ASK1 Regulates Bleomycin-induced Pulmonary Fibrosis

Samuel S. Valenca, Brittany E. Dong, Elizabeth M. Gordon, Ramon C. Sun, Christopher M. Waters

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Pulmonary fibrosis (PF) is an abnormal remodeling of cellular composition and extracellular matrix that results in histological and functional alterations in the lungs. Apoptosis signalregulating kinase-1 (ASK1) is a member of the mitogenactivated protein (MAP) kinase family that is activated by oxidative stress and promotes inflammation and apoptosis. Here we show that bleomycin-induced PF is reduced in Ask1 knockout mice (Ask12/2) compared with wild-type (WT) mice, with improved survival and histological and functional parameters restored to basal levels. In WT mice, bleomycin caused activation of ASK1, p38, and extracellular signalregulated kinase 1/2 (ERK1/2) in lung tissue, as well as changes in redox indicators (thioredoxin and heme-oxygenase-1), collagen content, and epithelial-mesenchymal transition markers (EMTs). These changes were largely restored toward untreated WT control levels in bleomycin-treated Ask12/2 mice. We further investigated whether treatment of WT mice with an ASK1 inhibitor, selonsertib (GS-4997), during the fibrotic phase would attenuate the development of PF. We found that pharmacological inhibition of ASK1 reduced activation of ASK1, p38, and ERK1/2 and promoted the restoration of redox and EMT indicators, as well as improvements in histological parameters. Our results suggest that ASK1 plays a central role in the development of bleomycininduced PF in mice via p38 and ERK1/2 signaling. Together, these data indicate a possible therapeutic target for PF that involves an ASK1/p38/ERK1/2 axis.

Original languageEnglish
Pages (from-to)484-496
Number of pages13
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume66
Issue number5
DOIs
StatePublished - May 2022

Bibliographical note

Publisher Copyright:
© 2022 American Thoracic Society. All rights reserved.

Keywords

  • apoptosis signalregulating kinase-1
  • bleomycin
  • pulmonary fibrosis
  • selonsertib

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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