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)-y已被证明能够调节多个器官的炎症反应。激活PPARy的配体，噻唑烷二酮(TZD)，是FDA批准的。在炎症性肺病动物模型中，使用这些药物调节PPARy活性与降低发病率有关。然而，该分子在肺上皮细胞和COPD中的重要性尚未确定。我们发现PPARy在人类COPD组织和吸烟者的上皮细胞中表达增加。在肺上皮细胞中，PPARy可以调节与肺组织重塑相关的基因。我们以前曾报道过，PPARy基因的缺失会导致小鼠肺成熟缺陷，从而导致肺结构和功能的变化。在这里，我们提供的数据表明，肺上皮细胞PPARy缺陷的小鼠也表现出对慢性香烟烟雾暴露导致肺气肿发展的易感性增加。这与炎性巨噬细胞的聚集增加有关，炎性巨噬细胞是肺气肿发病的关键效应细胞，肺趋化因子基因表达增加。我们提供的初步数据表明，在这个COPD临床前模型中，使用TZDS激活小鼠的PPARy可以减少吸烟相关的炎症和趋化因子的表达，这是关键的细胞和分子中间表型。在体内，上皮细胞对PPARy调节剂高度敏感，香烟烟雾暴露增加了PPARy的表达，支持了上皮细胞PPARy在调节烟雾诱导的炎症反应中的作用。总体而言，这些数据支持PPARy作为COPD的易感因素的作用，并有可能成为疾病修正治疗的靶点。我们假设，PPARy活性降低会增加吸烟引起的肺损伤的易感性，使用TZDS的PPARy的外源性激活将降低COPD的发病率。我们认为，上皮性PPARy特异性地调节上皮源性趋化因子的表达，这些上皮性趋化因子参与了炎症细胞募集、巨噬细胞激活和组织破坏，以应对慢性烟雾暴露。为了验证这些假说，我们建议：1)确定在缺乏肺上皮细胞PPARy功能的情况下，导致吸烟诱导的小鼠肺气肿易感性增加的细胞和分子机制。2)评估激活PPARy的治疗配体限制香烟烟雾暴露小鼠肺气肿病理的能力。3)作为II期临床试验的一部分，研究PPARy激活抑制吸烟诱导的人细胞和COPD受试者肺上皮细胞趋化因子表达的能力。总之，这些实验将测试PPARy在COPD临床前模型中的机制作用，特别是上皮细胞PPARy在调节疾病发病机制中的作用，并评估PPARy激活在人类COPD中的相关性和潜在的治疗益处。

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)-y has been previously shown to be capable of regulating inflammatory responses in multiple organs. PPARy-activating ligands, the thaizoladinediones (TZDs), are FDA approved. Regulation of PPARy 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 PPARy in human COPD tissues, and in epithelial cells from smokers. In lung epithelial cells, PPARy can regulate genes associated with lung tissue remodeling. We have previously reported that deficiency in PPARy 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 PPARy 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 PPARy 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 PPARy regulators, and exposure to cigarette smoke increased PPARy expression, supporting the contributions of epithelial cell PPARy in regulating smoke-induced inflammation. In total, these data support a role for PPARy as a susceptibility factor in COPD with potential as a target for disease-modifying therapy. We hypothesize that reduced PPARy activity increases susceptibility to smoke- induced lung injury and that exogenous activation of PPARy using TZDs will reduce COPD morbidity. We propose that epithelial PPARy 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 PPARy function in mice. 2) Evaluate PPARy-activating therapeutic ligands for the ability to limit emphysema pathology in mice exposed to cigarette smoke. 3) Investigate the ability of PPARy 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 PPARy in a preclinical model of COPD, specifically address the role of epithelial cell PPARy in regulating disease pathogenesis, and evaluate relevance and potential therapeutic benefits of PPARy activation in humans with COPD.