Insights on Alveolar Type 2 Cell Dysfunction and the Pathogenesis of Idiopathic Pulmonary Fibrosis: Expression of a Novel Sftpc BRICHOS Mutant in Murine Epithelia

Abstract

It is estimated that up to 45% of deaths within the United States can be attributed to some form of fibrotic disorder, which underscores the necessity of research on fibrotic diseases. In particular, the pathogenesis and treatment of fibrosis of the lungs remains poorly understood and elusive, in part due to the lungs’ constant exposure to environmental stressors, that in conjunction with genetic elements, variably affect the disease phenotype. Idiopathic pulmonary fibrosis (IPF) represents one such fibrotic disorder in which environmental and genetic factors have been implicated in the pathogenesis of this disease. IPF is a chronic and progressive disease of the lung that is typified by extensive scarring of the interstitium with resultant impairment of lung capacity and functionality. While the etiology of this disease is unknown, alveolar type 2 (AT2) cell dysfunction, as a result of injury incurred by intrinsic factors, such as genetic mutations, and/or extrinsic environmental stressors, has been postulated as a key driver of IPF. To test this theory in vivo, a knock-in mouse model was generated that is capable of regulated expression of a cysteine-to-glycine substitution at codon 185 within the BRICHOS domain of the surfactant protein C (SP-C) gene (Sftpc), which is solely expressed by AT2 cells. SftpcC185G expression during fetal development resulted in a toxic gain of function, which led to post-natal lethality. Consistent with in vitro studies on Sftpc BRICHOS mutations, inducible SftpcC185G expression in adult mice resulted in endoplasmic reticulum (ER) retention of the mutant proSP-C isoform with resultant AT2 cell ER stress. Additionally, the phenotype of the adult inducible model was characterized by diffuse parenchymal lung injury, poly-cellular alveolitis, and spontaneous fibrotic-like remodeling of lung architecture. This data in turn provides proof of concept of the association between a dysfunctional AT2 cell phenotype as a driver of pulmonary fibrosis and provides an informative platform that can be leveraged to further understand the role that the environment plays in the development of pulmonary fibrosis.