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Identifying a tractable mechanism for inactivating and possibly clearing these ultimate effector cells of progressive fibrosis, conventionally termed myofibroblasts (MFs), represents an appealing therapeutic strategy for patients with SSc. This can be accomplished by their phenotypic dedifferentiation, a process known to be promoted by the generation of the intracellular second messenger cyclic AMP (cAMP). Notably, however, the abilities of SSc fibroblasts derived from different tissues to generate cAMP\u2014and dedifferentiate in response to it\u2014have never been directly characterized or compared. Here we compared these two processes in lung and skin MFs derived from patients with SSc. While directly increasing intracellular cAMP induced comparable dedifferentiation of lung and skin SSc MFs, dedifferentiation in response to the well\u2010recognized cAMP stimulus prostaglandin E\n                    <jats:sub>2<\/jats:sub>\n                    (PGE\n                    <jats:sub>2<\/jats:sub>\n                    ) was diminished or absent in MFs from skin as compared to lung, in part due to differences in the expression of its target G protein\u2010coupled receptors (GPCRs). Importantly, treatment with a phosphodiesterase 4 inhibitor rescued the dedifferentiating effects of PGE\n                    <jats:sub>2<\/jats:sub>\n                    in skin SSc MFs. Finally, both cAMP\u2010mediated and direct pharmacologic inhibition of the MAPK p38\u03b1 promoted dedifferentiation of lung and skin SSc MFs. We conclude that activation of the cAMP pathway and its subsequent inhibition of p38\u03b1 dedifferentiates SSc MFs from both lung and skin, and may thus represent a therapeutic strategy to alleviate multi\u2010organ fibrosis in SSc.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500694rr","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T09:04:50Z","timestamp":1750755890000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Distinct cAMP Regulation in Scleroderma Lung and Skin Myofibroblasts Governs Their Dedifferentiation via p38\u03b1 Inhibition"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4088-4977","authenticated-orcid":false,"given":"Jared D.","family":"Baas","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine University of Michigan Medical School  Ann Arbor Michigan 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