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MAPK phosphatase 1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution
Sean M. Fortier, … , Anton M. Bennett, Marc Peters-Golden
Sean M. Fortier, … , Anton M. Bennett, Marc Peters-Golden
Published March 21, 2024
Citation Information: J Clin Invest. 2024;134(10):e172826. https://doi.org/10.1172/JCI172826.
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Research Article Cell biology Pulmonology

MAPK phosphatase 1 inhibition of p38α within lung myofibroblasts is essential for spontaneous fibrosis resolution

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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 MKP1’s dephosphorylation of p38α MAPK (p38α). 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 p38α inhibitor VX-702. We conclude that MKP1 is a critical antifibrotic brake whose inhibition of pathogenic p38α in lung fibroblasts is necessary for fibrosis resolution following lung injury.

Authors

Sean M. Fortier, Natalie M. Walker, Loka R. Penke, Jared D. Baas, Qinxue Shen, Jennifer M. Speth, Steven K. Huang, Rachel L. Zemans, Anton M. Bennett, Marc Peters-Golden

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Figure 3

Lung fibroblast expression of MKP1 mitigates peak fibrosis and is essential for spontaneous fibrosis resolution following in vivo administration of bleomycin.

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Lung fibroblast expression of MKP1 mitigates peak fibrosis and is essent...
(A) Schematic illustrating the peak fibrosis protocol. (B) PCR of the Dusp1 locus in Cre– and Cre+ mouse tails following tamoxifen administration (left), and subsequent MKP1 protein by Western blot in Cre– or Cre+ cultured lung fibroblasts (right). (C) Hydroxyproline content quantified from the left and right upper/middle lobe lung homogenates in saline-treated, bleomycin-treated Cre– , and bleomycin-treated Cre+ mice on day 21. (D) Representative images of Masson’s trichrome staining of the right lower lobe from the same mice used in C. Scale bar: 1 mm. (E) Schematic illustrating the resolution protocol. (F) Representative images of Masson’s trichrome staining of the right lower lobe in saline- and bleomycin-treated WT Cre– mice on day 21 and bleomycin-treated Cre– or bleomycin-treated Cre+ mice on days 42 or 63. Scale bars: 1 mm (top row) and 100 μm (bottom row). (G) Hydroxyproline content quantified in left and right upper/middle lobe lung homogenates from the same mice in F. (H–J) Immunofluorescence microscopy images of bleomycin-treated mice at mid-resolution (day 42) depicting type I (PDPN) and type II (pro-SPC) alveolar epithelial cells (H), parenchymal bronchiolization (E-cadherin) (I), and alveolar macrophages (CD68) (J). White arrows in I depict normal airways. Open white arrowheads depict E-cadherin staining of type II alveolar epithelial cells. Solid white arrowheads point to alveolar regions devoid of type I cells and type II cell hyperplasia in H, regions of parenchymal bronchiolization in I, and alveolar macrophages in J. Scale bars: 500 μm (top row) and 50 μm (bottom row). Each data point represents an individual mouse. Significance for hydroxyproline was determined by 1-way ANOVA. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Bleo, bleomycin.

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