1. MAPK phosphatase 1 inhibition of p38[alpha] within lung myofibroblasts is essential for spontaneous fibrosis resolution
- Author
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Fortier, Sean M., Walker, Natalie M., Penke, Loka R., Baas, Jared D., Shen, Qinxue, Speth, Jennifer M., Huang, Steven K., Zemans, Rachel L., and Peters-Golden, Anton M. Bennetand Marc
- Subjects
Pulmonary fibrosis -- Care and treatment -- Development and progression -- Diagnosis ,Enzyme inhibitors -- Identification and classification -- Testing ,Mitogen-activated protein kinases -- Physiological aspects -- Health aspects ,Health care industry - Abstract
Fibrosis following tissue injury is distinguished from normal repair by the accumulation of pathogenic and apoptosis-resistant myofibroblasts (MFs), which arise primarily by differentiation from resident fibroblasts. Endogenous molecular brakes that promote MF dedifferentiation and clearance during spontaneous resolution of experimental lung fibrosis may provide insights that could inform and improve the treatment of progressive pulmonary fibrosis in patients. MAPK phosphatase 1 (MKP1) influences the cellular phenotype and fate through precise and timely regulation of MAPK activity within various cell types and tissues, yet its role in lung fibroblasts and pulmonary fibrosis has not been explored. Using gain- and loss-of-function studies, we found that MKP1 promoted lung MF dedifferentiation and restored the sensitivity of these cells to apoptosis--effects determined to be mainly dependent on MKPI's dephosphorylation of p38[alpha] MAPK (p38[alpha]). Fibroblast-specific deletion of MKP1 following peak bleomycin-induced lung fibrosis largely abrogated its subsequent spontaneous resolution. Such resolution was restored by treating these transgenic mice with the p38[alpha] inhibitor VX-702. We conclude that MKP1 is a critical antifibrotic brake whose inhibition of pathogenic p38[alpha] in lung fibroblasts is necessary for fibrosis resolution following lung injury., Introduction Fibrosis is a disordered response to tissue injury characterized by abnormal wound healing and organ scarring. In pulmonary fibrosis, collagen accumulation and contraction of the parenchyma distort lung architecture [...]
- Published
- 2024
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