1 Combined Program in Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston 02115; and 2 Wyeth-Genetics Institute, Cambridge, Massachusetts 02140
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ABSTRACT |
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Levels of interleukin (IL)-13 are
increased in asthmatic airways. IL-13 has been shown to be necessary
and sufficient for allergen-induced airway hyperresponsiveness and
increased inflammatory cell counts in bronchoalveolar lavage (BAL)
fluid in a murine model of asthma but is thought to protect against
airway inflammation when low doses are provided to the guinea pig lung.
To determine the role of IL-13 in the guinea pig, we studied the
effects of a 360-µg/kg dose of nebulized IL-13 in naive animals and
of IL-13 abrogation after airway challenge of sensitized animals.
Nebulized IL-13 significantly decreased the dose of histamine required
to double baseline respiratory system resistance
(ED100, 22 ± 3 vs. 13 ± 2 nmol/kg;
P < 0.05) and was associated with recovery of significantly greater numbers of macrophages, lymphocytes, eosinophils, and neutrophils in BAL fluid. Guinea pigs pretreated with a fusion protein that binds IL-13 [soluble IL-13 receptor 2 (sIL-13R
2)] were protected from developing antigen-induced airway
hyperresponsiveness (ED100, 210 ± 50 vs. 20 ± 10 nmol/kg; P <0.01). sIL-13R
2 (2 doses of 20 mg/kg) significantly reduced the histological grade of allergen-induced lung eosinophil accumulation, whereas the effects of two doses of 10 mg/kg were not significant. These findings demonstrate that the tissue
levels of IL-13 induced by allergen challenge of sensitized animals
induce airway hyperresponsiveness and inflammation and that IL-13 is
required for the expression of allergen-induced airway
hyperresponsiveness in the guinea pig ovalbumin model.
interleukin-13; eosinophil; inflammation; airway hyperresponsiveness; ovalbumin
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INTRODUCTION |
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IN THE PAST DECADE, ASTHMA has been increasing in prevalence and is now thought to affect 15 million Americans (13). Advances have been made in our understanding of the immunobiology of sensitization (1); the role of interleukin (IL)-4, IL-5, and IL-13 in the development of airway hyperresponsiveness; the recruitment of inflammatory cells to the airway; and the augmented mucus production that follows allergen challenge in a murine system. Strong circumstantial evidence indicates that Th2 lymphocytes and the cytokines they produce are important in the pathogenesis of asthma (3, 5, 6, 10-12, 20, 26).
In the mouse, Th2 lymphocytes selectively develop and expand in a
process that depends on IL-4 (1, 5). Studies comparing allergen-induced airway hyperresponsiveness in genetically altered receptor- or ligand-deficient mice have demonstrated a greater dependence on the IL-4 receptor -chain than on IL-4 (2,
14). In addition to the IL-4 avid form of the heterodimeric
receptor (IL-4 receptor
-chain/common
-chain), the IL-4 receptor
-chain can combine with IL-13 receptor
1 and efficiently bind
IL-13 (9, 12, 24); this realization in murine biology led
to speculation that IL-13 was the mediator responsible for
allergen-induced pulmonary inflammatory cell recruitment and airway
hyperresponsiveness in the mouse model (2). The
availability of the fusion protein soluble sIL-13 receptor
2
(sIL-13R
2), which selectively limits the ability of murine IL-13 to
reach its receptor (8), allowed for differentiation of the
role of IL-13 from that of IL-4. In the murine system, IL-4 appears to
be critical for the selection and development of Th2 lymphocytes, but
its abrogation after sensitization has little effect on the development
of airway hyperresponsiveness and cellular recruitment after allergen
challenge (5, 7). In contrast, IL-13 appears to be
necessary for the induction of airway hyperresponsiveness after
allergen challenge and sufficient to induce it in the absence of
sensitization (14, 29). Although it is increasingly clear
that Th2 lymphocytes and their products play a pivotal role in allergy
immunogenesis in the mouse (1), a dominant role is less
well established in other species such as the guinea pig, where IL-13
has been reported to have a protective role in allergic inflammation.
In this study, we explore the effects of murine IL-13 and sIL-13R
2
on airway hyperresponsiveness and cellular recruitment in
allergen-challenged sensitized guinea pigs.
