Genes, other than Muc5b, play a role in bleomycin-induced lung fibrosis

Am J Physiol Lung Cell Mol Physiol. 2021 Aug 1;321(2):L440-L450. doi: 10.1152/ajplung.00615.2020. Epub 2021 Jun 23.

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.

Keywords: IPF; Muc5b; diversity outbred mice; lung fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bleomycin / adverse effects*
  • Bleomycin / pharmacology
  • Gene Expression Regulation / drug effects*
  • Idiopathic Pulmonary Fibrosis* / chemically induced
  • Idiopathic Pulmonary Fibrosis* / genetics
  • Idiopathic Pulmonary Fibrosis* / metabolism
  • Lung Injury / chemically induced
  • Lung Injury / genetics
  • Lung Injury / metabolism
  • Lung Injury / pathology
  • Male
  • Mice
  • Mucin-5B* / biosynthesis
  • Mucin-5B* / genetics
  • Respiratory Mucosa* / metabolism
  • Respiratory Mucosa* / pathology

Substances

  • Muc5b protein, mouse
  • Mucin-5B
  • Bleomycin

Associated data

  • figshare/10.6084/m9.figshare.13412555