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(American Journal of Pathology. 2002;160:481-490.)
© 2002 American Society for Investigative Pathology

Regular Articles

Stat6-Deficient Mice Develop Airway Hyperresponsiveness and Peribronchial Fibrosis during Chronic Fungal Asthma

Kate Blease*, Jane M. Schuh*, Claudia Jakubzick*, Nicholas W. Lukacs*, Steven L. Kunkel*, Bharat H. Joshi{dagger}, Raj K. Puri{dagger}, Mark H. Kaplan{ddagger} and Cory M. Hogaboam*

From the Department of Pathology,*
University ofMichigan Medical School, Ann Arbor, Michigan; the Laboratory ofMolecular Tumor Biology,{dagger}
Division of Cellularand Gene Therapies, Center for Biologics Evaluation and Research, Foodand Drug Administration, Bethesda, Maryland; and the Department ofMicrobiology and Immunology,{ddagger}
Walther OncologyCenter, Indiana University School of Medicine, Indianapolis, Indiana

Signal transducer and activator of transcription 6 (Stat6) is critical for Th2-mediated responses during allergic airway disease. To investigate the role of Stat6 in fungus-induced airway hyperresponsiveness and remodeling, Stat6-deficient (Stat6-/-) and Stat6-wildtype (Stat6+/+) mice were sensitized to Aspergillus fumigatus and airway disease was subsequently assessed in both groups at days 21, 30, 38, and 44 after an intratracheal challenge with live A. fumigatus conidia. At all times after conidia, histological analysis revealed an absence of goblet cell hyperplasia and markedly diminished peribronchial inflammation in Stat6-/- mice in contrast to Stat6+/+ mice. Airway hyperresponsiveness and peribronchial fibrosis in Stat6-/- mice were significantly reduced at day 21 after conidia compared with Stat6+/+ mice, but both groups exhibited significant, similar increases in these parameters at all subsequent times after conidia. In separate experiments, IL-13-responsive cells in Stat6-/- mice were targeted via the daily intranasal administration of 200 ng of IL-13-PE38QQR (IL13-PE), comprised of human IL-13 and a derivative of Pseudomonas exotoxin, from days 38 to 44 after the conidia challenge. IL13-PE treatment abolished airway hyperresponsiveness, but not peribronchial fibrosis in Stat6-/- mice. Taken together, these data demonstrate that the chronic development of airway hyperresponsiveness during fungal asthma is IL-13-dependent but Stat6-independent.




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