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METHODS |
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Tracheal Administration of Murine IL-13
Twenty-one guinea pigs (414-428 g) were anesthetized by intraperitoneal injection of ketamine (60 mg/kg) and xylazine (7 mg/kg) and were placed in the supine position. The trachea was cannulated with PE-240 polyethylene tubing (Intramedic, Becton-Dickinson, Parsippany, NJ), and 50 µl (360 µg/kg) of recombinant murine IL-13 or its diluent was nebulized into the trachea via a syringe nebulizer by a method similar to that which we used to study the effects of IL-5 (18) (Penn-Century, Philadelphia, PA); after injection, the tracheal cannula was removed, and the guinea pig was returned to the animal facility after recovery. Twenty-four hours later, contractile agonist responsiveness was measured by body plethysmography, and cells in bronchoalveolar lavage (BAL) fluid were enumerated as described below. The concentration of endotoxin in the preparation of IL-13 was measured at <2 eU/mg with a commercially available kit used according to the manufacturer's instructions (Cape Cod, LAL assay).Administration of sIL-13R2
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Sensitization Protocol
Antigen sensitization was accomplished with minor modifications of the repetitive ovalbumin exposure protocol that we have described previously (19, 22, 23, 27). Thirty male Hartley guinea pigs (300-350 g) were pretreated with 10 mg of pyrilamine maleate/kg ip and sensitized by exposure to aerosolized antigen [7% (wt/vol) ovalbumin in 0.9% sterile PBS, pH 7.4]; the aerosol exposure chamber exposed six animals simultaneously to a single aerosolized stream. Each animal had its snout fixed ~15 cm from the point of aerosol entry in a chamber with a volume of 33 l. For nebulization, a Devilbiss Ultra-99 large-volume nebulizer was used (Sunrise Medical, Somerset, PA). After an 8-min exposure period, the chamber was cleared of aerosol by vacuum suction through a filter apparatus, and room air was provided to the animals. Animals were sensitized by aerosol exposure on two occasions at 7-day intervals, challenged with nebulized allergen 14 days after the initial sensitization, and prepared for study 24 h after challenge (day 15). We previously demonstrated that exposure to the antigen-diluent has no significant effect on physiological responses or cell recovery in this model (19).Measurement of Histamine-Induced Contractile Responses
Animal preparation. Guinea pigs were prepared for study by body plethysmography in accordance with our previously described methods (18, 22, 23). In brief, guinea pigs were anesthetized by intraperitoneal injection of ketamine (60 mg/kg) and xylazine (7 mg/kg); a constant level of anesthesia was maintained, with additional doses of ketamine (20 mg/kg) administered at ~30-min intervals. When surgical anesthesia had been achieved, the anterior neck of the animal was shaved and dissected. Vascular access was established via the internal jugular vein, with 0.25/0.12-mm outer diameter/inner diameter silicone tubing (Technical Products, Decatur, GA). The common carotid artery was catheterized with a 24G Teflon catheter (Quick Cath; Baxter Healthcare, Deerfield, IL). Finally, the subglottic trachea was cannulated by anterior tracheotomy with PE-240 polyethylene tubing (Intramedic).
Body plethysmography. Guinea pigs were placed into a constant-mass body plethysmograph connected to a 4-l isothermal reservoir. The animals were ventilated in the supine position with room air by a constant-volume ventilator (Harvard Apparatus, South Natick, MA) at a tidal volume of 10 ml/kg, 60 breaths/min, a positive end expiratory pressure of 2.5 cm H2O, and a fixed inspiratory-to-expiratory time of 1:1. Plethysmograph pressures were measured relative to the pressure in a similar 4-l reservoir across a differential pressure transducer (Celesco, Canoga Park, CA), blood pressure was measured with a pressure transducer (P23Db; Statham Instruments, Oxnard, CA), and transrespiratory pressure was measured with a differential pressure transducer (Celesco) placed between a side tap of the tracheal cannula and the animal chamber of the plethysmograph. Tidal volume, mean arterial pressure (blood pressure), and transpulmonary pressure were monitored and recorded with a data acquisition program (Dataq Instruments, Akron, OH), whereas pulmonary resistance and dynamic compliance and conductance were calculated with GRC4 software (Andrew Jackson, Boston University, Boston, MA). Baseline values for respiratory system resistance (Rbaseline) were measured as the mean over 10 s, and this measurement was repeated after administration of increasing doses of histamine, as described below.
