Genes, other than Muc5b, play a role in bleomycin-induced lung fibrosis
Year: 2021
Type: article
Abstract: Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function MUC5B promoter variant rs35705950 is the dominant genetic risk factor for IPF, yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of MUC5B. Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is Muc5b dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for Muc5b expression and lung fibrosis 3 wk after intratracheal bleomycin administration. Although we identified strains with low Muc5b expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high Muc5b expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between Muc5b expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with Muc5b and cause lung fibrosis.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: U.S. Department of Defense, U.S. Department of Veterans Affairs, Cancer Center, University of Colorado, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: Rocky Mountain Neurological Disorders Core Center, Role of Genetics in Idiopathic Pulmonary Fibrosis (IPF), G1565180698, G2904642737, MUC5B, a novel therapeutic target for Idiopathic Pulmonary Fibrosis (IPF), G446473160, Genes and Transcripts that Interact with MUC5B in Pulmonary Fibrosis, IDIOPATHIC PULMONARY FIBROSIS, A DISEASE INITIATED BY MUCOCILIARY DYSFUNCTION, Mechanisms of Familial Pulmonary Fibrosis, Preclinical Pulmonary Fibrosis, an opportune rare disease cohort, University of Colorado Anschutz Medical Campus DRC, University of Colorado Cancer Center Support Grant, Multi-Disciplinary Research Training in Respiratory Disease
OpenAlex ID: W3175902464