Mechanisms Regulating Lung Injury and Early Lung Fibrosis

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.