title: Transgenic modeling of transforming growth factor-beta(1): role of apoptosis in fibrosis and alveolar remodeling.
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-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.
authors.affiliation: 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, USA.
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.forename: Hye-Ryun
authors.initials: HR
authors.lastname: Kang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chupp
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004247:DNA / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1
chemical_list: C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004247:DNA