Eisosanoid imbalance in fibrotic lung disease

(申请者摘要)越来越多的证据表明，孤独症 花生四烯酸的代谢产物调节炎症、免疫和 导致肺纤维化的间质成分。然而， 白三烯(LTS)促进所有这些过程，而前列腺素E-， (PGE2)通常会抑制它们。值得注意的是，我们的实验室已经鉴定出两个 慢性阻塞性肺疾病患者肺中二十烷类化合物合成的单独异常 纤维性疾病，特发性肺纤维化：即过度生产 它和前列腺素E_2的生产不足--此外，最近的其他研究表明 类似的二十烷类激素失衡是肺性心脏病动物模型的特征 纤维化，以及遗传或药物对这种不平衡的调节 意味着减少纤维化的形成。这项提议的假设是，这 二十烷基类化合物生成的促纤维化失衡在 肺纤维化的发病机制和预后。此外，我们假设 这种二十烷类激素的失衡会因使用 皮质类固醇，导致了令人失望的临床反应 纤维化的肺部疾病给这些药物。当前提案的目的是 为了扩大我们对细胞和酶机制的理解 在这种不平衡的基础上，它对药理和/或遗传的适应性 二十烷类化合物对细胞因子和生长因子的调节作用 从而影响纤维化肺部疾病的演变。这将是 通过研究肺组织和细胞(巨噬细胞和成纤维细胞)完成的 从博莱霉素诱导的肺纤维化小鼠和从患者 肺纤维化。在拟议的临床研究中，二十烷类异常 将与临床严重程度、组织学分类和 病程。此外，我们将确定三个因素的影响 肺纤维化的治疗方案(泼尼松、硫唑嘌呤加 强的松或LT合成抑制剂齐留通)对二十烷类化合物合成的影响， 病理生物学机制和临床结果。拟议的研究将 批判性地评估一种新的病理生理范式 对这一毁灭性的纤维性肺部疾病的治疗的启示。

(Applicant's Abstract) A growing body of evidence indicates that elcosanoid metabolites of arachidonic acid modulate the inflammatory, immune, and mesenchymal components contributing to pulmonary fibrosis. However, leukotrienes (LTs) promote all of these processes while prostaglandin E-, (PGE2) generally suppresses them. Of note, our laboratory has identified two separate abnormalities in eicosanoid synthesis in the lungs of patients with the fibrotic disease, idiopathic pulmonary fibrosis: namely, overproduction of LTs and underproduction of PGE2- Moreover, additional recent studies indicate that a similar eicosanoid imbalance characterizes animal models of pulmonary fibrosis, and that modulation of this imbalance by genetic or pharmacologic means attenuates fibrogenesis. The hypothesis of this proposal is that this pro-fibrotic imbalance of eicosanoid generation is centrally important in the pathogenesis and prognosis of pulmonary fibrosis. Furthermore, we hypothesize that this eicosanoid imbalance is exacerbated by treatment with corticosteroids, contributing to the disappointing clinical response of fibrotic lung diseases to these agents. The aims of the current proposal are to extend our understanding of the cellular and enzymatic mechanisms underlying this imbalance, its amenability to pharmacologic and/or genetic modulation, and the cytokines and (growth factors regulated by eicosanoids which influence the evolution of fibrotic lung disease. This will be accomplished by studying lung tissue and cells (macrophages and fibroblasts) from mice with bleomycin induced pulmonary fibrosis and from patients with pulmonary fibrosis. In the clinical studies proposed, eicosanoid abnormalities will be correlated with clinical severity, histologic classification, and course of disease. In addition, we will determine the effects of three treatment regimens for pulmonary fibrosis (prednisone, azathioprine plus prednisone, or the LT synthesis inhibitor zileuton) on eicosanoid synthesis, pathobiological mechanisms, and clinical outcomes. The proposed studies will critically evaluate a new pathophysiologic paradigm with important implications for therapy of this devastating group of fibrotic lung diseases.