Expression of a surfactant protein C mutation impairs postnatal expansion of alveolar type 2 epithelial cells leading to permanent cell loss and decreased repair capacity in adult lungs

ABSTRACT: Mutations in the gene encoding surfactant protein C (SFTPC) are associated with interstitial lung disease in children and adults. To assess the natural history of disease, we knocked-in a familial, disease-associated SFTPC mutation, L188Q (L184Q in mice), into the mouse Sftpc locus. Expression of the L184Q allele (LQ) resulted in formation of an unstable, misfolded proprotein (proSP-CLQ) that was rapidly degraded by the proteasome pathway. Translation of proSP-CLQ exceeded that of proSP-CWT in neonatal AT2 cells and was associated with transient activation of oxidative stress and apoptosis leading to impaired expansion of AT2 cells during postnatal alveolarization. Consequently, adult mutant mice demonstrated a decrease in the number of AT2 cells with no effect on lung homeostasis; however, lung regeneration in response to bleomycin challenge was substantially reduced in mutant mice. Collectively, these data support the hypothesis that susceptibility to disease in adult mutant mice is established during postnatal lung development and is associated with a permanent reduction in AT2 cell numbers.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Timothy E. Weaver  

PROVIDER: MSV000085976 | MassIVE | Wed Aug 19 06:54:00 BST 2020

REPOSITORIES: MassIVE