Strategies for Angiotensin Receptor Blocker Mediated Tissue Repair

项目摘要 COPD/肺气肿是一种慢性炎症性肺病，是美国第四大死因 通常是由长期接触香烟烟雾引发的。虽然许多治疗方法可以减轻 COPD，没有干预措施可以阻止或逆转广泛的结构和功能损伤， 给混乱加标点。因此，不仅减少炎症而且促进肺泡修复的疗法 （驻留细胞存活、再生基质产生）理想地适用于COPD功效。血管紧张 受体阻断剂发挥这种双重作用。科学前提是基于以下发现：1）血管紧张素 受体阻断剂逆转遗传性肺气肿，并防止香烟烟雾诱导的肺气肿， 动物模型表现为炎症减轻、肺泡细胞凋亡减少和基质改善 形态学和2）支持性观察性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， 在一个亚组的已确诊疾病的患者中， 一年的时间框架。这些发现导致了一项由NIH赞助的多中心研究， 确诊肺气肿的患者（LEEP试验）。这些数据重要地表明了一个意想不到的肺泡 血管紧张素受体阻滞剂的保护和修复机制。研究表明 香烟烟雾（CS）或遗传干扰诱导的TGFβ信号转导的拮抗作用是ARB的直接作用。 介导的保护机制。目前提供的新的初步数据 一项提案暗示ARB增强的PPARγ信号传导是一种平行的和潜在的强化机制（以 TGFβ拮抗作用）以保护免受CS诱导的肺损伤。LOS代谢产物EXP 3174（3174）和 EXP 3179（3179）分别选择性激活两者中的AT 1 R依赖性和AT 1 R非依赖性级联反应 细胞和动物模型系统。而AT 1 R依赖性修复参与选择性拮抗TGFβ 信号转导，AT 1 R非依赖性修复促进了PPARγ激动和PPAR γ信号转导。Aim 1研究 描述LOS作为典型ARB如何减弱CS诱导的肺部炎症和损伤， 通过协同激活PPARγ和抑制TGFβ进行肺泡修复。目的2研究确定ARB， 通过AT 1 R依赖性和非依赖性机制，抑制TGFβ级联，调节肺泡驻留细胞 CS诱导肺损伤中存活和空域修复。Aim 3研究使用来自 LEEP试验入选者接受LOS治疗，以1）确定血液LOS和代谢物水平是否与 TGFβ和PPARγ途径生物标志物和2）鉴定与代谢物水平相关的TGF β变体。 拟议的目标使用原代细胞模型、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促进空域再生的策略， 还确定LOS代谢产物产生的机制及其作为精确生物标志物的效用。

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.