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

肺泡破坏和肺纤维化在COPD和肺纤维化中并存。令人惊讶的是， 这些反应与同时破坏肺泡的机制之间的关系 导致纤维化的定义尚未确定。转化生长因子-β1(转化生长因子-β1)在 COPD和肺纤维化的夸大方式以及转化生长因子-β1的异常被认为与 肺气肿和瘢痕形成的发病机制。转化生长因子-β1诱导这些不同变化的机制 结果和控制这些不同反应的遗传因素还没有被研究。 我们建立了在小鼠肺内高表达生物活性的转化生长因子-β1的新型三重转基因小鼠。在……里面 57BL/6小鼠这种转化生长因子-β1可引起肺上皮细胞凋亡、肺纤维化和蜂窝状改变。在……里面 相比之下，在Balb/c小鼠中，转化生长因子-β1导致肺气肿，组织纤维化程度很小。夸大了细胞凋亡和 在Balb/c动物中观察到基质金属蛋白酶-12的诱导和赖氨酰的显著刺激 在C57BL/6动物中发现了氧化酶、精氨酸酶II和Cyr-61。这导致了以下假设： 1.转化生长因子-β1是一种多功能细胞因子，可同时诱导组织损伤和纤维化。 产生肺气肿和/或纤维化表型。 2.转化生长因子-β1的组织效应在一定程度上依赖于细胞凋亡、蛋白降解和纤维化的平衡。 3.转化生长因子-β1诱导这些不同表型的能力由可定义的转化生长因子-β1决定 效应器功能调节基因。为了解决这一假设，我们建议： 目的#1.建立可诱导、肺靶向过度表达转化生长因子-β1(OE)的转基因小鼠 C57BL/6和Balb/c的遗传背景。 目的#2.描述导致转化生长因子诱导的不同表型的机制 B1C57BL/6和Balb/c转基因动物。 目的#3.确定精氨酸酶系统在转化生长因子-β1诱导的表型形成中的作用 在C57BL/6和Balb/c转基因小鼠中。 目的#4：定义决定转化生长因子-β1是否诱导以纤维化为主的 C57BL/6和Balb/c小鼠的肺气肿反应。

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.