Genetic Factors Controlling Effector Function of TGF-beta in COPD and Fibrosis

点击翻译按钮获取中文摘要

Alveolar destruction and pulmonary fibrosis are juxtaposed in COPD and pulmonary fibrosis. Surprisingly, the relationships between these responses and the mechanisms that destroy alveoli while simultaneously nducing fibrosis have not been defined. Transforming Growth Factor-betal (TGF-b1) is expressed in an exaggerated fashion in COPD and pulmonary fibrosis and TGF-b1 abnormalities have been implicated in the pathogenesis of emphysema and scarring. The mechanisms that TGF-b1 uses to induce these different outcomes and the genetic factors that control these divergent responses have not been investigated. We developed novel triple transgenic mice overexpressing bioactive TGF-b1 in the murine lung. In 57BL/6 mice this TGF-b1 caused epithelial cell apoptosis, pulmonary fibrosis and honeycombing. In contrast, in Balb/c mice TGF-b1 caused emphysema with minimal tissue fibrosis. Exaggerated apoptosis and matrix metalloproteinase-12 induction were seen in Balb/c animals and prominent stimulation of lysyl oxidase, arginase II and Cyr-61 were seen in C57BL/6 animals. This led to the following hypothesis: 1. TGF-b1 is a multifunctional cytokine that simultaneously induces tissue injury and fibrosis and generates emphysematous and/or fibrotic phenotypes. 2. The tissue effects of TGF-b1 depend, in part, on the balance of apoptosis, proteolysis and fibrosis. 3. The ability of TGF-b1 to induce these divergent phenotypes is determined by definable TGF-b1 effector function regulating genes. To address this hypothesis, we propose to: AIM #1. Generate and characterize inducible, lung-targeted TGF-b1 overexpressing (OE) transgenic mice on C57BL/6 and Balb/c genetic backgrounds. AIM #2. Characterize the mechanisms that contribute to the different phenotypes that are induced by TGF- b1 in C57BL/6 and Balb/c transgenic animals. AIM #3. Characterize the roles of the arginase system in the generation of the TGF-b1-induced phenotypes in C57BL/6 and Balb/c transgenic mice. AIM #4. Define the genes that determine whether TGF-b1 induceds a predominantly fibrotic versus emphysematous response in C57BL/6 and Balb/c mice.