Baas Jared D, Varga John, Feghali-Bostwick Carol, Peters-Golden Marc, Fortier Sean M
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Division of Rheumatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
FASEB J. 2025 Jun 30;39(12):e70762. doi: 10.1096/fj.202500694RR.
Fibrosis in systemic sclerosis/scleroderma (SSc) is characterized by the progressive accumulation and persistence in multiple organs of pathologic fibroblasts whose contractile properties and exuberant secretion of collagens promote tissue stiffness and scarring. 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-and dedifferentiate in response to it-have 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-recognized cAMP stimulus prostaglandin E (PGE) 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-coupled receptors (GPCRs). Importantly, treatment with a phosphodiesterase 4 inhibitor rescued the dedifferentiating effects of PGE in skin SSc MFs. Finally, both cAMP-mediated and direct pharmacologic inhibition of the MAPK p38α promoted dedifferentiation of lung and skin SSc MFs. We conclude that activation of the cAMP pathway and its subsequent inhibition of p38α dedifferentiates SSc MFs from both lung and skin, and may thus represent a therapeutic strategy to alleviate multi-organ fibrosis in SSc.
系统性硬化症/硬皮病（SSc）中的纤维化特征在于病理性成纤维细胞在多个器官中进行性积累并持续存在，这些成纤维细胞的收缩特性和大量胶原蛋白分泌会促进组织僵硬和瘢痕形成。确定一种可处理的机制来使这些进行性纤维化的最终效应细胞（传统上称为肌成纤维细胞，MFs）失活并可能清除，这对SSc患者而言是一种有吸引力的治疗策略。这可以通过它们的表型去分化来实现，这一过程已知会因细胞内第二信使环磷酸腺苷（cAMP）的产生而得到促进。然而，值得注意的是，来自不同组织的SSc成纤维细胞产生cAMP以及对其作出反应而去分化的能力从未得到直接表征或比较。在这里，我们比较了来自SSc患者的肺和皮肤MFs中的这两个过程。虽然直接增加细胞内cAMP可诱导肺和皮肤SSc MFs产生相当的去分化，但与肺相比，皮肤MFs对公认的cAMP刺激物前列腺素E（PGE）的反应性去分化减弱或不存在，部分原因是其靶标G蛋白偶联受体（GPCRs）表达存在差异。重要的是，用磷酸二酯酶4抑制剂治疗可挽救PGE对皮肤SSc MFs的去分化作用。最后，cAMP介导的以及对丝裂原活化蛋白激酶p38α的直接药理学抑制均促进了肺和皮肤SSc MFs的去分化。我们得出结论，cAMP途径的激活及其随后对p38α的抑制可使肺和皮肤来源的SSc MFs去分化，因此可能代表一种减轻SSc中多器官纤维化的治疗策略。
