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An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis
Jeremy Katzen, … , Robin R. Deterding, Michael F. Beers
Jeremy Katzen, … , Robin R. Deterding, Michael F. Beers
Published February 5, 2019
Citation Information: JCI Insight. 2019;4(6):e126125. https://doi.org/10.1172/jci.insight.126125.
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Research Article Pulmonology

An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis

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Abstract

Alveolar type 2 (AT2) cell endoplasmic reticulum (ER) stress is a prominent feature in adult and pediatric interstitial lung disease (ILD and ChILD), but in vivo models linking AT2 cell ER stress to ILD have been elusive. Based on a clinical ChILD case, we identified a critical cysteine residue in the surfactant protein C gene (SFTPC) BRICHOS domain whose mutation induced ER stress in vitro. To model this in vivo, we generated a knockin mouse model expressing a cysteine-to-glycine substitution at codon 121 (C121G) in the Sftpc gene. SftpcC121G expression during fetal development resulted in a toxic gain-of-function causing fatal postnatal respiratory failure from disrupted lung morphogenesis. Induced SftpcC121G expression in adult mice resulted in an ER-retained pro-protein causing AT2 cell ER stress. SftpcC121G AT2 cells were a source of cytokines expressed in concert with development of polycellular alveolitis. These cytokines were subsequently found in a high-dimensional proteomic screen of bronchoalveolar lavage fluid from ChILD patients with the same class of SFTPC mutations. Following alveolitis resolution, SftpcC121G mice developed spontaneous pulmonary fibrosis and restrictive lung impairment. This model provides proof of concept linking AT2 cell ER stress to fibrotic lung disease coupled with translationally relevant biomarkers.

Authors

Jeremy Katzen, Brandie D. Wagner, Alessandro Venosa, Meghan Kopp, Yaniv Tomer, Scott J. Russo, Alvis C. Headen, Maria C. Basil, James M. Stark, Surafel Mulugeta, Robin R. Deterding, Michael F. Beers

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Figure 7

Pediatric SFTPC BRICHOS mutation patients elaborate multiple cytokines associated with macrophage/monocyte recruitment found in SftpcC121G mice.

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Pediatric SFTPC BRICHOS mutation patients elaborate multiple cytokines a...
(A) Volcano plot of SOMAscan proteomics platform analysis of BALF from SFTPC BRICHOS mutations cases (n = 5) and disease control (n = 9). Minus log10–transformed P value on y axis, and log2 difference on x axis. Conservative selection of cytokines associated with immune cell recruitment with relative florescence units (RFU) difference greater than 1 on a log2 scale and P < 0.001 (shown in red). (B–D) Individual dot plots of mean ± SEM log2 RFU for (B) CCL2, (C) CCL17, and (D) CCL7. *P < 0.05 for SFTPC BRICHOS mutation cases versus disease control using unpaired 2-tailed t test.

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