Contractile agonist administration. Baseline measurements of RRS were recorded 5 and 10 min after the initiation of body plethysmography and 5 min before contractile agonist administration. A large-volume breath (three stacked tidal volumes) was given 30 s before each measurement to standardize volume history. Geometrically increasing doses of histamine (1-100 nmol/kg) were administered through the jugular venous catheter at 5-min intervals. The airway contractile responses were assessed by recording changes in RRS for the subsequent 3 min (22, 23). The peak increase in resistance after challenge (Rmax) was divided by the baseline resistance (Rbaseline), multiplied by 100, and recorded as Rmax/Rbaseline. Injection of 100-500 µl of agonist diluent had no effect on the measured physiological parameters.
Histological identification of eosinophils. A carbol chromotrope stain was used to identify guinea pig eosinophils, with an adaptation of the method described by Lendrum (17). This stain is concentrated in the granules of eosinophils due to their avidity for acid dyes and has been shown by several investigators to be specific for eosinophils (15-17, 25). Briefly, paraffin slides were dewaxed in xylenes, rehydrated through graded alcohols, and washed in PBS. The slides were transferred to Mayer's hematoxylin solution for 4 min and then washed in deionized water. Next, they were incubated in acidified alcohol (1% HCL, 70% ETOH) for 2 min, washed in deionized water, incubated in an aqueous solution of 1% wt/vol chromotrope 2R (Sigma, St. Louis, MO) with 5% wt/vol phenol (Sigma) for 20 min, and washed again in deionized water. The slides were then dehydrated, and a coverslip was applied.
Morphometric analysis. The density of eosinophilic infiltration was evaluated by a semiquantitative scale, 0-5+: 0 was defined as the absence of any visible eosinophil staining; 1+ as the presence of a few scattered eosinophils around airways and blood vessels; 2+ as the presence of frequent eosinophil infiltration, with nearly all the eosinophils being identified in a single cell layer surrounding the airways and/or the blood vessels; 3+ as eosinophil infiltration of a moderate density within a band at least 10 µm wide surrounding at least one-third of the airways and blood vessels; 4+ as abundant eosinophil infiltration of most of the airways and blood vessels, but with clear separation of the infiltrates between most of the airways and blood vessels; and 5+ as abundant eosinophil infiltration with lack of separation between the airway and perivascular infiltrates in at least one-quarter of the airways. The individual who determined the histological score was unaware of the treatment status of the animals from which the tissues were derived.
Statistical Methods
Results are expressed as the group mean followed by the SE, unless otherwise specified. The data were tested for normalcy and compared by one-way ANOVA, ANOVA based on ranks, t-test, or Mann-Whitney's rank sum test, as appropriate. Data that met normalcy assumptions are presented as the mean and SE, and those that did not are presented as the median and interquartile range. A P value < 0.05 was considered significant. ![]() |
RESULTS |
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Effects of Exogenous IL-13
Tracheal injection of recombinant murine IL-13 (360 µg/kg) was associated with significant increases in the contractile effects of histamine at doses of 33 nmol/kg (580 ± 80 vs. 320 ± 35% increase in baseline Rresp, P = 0.003) and 100 nmol/kg (1,200 ± 170 vs. 770 ± 110% increase in baseline Rresp, P = 0.04, Fig. 1). The dose of histamine required to double baseline RRS (ED100) was significantly greater in control animals than in IL-13-treated animals (22 ± 3 vs. 13 ± 2 nmol/kg; n = 8 and 13, respectively; P < 0.05). IL-13-induced airway hyperresponsiveness was accompanied by the recovery of significantly more cells from BAL fluid [total cells 120 (56) vs. 10 (7-19), P < 0.0001; macrophages 41 (18-62) vs. 8 (7-15), P = 0.004; eosinophils 9 (5-20) vs. 2 (1-3), P < 0.0001; lymphocytes 3 (1-8) vs. 0.08 (0-0.3), P = 0.01; neutrophils 42 (32-110) vs. 0.05 (0.01-0.1), P < 0.0001; millions of cells, median and interquartile range (Fig. 2)].
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Effects of sIL-13R2 on Antigen-Induced Airway
Hyperresponsiveness
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Effects of sIL-13R2 on Lung Tissue Eosinophil
Recruitment
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DISCUSSION |
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Our findings that IL-13 induces airway hyperresponsiveness and is
required for its expression after allergen challenge in the guinea pig
are consistent with the findings of other investigators in the mouse
model. We found that a single exposure to nebulized murine IL-13
induced a significant increase in airway hyperresponsiveness and was
associated with greater numbers of eosinophils, lymphocytes, neutrophils, and monocytes in BAL fluid 24 h after exposure.
