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Transgenic Modeling of Transforming Growth Factor-ß₁

Role of Apoptosis in Fibrosis and Alveolar Remodeling

Section of Pulmonary and Critical Care Medicine and Department of Pathology, Yale University School of Medicine, New Haven; and Pathology and Laboratory Medicine Service, VA-CT Health Care System, West Haven, Connecticut

Correspondence and requests for reprints should be addressed to Jack A. Elias, M.D., Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, P.O. Box 208057, 300 Cedar Street (S441 TAC), New Haven, CT 06520-8040. E-mail: jack.elias{at}yale.edu

ABSTRACT

Inflammation and tissue remodeling with pathologic fibrosis are common consequences of Th2 responses in the lung and other organs. Interleukin (IL)-13 and transforming growth factor-ß1 (TGF-ß₁) are frequently coexpressed in these responses and are believed to play important roles in the pathogenesis of Th2-induced pathologies. To shed light on the mechanisms of these responses, overexpression transgenic approaches were used to selectively target each of these cytokines to the murine lung. IL-13 proved to be a potent stimulator of eosinophilic inflammation, mucus metaplasia, tissue fibrosis, and alveolar remodeling. CC chemokines, specific chemokine receptors (CCR2, CCR1), adenosine metabolism, vascular endothelial growth factor, and IL-11 contributed to the genesis of these responses. IL-13 also induced tissue fibrosis, at least in part, via its ability to induce and activate TGF-ß₁. In the TGF-ß₁ transgenic mouse, epithelial apoptosis preceded the onset of tissue fibrosis and alveolar remodeling. In addition, chemical (Z-VAD-fmk) and genetic (null mutations of early growth response gene 1) interventions blocked apoptosis and ameliorated TGF-ß₁–induced fibrosis and alveolar restructuring. These studies define an IL-13–TGF-ß₁ pathway of tissue remodeling that regulates inflammation, mucus metaplasia, apoptosis, vascular responses, and fibrosis in the lung. They also highlight the intimate relationship between apoptosis and fibrosis induced by TGF-ß₁. By defining the complexities of this pathway, these studies highlight sites at which therapies can be directed to control these important responses.

Key Words: asthma • fibrosis • interleukin-13 • transforming growth factor-ß • 1 • transgenic

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