosis, in Stat6-/- mice is dependent on IL-13 receptor-expressing
cells.
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Stat6 appeared to modulate a number of features of chronic fungal
asthma regardless of when these parameters were analyzed. First, the
present study confirmed previous
observations9
12
that serum IgE generation and
goblet cell hyperplasia during allergic airway disease unequivocally
require Stat6 signaling. Mucus overproduction and goblet cell
hyperplasia are characteristic of the remodeled asthmatic
airway,30
and the appearance of goblet cells in the
airways is a Th2-mediated response.31,32
Second, the
intensity of allergic airway inflammation was markedly diminished in
Stat6-/- mice compared with their wild-type counterparts. Although it
was noted that T cell accumulation in the airways of allergic
Stat6-/- mice did progressively increase during the course of fungal
asthma, the lymphocyte counts in the BAL of Stat6-/- mice remained
considerably lower than similar counts in BALs from Stat6+/+ mice.
These finding were consistent with those of Trifilieff et
al13
who demonstrated that the airway inflammatory
response was only partially mediated by Stat6 in the context of a
chronic OVA challenge. Third, it was observed that Stat6 deficiency
significantly attenuated the levels of major pro-allergic CC chemokines
such as MCP-1, RANTES, and eotaxin.33
These findings are
consistent with results showing that Stat6 was necessary for TNF-
and IL-4 to promote eotaxin gene expression in human airway epithelial
cells22
and for IL-13 to induce MCP-1 in endothelial
cells.23
Our finding that RANTES/CCL5 was also decreased
in Stat6-/- mice during chronic fungal asthma was novel; previous
studies suggested that this chemokine was a product of Th1
cells.24
The present study demonstrated that a number of
major characteristics of chronic fungal asthma in Stat6+/+ mice were
absent or diminished in Stat6-/- mice at all times after conidia
challenge.
Persistent airway hyperresponsiveness and airway remodeling due to excessive collagen deposition and subepithelial fibrosis characterize fungus-induced asthma.14 In light of previous studies showing that OVA-sensitized and -challenged Stat6-/- mice remained hyporesponsive to a methacholine challenge,9,10,13 the delayed appearance of methacholine-induced airway hyperresponsiveness in Stat6-/- mice during chronic fungal asthma was a novel and surprising finding from the present study. Additionally, the development of pulmonary fibrosis was unique to the present study, as it had been previously reported that Stat6-/- mice failed to develop pulmonary and hepatic fibrosis in the context of granuloma formation induced by Schistosoma mansoni eggs.26 Airway hyperresponsiveness and peribronchial fibrosis were significantly reduced at day 21 after conidia challenge in Stat6-/- mice compared with their wild-type controls, but at all subsequent times after conidia, Stat6-/- mice exhibited vigorous methacholine-induced bronchoconstriction and peribronchial fibrosis comparable to Stat6+/+ mice. Furthermore, the appearance of peribronchial fibrosis at day 30 in the Stat6-/- mice was associated with a significant increase in whole lung levels of the profibrotic cytokine, TGF-ß. The discrepancy between our findings and those of previous investigators may be linked to the manner in which Stat6-/- mice were sensitized and challenged with allergen, the genetic background of the Stat6-/- mice examined (ie, BALB/c versus C57BL/6), and/or the duration over which the features of allergic airway disease was monitored.
Biological Th2 responses elicited by IL-4 and IL-13 binding to their appropriate receptors involves a complex array of signaling pathways and regulators of which Stat6 appears to be the major contributor.34 The lack of Th2 responses in Stat6-/- mice during acute allergic airway disease was consistent with initial in vitro studies demonstrating the Stat6 requirement for IL-4-induced Th2 cell differentiation and immunoglobulin class switching to IgE.5 However, more recently, it was shown that NK T cells, which do not require IL-4 for maturation, produce IL-4 in the absence of Stat6.35 In the present study, Stat6-independent pathways were activated leading to the appearance of airway hyperresponsiveness and peribronchial fibrosis at time points after day 21 post conidia. Although these alternative pathways were not specifically examined in the present study, it is probable that cell-signaling pathways involving Stat336 and/or phosphatidylinositol 3-kinase37 compensated for the absence of Stat6 at days 30 to 44 after the conidia challenge. Furthermore, Th2-mediated inflammatory disease progressed in the absence of Stat6 and IL-4 when the transcriptional repressor that shares DNA-binding motifs with Stats, Bcl-6, was deleted from mice.38 Thus, the ultimate development of airway disease in A. fumigatus-sensitized Stat6-/- mice after an A. fumigatus conidia challenge presumably reflects the fact that other cell signaling pathways are activated in the chronic stages of this model. Presently, it is not apparent which cell signal pathway compensates for the lack of Stat6 during chronic fungal asthma, but this question is the focus of ongoing investigations.