Whereas the tracheal nebulization procedure employed to deliver IL-13 to the lower airways itself increases airway hyperresponsiveness, IL-13
significantly increased responsiveness beyond that of the instillation
procedure alone. In the A/J strain of mice, eosinophils were strikingly
increased 24 h after IL-13 exposure and returned to normal levels
by 96 h, whereas airway responsiveness was normal at 24 h and
increased at 96 h after IL-13 exposure (29). BALB/c mice repeatedly exposed to IL-13 and studied 12-15 h after a third dose demonstrated both airway hyperresponsiveness and increased recovery of inflammatory cells (14). Our findings from
microgram doses of nebulized murine IL-13 contrast with those of Watson et al. (28), who reported the effects of nanogram
quantities of tracheally instilled human IL-13. Watson et al. reported
that tracheal instillation of IL-13 had little effect on BAL eosinophil recovery and was associated with small increases in BAL neutrophil recovery in some experiments. We found that tracheal nebulization of
microgram quantities of IL-13 was associated with a significant increase in BAL eosinophils and a robust increase in neutrophils. It is
not likely that endotoxin contamination could account for these
findings because the levels in our preparations were less than 2 eU/mg.
Watson et al. also reported that nanogram quantities of IL-13,
instilled into the trachea before allergen challenge, limited BAL
eosinophil recovery in sensitized guinea pigs in a dose-dependent
manner. This observation leads to the interesting possibility that
endogenously released IL-13 may protect against allergen-induced
increases in BAL eosinophil recovery. We studied a higher dose of IL-13
and found both increased BAL inflammatory cell recovery and airway
hyperresponsiveness. Although the dose of IL-13 studied was
significantly greater in our study, there are other differences that
could also be important. Different homologues of IL-13 were studied,
and the alternative modes of tracheal delivery could have resulted in
different distributions of IL-13 within the lung. To more directly
determine whether IL-13 is promoting or limiting airway inflammation
and hyperresponsiveness in sensitized and challenged guinea pigs, we
studied lung eosinophil accumulation in the presence of an agent that
binds guinea pig IL-13 and limits its availability at the receptor. The
20-mg/kg dose of sIL-13R2 significantly reduced pulmonary eosinophil
accumulation as judged by direct histological examination of the lung.
This finding suggests that endogenously mobilized IL-13 contributes to
pulmonary eosinophilia after allergen challenge in the guinea pig.
IL-13 also appears to be required for the induction of airway hyperresponsiveness in this model.
The demonstration that higher doses of sIL-13R2 are required to
reduce airway eosinophilia than to eliminate allergen-induced hyperresponsiveness is another indication that the mechanisms responsible for these phenomena are distinct. It is also possible that
the lower dose of sIL-13R
2 may have affected the presence or
distribution of eosinophils in a manner that we were not able to detect
with the semiquantitative method employed. Although our
findings demonstrate that endogenously mobilized IL-13 promotes airway
eosinophilia after allergen challenge in the guinea pig, they do not
exclude a protective role for exogenous IL-13 in some circumstances.
We found that both doses of sIL-13R2 prevented allergen-induced
airway hyperresponsiveness when given 2 and 24 h before challenge. Pretreatment at 2 and 24 h before challenge appears to be
required; treatment 2 h before challenge did not prevent
allergen-induced hyperresponsiveness. This requirement for pretreatment
may reflect a long time constant for penetration into airway smooth
muscle, but this seems unlikely based on the known ability of
therapeutic immunoglobulins to rapidly penetrate the guinea pig airway
(21). Reasonable explanations for the necessity of
pretreatment include a direct time-dependent "priming" effect of
IL-13 or indirect effects that are dependent on the synthesis of other
mediators with prolonged effects. These findings are similar to those
reported in murine models where sIL-13R
2 is dosed before allergen
challenge (14, 29). The main finding of our studies is
that abrogation of IL-13 activity with sIL-13R
2 is a highly
effective strategy for limiting allergen-induced airway
hyperresponsiveness in the guinea pig.
