Hepatocyte Growth Factor Signaling and Airspace Maintenance

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Project Summary Our overall objective is to elucidate the role of hepatocyte growth factor (HGF) signaling in chronic obstructive pulmonary disease (COPD) in order to develop therapies to promote repair within lung epithelium. COPD is the third leading cause of death in the United States and the incidence is rising globally. Here, we seek to exploit regenerative pathways to confer protection and enhance repair within lung epithelium following injuries that result in airspace simplification. We focus on HGF (hepatocyte growth factor) and its receptor cMet based on the following : 1) HGF, is a pleiotrophic morphogen and the only known ligand for cMet, a trophic growth factor receptor expressed on a variety of epithelial cell types, including alveolar type II cells (AECII); 2) HGF/cMet enables morphogenic, motogenic, angiogenic and anti-apoptotic signaling, a complex skill set especially directive of alveolar formation and repair; and 3) studies in our lab and others have demonstrated reliable effects of this pathway on alveolar development and homeostasis. We previously reported that the loss of cMet signaling in the alveolar epithelial cell (AEC) compartment impairs alveolar formation via enhanced oxidative stress, apoptosis and reduced vascularization. Augmentation of HGF signaling partially reverses genetic emphysema and elastase-induced emphysema in preclinical models. However, the airspace epithelial effects of HGF/cMet in response to cigarette smoke (CS) and the relevance to clinical lung disease are still largely unknown. In preliminary data, we show that cMet is downregulated in COPD lungs, airspaces of adult mice exposed to chronic CS and in both murine alveolar and human bronchial epithelial cells exposed to CS. The neonatal loss of cMet signaling in the distal epithelial compartment delays airspace maturation and increases susceptibility to CS-induced lung injury in adult mice. Mir34a which targets cMet for downregulation is increased in COPD lungs and in human epithelial cells exposed to CS. A large genetic study identified genome-wide significant associations for reduced lung function near MET (the gene encoding cMet) and near HGFAC, the major activator for HGF. Based on this compelling data, we offer the central hypothesis that HGF/cMet signaling is critical to airspace protection and function in both the developing and adult lung and can be harnessed to treat acquired emphysema. The specific hypotheses that we test are 1) maintenance or augmentation of cMet expression or signaling can protect against CS-induced airspace injury via preserved alveolar epithelial homeostasis and dynamics, 2) CS-induced miRNAs contribute to reduced cMet expression in the injured airspace epithelium, and 3) integrative multiomics anchored on cMet signaling in large informative cohorts will identify molecular signatures that contribute to COPD susceptibility.