PPAR gamma as a therapeutic target in COPD

描述（由申请人提供）：需要更好地理解导致COPD发病机制的机制以及治疗干预的新靶点。过氧化物酶体增殖物激活受体（PPAR）-？先前已显示能够调节多个器官中的炎症反应。过氧化物酶体过氧化物酶体？活化配体噻唑烷二酮（TZD）是FDA批准的。对PPAR？使用这些药物的活性与炎性肺病动物模型中发病率的降低有关。然而，这种分子在肺上皮细胞和COPD中的重要性尚未确定。我们发现增加表达的过氧化物酶体增殖物激活受体？在人COPD组织和吸烟者的上皮细胞中。在肺上皮细胞，过氧化物酶体增殖物激活受体？可以调节与肺组织重塑相关的基因。我们以前曾报道过，缺乏过氧化物酶体增殖物激活受体？特别是在上皮细胞内，导致肺成熟缺陷，导致小鼠肺结构和功能的变化。在这里，我们目前的数据表明，小鼠缺乏肺上皮细胞过氧化物酶体增殖物激活受体？也显示出对慢性香烟烟雾暴露的肺气肿发展的敏感性增加。这与炎性巨噬细胞（肺气肿发病机制的关键效应细胞）的积累增加和肺趋化因子基因表达增加有关。我们目前的初步数据表明，激活过氧化物酶体增殖物激活受体？在小鼠中使用TZD减少了吸烟相关的炎症和趋化因子表达，这是COPD临床前模型中的关键细胞和分子中间表型。在体内，上皮细胞对过氧化物酶体增殖物激活受体高度敏感？调节剂，和暴露于香烟烟雾增加过氧化物酶体增殖物激活受体？表达，支持上皮细胞的贡献？调节吸烟引起的炎症。总之，这些数据支持的作用，过氧化物酶体增殖物激活受体？作为COPD的易感因素，有可能作为疾病缓解治疗的靶点。我们假设降低了过氧化物酶体增殖物激活受体？活动增加对烟雾诱导的肺损伤的易感性，外源性激活的过氧化物酶体增殖物激活体？使用TZD将降低COPD发病率。我们认为上皮细胞的过氧化物酶体增殖体激活受体？特异性地调节上皮来源的趋化因子的表达，所述趋化因子参与炎症细胞募集、巨噬细胞活化和响应于慢性烟雾暴露的组织破坏。为了验证这些假设，我们提出：1）定义细胞和分子机制，导致增加易感性香烟烟雾诱导的肺气肿的情况下，肺上皮细胞的过氧化物酶体增殖物激活受体？在小鼠中的功能。2)评估PPAR？-激活治疗配体以限制暴露于香烟烟雾的小鼠中的肺气肿病理学的能力。3)研究PPAR的能力？作为II期临床试验的一部分，在人细胞中和COPD受试者中进行活化以抑制烟雾诱导的肺上皮细胞趋化因子表达。总之，这些实验将测试的机制作用的过氧化物酶体增殖物激活受体？在COPD的临床前模型中，特别是解决上皮细胞PPAR的作用？在调节疾病发病机制，并评估相关性和潜在的治疗效益的过氧化物酶体增殖物激活受体？在患有COPD的人中激活。

DESCRIPTION (provided by applicant): An improved understanding of the mechanisms leading to COPD pathogenesis, as well as novel targets for therapeutic intervention, are needed. Peroxisome proliferator-activating receptor (PPAR)-? has been previously shown to be capable of regulating inflammatory responses in multiple organs. PPAR?-activating ligands, the thaizoladinediones (TZDs), are FDA approved. Regulation of PPAR? activity, using these drugs, is associated with reduced morbidity in animal models of inflammatory lung disease. However, the importance of this molecule in lung epithelial cells and in COPD has not been determined. We find increased expression of PPAR? in human COPD tissues, and in epithelial cells from smokers. In lung epithelial cells, PPAR? can regulate genes associated with lung tissue remodeling. We have previously reported that deficiency in PPAR? specifically within epithelial cells leads to a defect in lung maturation resulting in variation in lung structure and function in mice. Here, we present data indicating that mice deficient in lung epithelial cell PPAR? also show increased susceptibility to the development of emphysema in response to chronic cigarette smoke exposure. This is associated with an increase in the accumulation of inflammatory macrophages, the critical effector cell for emphysema pathogenesis, and increased lung chemokine gene expression. We present preliminary data indicating that activating PPAR? using TZDs in mice reduces smoke-related inflammation and chemokine expression, critical cellular and molecular intermediate phenotypes in this pre-clinical model of COPD. In vivo, epithelial cells are highly responsive to PPAR? regulators, and exposure to cigarette smoke increased PPAR? expression, supporting the contributions of epithelial cell PPAR? in regulating smoke-induced inflammation. In total, these data support a role for PPAR? as a susceptibility factor in COPD with potential as a target for disease-modifying therapy. We hypothesize that reduced PPAR? activity increases susceptibility to smoke- induced lung injury and that exogenous activation of PPAR? using TZDs will reduce COPD morbidity. We propose that epithelial PPAR? functions specifically to regulate the expression of epithelial-derived chemokines involved in inflammatory cell recruitment, macrophage activation and tissue destruction in response to chronic smoke exposure. In an effort to test these hypotheses we propose to: 1) Define the cellular and molecular mechanisms leading to increased susceptibility to cigarette smoke-induced emphysema in the absence of lung epithelial cell PPAR? function in mice. 2) Evaluate PPAR?-activating therapeutic ligands for the ability to limit emphysema pathology in mice exposed to cigarette smoke. 3) Investigate the ability of PPAR? activation to suppress smoke-induced lung epithelial cell chemokine expression in human cells and in COPD subjects as part of a phase II clinical trial. In total, these experiments will test the mechanistic role of PPAR? in a preclinical model of COPD, specifically address the role of epithelial cell PPAR? in regulating disease pathogenesis, and evaluate relevance and potential therapeutic benefits of PPAR? activation in humans with COPD.