Our data indicate that IL-13 can induce airway hyperresponsiveness and inflammation in the guinea pig. It is required for the expression of allergen-induced airway hyperresponsiveness and contributes to, rather than inhibits, airway eosinophilia in allergen-challenged guinea pigs. Our findings are consistent with those obtained in murine models and suggest that effective treatment with agents that abrogate IL-13 receptor activation should be administered in advance of allergen challenge.
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ACKNOWLEDGEMENTS |
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This study was supported by Genetics Institute and by National Institutes of Health Grants RO1 HL/AI-64104 and KO8 HL-67910. We are grateful to Stephen Mulholland for his technical assistance in performing the IL-13 binding studies.
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. M. Lilly, Respiratory Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115 (E-mail: clilly{at}partners.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajplung.00296.2001
Received 31 July 2001; accepted in final form 28 September 2001.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abbas, AK,
Murphy KM,
and
Sher A.
Functional diversity of helper T lymphocytes.
Nature
383:
787-793,
1996[ISI][Medline].
2.
Barner, M,
Mohrs M,
Brombacher F,
and
Kopf M.
Differences between IL-4R alpha-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses.
Curr Biol
8:
669-672,
1998[ISI][Medline].
3.
Brusselle, G,
Kips J,
Joos G,
Bluethmann H,
and
Pauwels R.
Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice.
Am J Respir Cell Mol Biol
12:
254-259,
1995[Abstract].
4.
Chiaramonte, MG,
Cheever AW,
Malley JD,
Donaldson DD,
and
Wynn TA.
Studies of murine schistosomiasis reveal interleukin-13 blockade as a treatment for established and progressive liver fibrosis.
Hepatology
34:
273-282,
2001[ISI][Medline].
5.
Corry, DB,
Folkesson HG,
Warnock ML,
Erle DJ,
Matthay MA,
Wiener-Kronish JP,
and
Locksley RM.
Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity.
J Exp Med
183:
109-117,
1996[Abstract].
6.
Corry, DB,
Grunig G,
Hadeiba H,
Kurup VP,
Warnock ML,
Sheppard D,
Rennick DM,
and
Locksley RM.
Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice.
Mol Med
4:
344-355,
1998[ISI][Medline].
7.
Coyle, AJ,
Le Gros G,
Bertrand C,
Tsuyuki S,
Heusser CH,
Kopf M,
and
Anderson GP.
Interleukin-4 is required for the induction of lung Th2 mucosal immunity.
Am J Respir Cell Mol Biol
13:
54-59,
1995[Abstract].
8.
Donaldson, DD,
Whitters MJ,
Fitz LJ,
Neben TY,
Finnerty H,
Henderson SL,
O'Hara RMJ,
Beier DR,
Turner KJ,
Wood CR,
and
Collins M.
The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1.
J Immunol
161:
2317-2324,
1998
9.
Feng, N,
Lugli SM,
Schnyder B,
Gauchat JF,
Graber P,
Schlagenhauf E,
Schnarr B,
Wiederkehr-Adam M,
Duschl A,
Heim MH,
Lutz RA,
and
Moser R.
The interleukin-4/interleukin-13 receptor of human synovial fibroblasts: overexpression of the nonsignaling interleukin-13 receptor alpha2.
Lab Invest
78:
591-602,
1998[ISI][Medline].
10.
Foster, PS,
Hogan SP,
Ramsay AJ,
Matthaei KI,
and
Young IG.
Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model.
J Exp Med
183:
195-201,
1996[Abstract].
11.
Garssen, J,
Nijkamp FP,
Vandervliet H,
and
Vanloveren H.
T-cell-mediated induction of airway hyperreactivity in mice.
Am Rev Respir Dis
144:
931-938,
1991[ISI][Medline].
12.
Gavett, SH,
Chen X,
Finkelman F,
and
Wills-Karp M.
Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia.
Am J Respir Cell Mol Biol
10:
587-593,
1994[Abstract].
13.
Grant, EN,
Wagner R,
and
Weiss KB.
Observations on emerging patterns of asthma in our society.
J Allergy Clin Immunol
104:
S1-S9,
1999[ISI][Medline].
14.
Grunig, G,
Warnock M,
Wakil AE,
Venkayya R,
Brombacher F,
Rennick DM,
Sheppard D,
Mohrs M,
Donaldson DD,
Locksley RM,
and
Corry DB.
Requirement for IL-13 independently of IL-4 in experimental asthma.
Science
282:
2261-2263,
1998
15.