The time-dependent increases in whole lung levels of IL-4 and IL-13 in Stat6-/- mice relative to Stat6+/+ mice appeared to correlate with the advent of airway hyperresponsiveness and peribronchial fibrosis in Stat6-/- mice. T cells were presumably the source of IL-4 and IL-13 since increased levels of both cytokines correlated with an increased accumulation of lymphocytes in the airways of Stat6-/- mice at days 30 to 44 after the conidia challenge. Previous experimental evidence from this chronic fungal asthma model strongly suggested that IL-13-responsive T cells were the major effectors in this chronic fungal asthma model.18 Therefore, we investigated whether the targeting of IL-13-responsive cells with IL13-PE, a chimeric protein consisting of IL-13 and Pseudomonas exotoxin, would reverse the Stat6-independent features of the chronic asthma model. Accordingly, Stat6-/- mice were treated daily with IL13-PE from days 38 to 44 after the conidia challenge, and airway hyperresponsiveness and peribronchial fibrosis were examined at day 44 after conidia. The IL13-PE treatment abolished the presence of T cells, eosinophils, and neutrophils in the BAL and significantly reduced the airway hyperresponsiveness to methacholine in Stat6-/- mice. However, the IL13-PE treatment did not appear to have an effect on the peribronchial fibrosis manifest in Stat6-/- mice at day 44 after the conidia challenge. These data differ from our previous findings that showed IL13-PE treatment from days 14 to 28 after the conidia challenge in A. fumigatus-sensitized CBA/J mice prevented the appearance of peribronchial fibrosis at day 28. The discrepancy between the previous findings and those from the present study may be related to the fact that IL13-PE therapy is necessary during the time of fibroblast activation and matrix deposition. It appears that the peribronchial fibrotic process is complete in Stat6-/- mice by day 38 after the conidia challenge and is consequently impervious to IL13-PE therapy. Thus, the Stat6-independent events leading to airway inflammation and hyperresponsiveness in Stat6-/- mice were dependent on the presence of lung cells that responded to IL-13.
In conclusion, while IL-4 and IL-13 have been shown to be central mediators in the development of fungus-induced asthma, the role of Stat6-mediated signaling had not been previously investigated during the course of this disease. The data presented herein demonstrate that Stat6 was absolutely required for goblet cell hyperplasia but other features of chronic fungal asthma including airway inflammation, airway hyperresponsiveness, and peribronchial fibrosis could develop in the absence of Stat6. However, all Stat6-independent events required IL-13 since the depletion of IL-13-responsive cells in the lung reversed many prominent features of chronic fungal asthma in Stat6-/- mice. The IL13-PE treatment strategy obviates the need to target multiple signal transduction pathways involved in the Th2 responses leading to chronic fungal asthma. Furthermore, these findings suggest that the prolonged targeting of Stat6 in the context of allergic or asthmatic airway disease may provide diminishing therapeutic effects.
|
Footnotes |
|---|
Supported by National Institutes of Health grants 1P50HL60289, HL35276, and P01-HL31963.
Accepted for publication October 17, 2001.
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  T. X. Lu, A. Munitz, and M. E. Rothenberg MicroRNA-21 Is Up-Regulated in Allergic Airway Inflammation and Regulates IL-12p35 Expression J. Immunol., April 15, 2009; 182(8): 4994 - 5002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Murray, D. A. Knight, L. McAlonan, R. Argentieri, A. Joshi, F. Shaheen, M. Cunningham, L. Alexopolou, R. A. Flavell, R. T. Sarisky, et al. Deleterious Role of TLR3 during Hyperoxia-induced Acute Lung Injury Am. J. Respir. Crit. Care Med., December 15, 2008; 178(12): 1227 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Moynihan, B. Tolloczko, M.-C. Michoud, M. Tamaoka, P. Ferraro, and J. G. Martin MAP kinases mediate interleukin-13 effects on calcium signaling in human airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L171 - L177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Fattouh, N. G. Midence, K. Arias, J. R. Johnson, T. D. Walker, S. Goncharova, K. P. Souza, R. C. Gregory Jr., S. Lonning, J. Gauldie, et al. Transforming Growth Factor-{beta} Regulates House Dust Mite-induced Allergic Airway Inflammation but Not Airway Remodeling Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 593 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Chapoval, A. Al-Garawi, J. M. Lora, I. Strickland, B. Ma, P. J. Lee, R. J. Homer, S. Ghosh, A. J. Coyle, and J. A. Elias Inhibition of NF-{kappa}B Activation Reduces the Tissue Effects of Transgenic IL-13 J. Immunol., November 15, 2007; 179(10): 7030 - 7041. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mishra, M. Wang, J. Schlotman, N. M. Nikolaidis, C. W. DeBrosse, M. L. Karow, and M. E. Rothenberg Resistin-like molecule-beta is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L305 - L313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Maeda, V. Dave, and J. A. Whitsett Transcriptional Control of Lung Morphogenesis Physiol Rev, January 1, 2007; 87(1): 219 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P. Kurup, R. Raju, and P. Manickam Profile of Gene Expression in a Murine Model of Allergic Bronchopulmonary Aspergillosis Infect. Immun., July 1, 2005; 73(7): 4381 - 4384. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Fish, D. D. Donaldson, S. J. Goldman, C. M. M. Williams, and M. T. Kasaian IgE Generation and Mast Cell Effector Function in Mice Deficient in IL-4 and IL-13 J. Immunol., June 15, 2005; 174(12): 7716 - 7724. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Zimmermann, M. P. Doepker, D. P. Witte, K. F. Stringer, P. C. Fulkerson, S. M. Pope, E. B. Brandt, A. Mishra, N. E. King, N. M. Nikolaidis, et al. Expression and Regulation of Small Proline-Rich Protein 2 in Allergic Inflammation Am. J. Respir. Cell Mol. Biol., May 1, 2005; 32(5): 428 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Takatori, H. Nakajima, K. Hirose, S.-i. Kagami, T. Tamachi, A. Suto, K. Suzuki, Y. Saito, and I. Iwamoto Indispensable Role of Stat5a in Stat6-Independent Th2 Cell Differentiation and Allergic Airway Inflammation J. Immunol., March 15, 2005; 174(6): 3734 - 3740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Burdick, L. A. Murray, M. P. Keane, Y. Y. Xue, D. A. Zisman, J. A. Belperio, and R. M. Strieter CXCL11 Attenuates Bleomycin-induced Pulmonary Fibrosis via Inhibition of Vascular Remodeling Am. J. Respir. Crit. Care Med., February 1, 2005; 171(3): 261 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. K. Kumar, C. Herbert, D. C. Webb, L. Li, and P. S. Foster Effects of Anticytokine Therapy in a Mouse Model of Chronic Asthma Am. J. Respir. Crit. Care Med., November 15, 2004; 170(10): 1043 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Liu, H. Jin, M. Ullenbruch, B. Hu, N. Hashimoto, B. Moore, A. McKenzie, N. W. Lukacs, and S. H. Phan Regulation of Found in Inflammatory Zone 1 Expression in Bleomycin-Induced Lung Fibrosis: Role of IL-4/IL-13 and Mediation via STAT-6 J. Immunol., September 1, 2004; 173(5): 3425 - 3431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Zimmermann, A. Mishra, N. E. King, P. C. Fulkerson, M. P. Doepker, N. M. Nikolaidis, L. E. Kindinger, E. A. Moulton, B. J. Aronow, and M. E. Rothenberg Transcript Signatures in Experimental Asthma: Identification of STAT6-Dependent and -Independent Pathways J. Immunol., February 1, 2004; 172(3): 1815 - 1824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. M. Nikolaidis, N. Zimmermann, N. E. King, A. Mishra, S. M. Pope, F. D. Finkelman, and M. E. Rothenberg Trefoil Factor-2 Is an Allergen-Induced Gene Regulated by Th2 Cytokines and STAT6 in the Lung Am. J. Respir. Cell Mol. Biol., October 1, 2003; 29(4): 458 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jakubzick, E. S. Choi, B. H. Joshi, M. P. Keane, S. L. Kunkel, R. K. Puri, and C. M. Hogaboam Therapeutic Attenuation of Pulmonary Fibrosis Via Targeting of IL-4- and IL-13-Responsive Cells J. Immunol., September 1, 2003; 171(5): 2684 - 2693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Jakubzick, E. S. Choi, S. L. Kunkel, B. H. Joshi, R. K. Puri, and C. M. Hogaboam Impact of Interleukin-13 Responsiveness on the Synthetic and Proliferative Properties of Th1- and Th2-Type Pulmonary Granuloma Fibroblasts Am. J. Pathol., May 1, 2003; 162(5): 1475 - 1486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jakubzick, S. L. Kunkel, B. H. Joshi, R. K. Puri, and C. M. Hogaboam Interleukin-13 Fusion Cytotoxin Arrests Schistosoma mansoni Egg-Induced Pulmonary Granuloma Formation in Mice Am. J. Pathol., October 1, 2002; 161(4): 1283 - 1297. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
0.01 compared with lymphocyte numbers counted
in the Stat6+/+ mice at day 21 after conidia. #, P
< 0.05 demonstrates a significant difference in lymphocyte numbers
between Stat6-/- mice at days 21 and 30 after conidia.
