Mechanisms Regulating Lung Injury and Early Lung Fibrosis

摘要 本计划的总体目标是了解MUC5B在建立脆弱肺和 易损肺向以持续的支气管肺泡上皮损伤为特征的肺的转变 肺成纤维细胞的活化。虽然我们的发现已经确定了一种新的分子(MUC5B)和靶点 (支气管肺泡上皮)对于特发性肺间质纤维化，只有5%的≈基因变异的个体发展为正常的间质。 HRCT扫描肺炎(UIP)，提示需要再次侮辱(二次打击)才能启动和加强 纤维增殖过程。根据我们的初步发现，我们假设虽然过度表达 MUC5B通过导致持续的细支气管内稳态内质网应激，使个体面临发生IPF的风险 上皮细胞、成纤维细胞募集和促纤维化编程需要对细支气管上皮进行二次打击。 导致有害的内质网应激和成纤维细胞的募集和激活。我们的计划包括3个科学项目 项目和4个核心，我们统一的科学主题包括：1)IPF是通过增强 MUC5B(首次命中)，建立以持续的动态平衡ER应激为特征的脆弱肺(没有 大量UPR或细胞凋亡)；2)对支气管肺泡上皮细胞的继发性损伤导致 易受有害内质网应激(涉及大量UPR和细胞凋亡)的肺的影响 显微镜下细支气管性纤维增生的发展；3)了解病因和初始状态 远端呼吸道上皮和AEC2细胞的生物学反应及支气管肺泡上皮细胞间的相互作用 肺成纤维细胞将为疾病预防和早期干预创造机会。最重要的是 我们项目的假设是，IPF的发展需要两次打击，MUC5B在 细支气管上皮诱导内环境平衡、启动反应和随后的损伤 导致有害的内质网应激、异常上皮和成纤维细胞激活的细支气管上皮细胞。 项目1将明确解决MUC5B过度表达的驱动因素，项目2将确定决定因素 上皮损伤和有害的内质网应激之间的关系，项目3将研究 MUC5B诱导的上皮损伤和成纤维细胞激活。在完成这一高度整合的计划时， 我们将：1)建立调控MUC5B诱导的损伤/修复过程的基本分子机制 纤维增殖；2)明确的机制，将创建一次和二次干预的路线图 IPF；以及3)为早期干预这种疾病提供了理由和目标，这种疾病仍然是一个重要的公众 健康问题，并可能增加后Covid。

ABSTRACT The overall goal of this Program is to understand the role of MUC5B in establishing a vulnerable lung and the transition of a vulnerable lung to a lung characterized by persistent injury of bronchoalveolar epithelia and activation of lung fibroblasts. While our findings have identified a novel molecule (MUC5B) and target (bronchoalveolar epithelia) for IPF, only ≈5% of individuals with this genetic variant develop usual interstitial pneumonia (UIP) on HRCT scan, suggesting the need for another insult (a ‘second hit’) to initiate and intensify the fibroproliferative process. Based on our preliminary findings, we postulate that while overexpression of MUC5B places individuals at risk of developing IPF by causing persistent homeostatic ER stress of bronchiolar epithelia, fibroblast recruitment and pro-fibrotic programming requires a second hit to the bronchiolar epithelia resulting in detrimental ER stress and recruitment and activation of fibroblasts. Our Program includes 3 Scientific Projects and 4 Cores, and our unifying scientific themes include: 1) IPF is initiated by enhanced expression of MUC5B (first hit) that establish a vulnerable lung characterized by persistent homeostatic ER stress (without substantial UPR or apoptosis); 2) secondary injury to the bronchoalveolar epithelia results in transition of a vulnerable lung to a lung characterized by detrimental ER stress (involving substantial UPR and apoptosis) and the development of microscopic bronchiolar-centric fibroproliferation; and 3) understanding etiologic and initial biological responses in distal airway epithelia and AEC2 cells, and the interaction of bronchoalveolar epithelia with lung fibroblasts will create opportunities for disease prevention and early intervention. The overarching hypothesis of our Program is that the development of IPF requires two hits, MUC5B overexpression in bronchiolar epithelia that induces a homeostatic, priming response and subsequent injury of the bronchiolar epithelia that results in detrimental ER stress, aberrant epithelia, and fibroblast activation. Project 1 will definitively address the drivers of MUC5B overexpression, Project 2 will identify the determinants of epithelial injury and detrimental ER stress, and Project 3 will investigate the molecular interface between MUC5B-induced epithelial injury and fibroblast activation. At the completion of this highly integrated Program, we will have: 1) established the basic molecular mechanisms that regulate MUC5B-induced injury/repair process in fibroproliferation; 2) defined mechanisms that will create a roadmap for primary and secondary intervention in IPF; and 3) provided a rationale and targets for early intervention in a disease that remains a significant public health problem and may increase post-Covid.