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lüll Transgenic modeling of transforming growth factor-beta(1): role of apoptosis in fibrosis and alveolar remodeling Lee CG; Kang HR; Homer RJ; Chupp G; Elias JAProc Am Thorac Soc 2006[Jul]; 3 (5): 418-23Inflammation 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-beta1 (TGF-beta(1)) 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-beta(1). In the TGF-beta(1) 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-beta(1)-induced fibrosis and alveolar restructuring. These studies define an IL-13-TGF-beta(1) 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-beta(1). By defining the complexities of this pathway, these studies highlight sites at which therapies can be directed to control these important responses.|*Pulmonary Fibrosis/genetics/metabolism/pathology[MESH]|Animals[MESH]|Apoptosis/*physiology[MESH]|DNA/*genetics[MESH]|Gene Expression[MESH]|Humans[MESH]|Pulmonary Alveoli/metabolism/*pathology[MESH]|Transforming Growth Factor beta/*genetics[MESH]|Transforming Growth Factor beta1[MESH] |