Hakansson, L,
Westerlund D,
and
Venge P.
New method for the measurement of eosinophil migration.
J Leukoc Biol
42:
689-696,
1987[Abstract].
16.
Lea, RG,
Stewart F,
Allen WR,
Ohno I,
and
Clark DA.
Accumulation of chromotrope 2R positive cells in equine endometrium during early pregnancy and expression of transforming growth factor-beta 2 (TGF-beta 2).
J Reprod Fertil
103:
339-347,
1995[Abstract].
17.
Lendrum, AC.
The staining of eosinophil polymorphs and enterochromaffin cells in histological sections.
J Pathol Bacteriol
56:
441-442,
1944.
18.
Lilly, CM,
Chapman RW,
Sehring SJ,
Mauser PJ,
Egan RW,
and
Drazen JM.
Effects of interleukin-5-induced pulmonary eosinophilia on airway reactivity in the guinea pig.
Am J Physiol Lung Cell Mol Physiol
270:
L368-L375,
1996
19.
Lilly, CM,
Kobzik L,
Hall AE,
and
Drazen JM.
Effects of chronic airway inflammation on the activity and enzymatic inactivation of neuropeptides in guinea pig lungs.
J Clin Invest
93:
2667-2674,
1994[ISI][Medline].
20.
Mauser, PJ,
Pitman AM,
Fernandez X,
Foran SK,
Adams GK,
Kreutner W,
Egan RW,
and
Chapman RW.
Effects of an antibody to IL-5 in a monkey model of asthma.
Am J Respir Crit Care Med
152:
467-472,
1995[Abstract].
21.
Mauser, PJ,
Pitman A,
Witt A,
Fernandez X,
Zurcher J,
Kung T,
Jones H,
Watnick AS,
Egan RW,
Kreutner W,
and
Adams GK.
Inhibitory effect of the Trfk-5 anti-IL-5 antibody in a guinea pig model of asthma.
Am Rev Respir Dis
148:
1623-1627,
1993[ISI][Medline].
22.
Mehta, S,
Drazen JM,
and
Lilly CM.
Endogenous nitric oxide and allergic bronchial hyperresponsiveness in guinea pigs.
Am J Physiol Lung Cell Mol Physiol
273:
L656-L662,
1997
23.
Mehta, S,
Lilly CM,
Rollenhagen J,
Haley KJ,
Asano K,
and
Drazen JM.
The acute and chronic effects of allergic airway inflammation on pulmonary nitric oxide production.
Am J Physiol Lung Cell Mol Physiol
272:
L124-L131,
1997
24.
Nelms, K,
Keegan AD,
Zamorano J,
Ryan JJ,
and
Paul WE.
The IL-4 receptor: signaling mechanisms and biologic functions.
Annu Rev Immunol
17:
701-738,
1999[ISI][Medline].
25.
Ohno, I,
Lea RG,
Flanders KC,
Clark DA,
Banwatt D,
Dolovich J,
Denburg J,
Harley CB,
Gauldie J,
and
Jordana M.
Eosinophils in chronically inflamed human upper airway tissues express transforming growth factor beta 1 gene (TGF beta 1).
J Clin Invest
89:
1662-1668,
1992[ISI][Medline].
26.
Rankin, JA,
Picarella DE,
Geba GP,
Temann UA,
Prasad B,
DiCosmo B,
Tarallo A,
Stripp B,
Whitsett J,
and
Flavell RA.
Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity.
Proc Natl Acad Sci USA
93:
7821-7825,
1996
27.
Rothenberg, ME,
Luster AD,
Lilly CM,
Drazen JM,
and
Leder P.
Constitutive and allergen-induced expression of eotaxin mRNA in the guinea pig lung.
J Exp Med
181:
1211-1216,
1995[Abstract].
28.
Watson, ML,
White AM,
Campbell EM,
Smith AW,
Uddin J,
Yoshimura T,
and
Westwick J.
Anti-inflammatory actions of interleukin-13: suppression of tumor necrosis factor-alpha and antigen-induced leukocyte accumulation in the guinea pig lung.
Am J Respir Cell Mol Biol
20:
1007-1012,
1999
29.
Wills-Karp, M,
Luyimbazi J,
Xu X,
Schofield B,
Neben TY,
Karp CL,
and
Donaldson DD.
Interleukin-13: central mediator of allergic asthma.
Science
282:
2258-2261,
1998