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.
|Number of pages||13|
|Journal||American Journal of Respiratory Cell and Molecular Biology|
|State||Published - May 2022|
Bibliographical noteFunding Information:
Acknowledgment: The authors thank Dr. Wendy Katz from the University of Kentucky Pathology Research Core for providing sections/stains for histology for this study (supported by COBRE Grant P30 GM127211). S.S.V. was granted a sabbatical from the Federal University of Rio de Janeiro (Brazil).
Supported by the National Heart, Lung, and Blood Institute grants HL131526 and HL151419 (C.M.W.).
© 2022 American Thoracic Society. All rights reserved.
- apoptosis signalregulating kinase-1
- pulmonary fibrosis
ASJC Scopus subject areas
- Molecular Biology
- Pulmonary and Respiratory Medicine
- Clinical Biochemistry
- Cell Biology