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Epithelial cell dysfunction is postulated as an important component in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mutations in the surfactant protein C (SP-C) gene (SFTPC), an alveolar type II (AT2) cell-restricted protein, have been found in sporadic and familial IPF. To causally link these events, we developed a knockin mouse model capable of regulated expression of an IPF-associated isoleucine-to-threonine substitution at codon 73 (I73T) in Sftpc ([SP-C.sup.I73T]). Tamoxifen-treated [SP-C.sup.I73T] cohorts developed rapid increases in [Sftpc.sup.I73T] mRNA and misprocessed [proSP- C.sup.I73T] protein accompanied by increased early mortality (days 7-14). This acute phase was marked by diffuse parenchymal lung injury, tissue infiltration by monocytes, polycellular alveolitis, and elevations in bronchoalveolar lavage and AT2 mRNA content of select inflammatory cytokines. Resolution of alveolitis (2-4 weeks), commensurate with a rise in TGF-[beta]1, was followed by aberrant remodeling marked by collagen deposition, AT2 cell hyperplasia, a-smooth muscle actin- positive ([alpha]-SMA-positive) cells, and restrictive lung physiology. The translational relevance of the model was supported by detection of multiple IPF biomarkers previously reported in human cohorts. These data provide proof of principle that mutant SP- C expression in vivo causes spontaneous lung fibrosis, strengthening the role of AT2 cell dysfunction as a key upstream driver of IPF pathogenesis., Introduction Idiopathic pulmonary fibrosis (IPF) represents the most common subtype of a larger family of diffuse parenchymal lung diseases (DPLDs) of unknown etiology in adults (1). The incidence of IPF [...]