Antifibrotic effects of 2-carba cyclic phosphatidic acid (2ccPA) in systemic sclerosis: contribution to the novel treatment.

Publisher: BioMed Central Country of Publication: England NLM ID: 101154438 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-6362 (Electronic) Linking ISSN: 14786354 NLM ISO Abbreviation: Arthritis Res Ther Subsets: MEDLINE

Original Publication: London : BioMed Central, 2003-

Cell Proliferation/*drug effects ; Fibroblasts/*drug effects ; Phosphatidic Acids/*therapeutic use ; Scleroderma, Systemic/*drug therapy; Animals ; Cell Proliferation/physiology ; Cells, Cultured ; Female ; Fibroblasts/pathology ; Fibrosis/drug therapy ; Fibrosis/pathology ; Humans ; Mice ; Mice, Inbred BALB C ; Phosphatidic Acids/pharmacology ; Scleroderma, Systemic/pathology ; Treatment Outcome

Background: Cyclic phosphatidic acid (cPA) has an inhibitory effect on the autotaxin (ATX)/lysophosphatidic acid (LPA) axis, which has been implicated to play an important role in the progression of fibrosis in systemic sclerosis (SSc). The purpose of this study is to assess the antifibrotic activity of cPA for the treatment of SSc using SSc skin fibroblasts and an animal model of bleomycin-induced skin fibrosis.
Methods: We used a chemically stable derivative of cPA (2ccPA). First, we investigated the effect of 2ccPA on extracellular matrix (ECM) expression in skin fibroblasts. Next, the effect of 2ccPA on the intracellular cAMP levels was determined to investigate the mechanisms of the antifibrotic activity of 2ccPA. Finally, we administered 2ccPA to bleomycin-induced SSc model mice to evaluate whether 2ccPA prevented the progression of skin fibrosis.
Results: 2ccPA decreased ECM expression in SSc skin fibroblasts and TGF-β1-treated healthy skin fibroblasts without LPA stimulation. 2ccPA increased the intracellular cAMP levels in skin fibroblasts, suggesting that the antifibrotic effect of 2ccPA was the consequence of the increase in the intracellular cAMP levels. Administration of 2ccPA also ameliorated the progression of bleomycin-induced skin fibrosis in mice.
Conclusions: Our data indicated that 2ccPA had inhibitory effects on the progression of skin fibrosis by abrogating ECM production from activated skin fibroblasts. These cells were repressed, at least in part, by increased intracellular cAMP levels. 2ccPA may be able to be used to treat fibrotic lesions in SSc.

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Keywords: Cyclic phosphatidic acid; Fibroblasts; Fibrosis; Systemic sclerosis; Treatment

0 (2-carba-cyclic phosphatidic acid)
0 (Phosphatidic Acids)

Date Created: 20190420 Date Completed: 20200513 Latest Revision: 20200513

20240829

PMC6472078

10.1186/s13075-019-1881-3

30999934