Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair

项目摘要 慢性阻塞性肺病/肺气肿是美国第四大死因，是一种慢性炎症性肺部疾病 通常由长期接触香烟烟雾引发。尽管许多治疗方法可以减少 COPD，不存在阻止或逆转广泛的结构和功能损害的干预措施 用标点符号标示混乱。因此，不仅减少炎症而且促进肺泡修复的治疗方法 (驻留细胞存活、再生基质产生)是COPD疗效的理想选择。血管紧张素 受体阻滞剂起到了双重作用。科学前提是基于以下发现：1)血管紧张素 受体阻断逆转遗传性肺气肿并预防吸烟引起的肺气肿 动物模型表现为炎症减轻，肺泡细胞凋亡减少，基质改善 形态学和2)支持性观察研究和随机、双盲、安慰剂对照试验 血管紧张素受体阻滞剂(ARB)氯沙坦(LOS)在NIH SCCOR机制下进行的 在一组已确诊疾病的治疗患者中，肺气肿出现逆转或稳定 一年时间框架。这些发现导致了一项由美国国立卫生研究院赞助的对洛杉矶的多中心研究，研究对象包括 已确诊的肺气肿患者(LEEP试验)。这些数据重要地表明了一个意想不到的肺泡 血管紧张素受体阻断的保护和修复机制。研究表明， 香烟烟雾或遗传干扰诱导的转化生长因子β信号的拮抗作用是一种直接的ARB- 实验性肺气肿的中介保护机制。当前提供的新的初步数据 建议暗示ARB增强的PPARγ信号是一种并行的潜在强化机制(TO 转化生长因子β拮抗剂)对CS所致肺损伤具有保护作用。LOS代谢物EXP3174(3174)和 EXP3179(3179)分别选择性地激活AT1R依赖级联和AT1R非依赖级联 细胞和动物模型系统。而AT1R依赖的修复参与转化生长因子β的选择性拮抗 信号，AT1R非依赖性修复促进PPARγ激动化和抗炎信号转导。目标1研究 LOS作为一种典型的ARB如何减轻CS诱导的肺部炎症和损伤并促进 通过协同激活PPARγ和抑制转化生长因子β来修复肺泡。目标2研究确定ARB是如何， 通过AT1R依赖和非依赖机制抑制转化生长因子β级联调节肺泡驻留细胞 CS致肺损伤的存活期及肺间隙修复。Aim 3研究使用了来自 接受LOS治疗的LEEP试验参与者1)确定血液LOS和代谢物水平是否与 转化生长因子β和PPARγ途径生物标记物和2)确定与代谢物水平相关的细胞色素PYP变异体。 建议的目标是使用原代细胞模型、实验小鼠模型和患者的临床样本。 用LOS治疗肺气肿，以阐明ARB促进空域再生和 还要确定LOS代谢物产生的机制及其作为精确生物标记物的效用。

Project Summary COPD/emphysema, the fourth leading cause of death in the US, is a chronic inflammatory lung disorder usually triggered by long-term cigarette smoke exposure. Although many therapies reduce the symptoms of COPD, no interventions exist which arrest or reverse the extensive architectural and functional damage that punctuate the disorder. Thus, therapies which not only reduce inflammation but also promote alveolar repair (resident cell survival, regenerative matrix production) are ideally suited for COPD efficacy. Angiotensin receptor blockers fulfill this dual role. The scientific premise is anchored on findings that: 1) angiotensin receptor blockade reverses genetic emphysema and protects against cigarette smoke induced emphysema in animal models manifest in reduced inflammation, reduced alveolar cell apoptosis and improved matrix morphology and 2) supportive observational studies and a randomized double-blinded placebo controlled trial of the angiotensin receptor blocker (ARB) Losartan (LOS) conducted under an NIH SCCOR mechanism that showed reversal or stabilization of emphysema in a subset of treated patients with established disease over a one year time frame. Such findings have led to an NIH-sponsored multicenter study of LOS in a cohort of patients with established emphysema (LEEP Trial). These data importantly suggest an unanticipated alveolar protective and reparative mechanism attached to angiotensin receptor blockade. Studies show that the antagonism of TGFβ signaling induced by cigarette smoke (CS) or genetic perturbation is a direct ARB- mediated protective mechanism in experimental emphysema. New preliminary data presented in current proposal implicate enhanced PPARγ signaling by ARBs as a parallel and potentially reinforcing mechanism (to TGFβ antagonism) for protection against CS-induced lung injury. LOS metabolites EXP3174 (3174) and EXP3179 (3179) selectively activate AT1R-dependent and AT1R-independent cascades, respectively, in both cell and animal model systems. Whereas AT1R-dependent repair engages selective antagonism of TGFβ signaling, AT1R-independent repair promotes PPARγ agonism and antiinflammatory signaling. Aim 1 studies delineate how LOS as a prototypical ARB attenuates CS-induced lung inflammation and injury and promotes alveolar repair via coordinated activation of PPARγ plus inhibition of TGFβ. Aim 2 studies establish how ARBs, via AT1R-dependent and -independent mechanisms, inhibit TGFβ cascades to modulate alveolar resident cell survival and airspace repair in setting of CS-induced lung injury. Aim 3 studies utilize blood samples from LEEP trial enrollees treated with LOS to 1) establish whether blood LOS and metabolite levels associate with TGFβ and PPARγ pathway biomarkers and 2) identify CYP variants that associate with metabolite levels. The proposed aims use primary cell models, experimental murine models and clinical samples from patients with emphysema treated with LOS to clarify the strategy by which ARBs promote airspace regeneration and also identify mechanisms for LOS metabolite production and their utility as precision biomarkers.