Mechanisms of Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

Hermansky-Pudlak 综合征肺纤维化的机制

• 批准号: 8559643
• 负责人: Lisa R. Young
• 金额: $ 37.13万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8559643
• 关键词: Adult; Affect; Alveolar; Alveolar Macrophages; Apoptosis; Attenuated; Automobile Driving; Biogenesis; Bleomycin; Chloride Ion; Chlorides; Complex; Data; Defect; Development; Disease; Epithelial; Exposure to; Family; Fibrosis; Functional disorder; Generations; Genetic; Genetic Models; Genotype; Hermanski-Pudlak Syndrome; Hyperplasia; In Vitro; Inborn Genetic Diseases; Inflammation; Interruption; Interstitial Lung Diseases; Lead; Light; Lipids; Lung; Lung Transplantation; Lung diseases; Lysosomes; Macrophage Activation; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Mus; Mutant Strains Mice; Mutation; NADPH Oxidase; Organelles; Oxidative Stress; Pathway interactions; Patients; Phenotype; Predisposition; Production; Proteins; Publishing; Pulmonary Fibrosis; Reactive Oxygen Species; Recruitment Activity; Regulation; Risk; Role; Shortness of Breath; Stimulus; TFF1 gene; Testing; Therapeutic; Transgenic Organisms; Type II Epithelial Receptor Cell; Work; adapter protein; alveolar epithelium; alveolar homeostasis; alveolar lamellar body; base; cell type; cytokine; effective therapy; fibrogenesis; human disease; improved; in vivo; macrophage; mouse model; paracrine; protein transport; public health relevance; respiratory; response; trafficking

DESCRIPTION (provided by applicant): Pulmonary fibrosis is a final common pathway in many forms of interstitial lung diseases (ILD). Currently there are no effective treatments for most fibrotic lung diseases, and the development of preventative and therapeutic strategies remains limited by incomplete understanding of the cellular and molecular mechanisms underlying alveolar fibrosis. Monogenic disorders provide a unique opportunity to study lung fibrogenesis from the vantage point of a primary molecular defect. Hermansky-Pudlak Syndrome (HPS) is a family of autosomal recessive disorders involving dysfunction of intracellular trafficking and abnormal lysosome-related organelle biogenesis. Pulmonary fibrosis is highly penetrant in HPS types 1, 2, and 4, but does not occur in other HPS subtypes. In HPS patients with fibrotic predisposition, alveolar epithelial type II cells are hyperplastic with irreular lamellar bodies and lipid accumulation. In addition, macrophage-mediated inflammation precedes pulmonary fibrosis in HPS patients. We have shown that naturally-occurring HPS mice reliably model important features of the human disease, including HPS genotype-specific alveolar macrophage (AM) activation and susceptibility to pro-fibrotic stimuli. In addition, we have recently demonstrated that the alveolar epithelium is the primary driver of fibrotic susceptibility, as transgenic epithelial-specific correction of the HPS2 defect significantly attenuated type II cell apoptosis, excess monocyte-chemotactic protein-1 (MCP-1) secretion, AM activation, and susceptibility to bleomycin-induced fibrosis. Although the mechanisms by which HPS trafficking defects regulate type II cell phenotype remain poorly defined, our preliminary data demonstrate excess oxidative stress in type II cells of HPS2 mutant mice, as well as markedly increased expression of Nox4. Based on these data, we propose the hypothesis that HPS trafficking defects result in increased Nox4- dependent reactive oxygen species (ROS) production and enhanced secretion of mediators, including MCP-1, that recruit and activate AMs in the local microenvironment. After exposure to injurious stimuli, marginally compensated type II cells are at increased risk for apoptosis, which accelerates the fibrotic response in conjunction with activated AMs. To test this hypothesis, we propose the following specific aims using HPS models which experimentally mimic human disease: 1) to define the role of oxidative stress in HPS type II cell dysfunction, 2) to investigate the mechanisms underlying susceptibility to bleomycin-induced type II cell apoptosis and accelerated fibrosis in HPS mice, and 3) to determine the epithelial-derived factors regulating AM activation in HPS and the role of activated AMs in HPS-related pulmonary fibrosis. Overall, our studies will lead to improved understanding of the mechanisms of type II cell dysfunction in HPS and could facilitate therapeutic strategies for this fatal disorder. Because type II cell dysfunction is a unifying feature of many fibrotic lung diseases, further study of HPS trafficking defects will likey elucidate mechanisms of pulmonary fibrosis with broad relevance.

描述（由申请人提供）：肺纤维化是多种形式的间质性肺疾病（ILD）的最终共同途径。当前，对于大多数纤维化的肺部疾病尚无有效的治疗方法，预防性和治疗策略的发展仍然受到对肺泡纤维化下细胞和分子机制的不完全了解的限制。单基因疾病为从主要分子缺陷的有利位置研究肺纤维发生提供了独特的机会。 Hermansky-Pudlak综合征（HPS）是一个常染色体隐性疾病家族，涉及细胞内贩运和异常溶酶体相关的细胞器生物发生功能障碍。在1、2和4型的HPS中，肺纤维化高度渗透，但在其他HPS亚型中不发生。在患有纤维化易感性易感性的HPS患者中，肺泡上皮II型细胞具有非乳腺层状体和脂质积累的增生。此外，巨噬细胞介导的炎症先于HPS患者的肺纤维化。我们已经表明，自然存在的HPS小鼠可靠地模型人类疾病的重要特征，包括HPS基因型特异性肺泡巨噬细胞（AM）激活和对促纤维化刺激的敏感性。此外，我们最近证明，肺泡上皮是纤维化易感性的主要驱动力，因为HPS2缺损的转基因上皮特异性校正显着减弱了II型细胞凋亡，单型单型化学蛋白1（MCP-1）的过多，单型化学蛋白-1（MCP-1）分泌，AM激活和bLeymycir-Myshyscir-Indimpibibibis insived fibibristion。尽管HPS运输缺陷调节II型细胞表型的机制仍然很差，但我们的初步数据表明，HPS2突变小鼠II型细胞中的氧化应激过量，并且显着增加了NOX4的表达。基于这些数据，我们提出了以下假设：HPS运输缺陷会导致NOX4依赖性活性氧（ROS）产生（ROS）产生和包括MCP-1在内的介体的分泌增强，这些分泌物（包括MCP-1）在局部微环境中募集和激活AM。暴露于有害刺激后，少量补偿的II型细胞的凋亡风险增加，这加速了与活化的AMS结合的纤维化反应。为了检验这一假设，我们提出了使用HPS模型的以下特定目的，这些模型在实验中模仿了人类疾病：1）定义氧化应激在HPS II型细胞功能障碍中的作用，2）研究，以调查对博菌素II型II型生成型的易感性的基础机制，并在HPS中诱导的纤维化因素，并在HPS米尔斯中进行了Epitial inivitiativation-epith，并在HPS中的激进因素确定了3）。 HPS和活化AM在与HPS相关的肺纤维化中的作用。总体而言，我们的研究将提高对HPS II型细胞功能障碍机制的了解，并可能促进这种致命疾病的治疗策略。由于II型细胞功能障碍是许多纤维化肺部疾病的统一特征，因此对HPS运输缺陷的进一步研究将喜欢阐明肺纤维化的机制以及广泛的相关性。