Chronic Expression of a Clinical SFTPC Mutation Causes Murine Lung Fibrosis with IPF Features.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive fibrotic interstitial lung disease (ILD). A barrier to developing more effective therapies for IPF is the dearth of preclinical models that recapitulate the early pathobiology of this disease. Intratracheal bleomycin, the conventional preclinical murine model of IPF, fails to reproduce the intrinsic dysfunction to the alveolar epithelial type 2 cell (AEC2) that is thought to be a proximal event in the pathogenesis of IPF. Murine fibrosis models based on Surfactant Protein C gene ( SFTPC ) mutations identified in ILD patients cause activation of the AEC2 Unfolded Protein Response (UPR) and ER stress-an AEC2 dysfunction phenotype observed in IPF. While these models achieve spontaneous fibrosis, they do so with precedent lung injury and thus are challenged to phenocopy the general clinical course of patients with IPF-gradual progressive fibrosis and loss of lung function. Here, we report a refinement of a murine Sftpc mutation model to recapitulate the clinical course, physiological, parenchymal cellular composition, and biomarkers associated with IPF. This platform provides the field with an innovative model to understand IPF pathogenesis and index preclinical therapeutic candidates.