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ORIGINAL ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 1  |  Page : 43-48

Dual inhibition by phosphodiesterase 5 and 5-HT2BInhibitor leads to near complete amelioration of fibrotic potential of human adult dermal fibroblasts isolated from a scleroderma patient


1 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Correspondence Address:
Prof. Vikas Agarwal
Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_169_19

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Background: Conversion of quiescent resident fibroblasts to activated myofibroblasts by transforming growth factor-beta 1 (TGF-β1) is the hallmark of fibrotic pathogenesis of systemic sclerosis (SSc). Myofibroblasts are characterized by increased alpha smooth muscle actin (α-SMA) expression and extracellular matrix (ECM) proteins production. Objective: The aim of this study is to evaluate anti-fibrotic potential of dual inhibition by phosphodiesterase5 (PDE5) inhibitor, sildenafil plus 5-HT2Binhibitor, SB204741 in human adult dermal fibroblasts (HADFs) isolated from mid-forearm skin of a scleroderma patient. Materials and Methods: In disease-mimicking strategy, HADFs were incubated with TGF-β1 (10 ng/ml) for 1 hour, followed by TGF-β1 (10 ng/ml)/[sildenafil (10 μM) or SB204741 (1 μM)] or combination of the two for 24 hours. In pretreatment strategy, HADFs were pretreated with sildenafil (10 μM) or SB204741 (1 μM) or combination of the two for 1 hour and later with only TGF-β1 (10 ng/ml) for 24 hours. Real time quantitative polymerase chain reaction for pro-fibrotic (COL1A1, COL1A2, ACTA2, CCN2 and FN1) and anti-fibrotic genes (MMP2, TIMP1) was performed. Results: In TGF-β1 stimulated HADFs, upregulated expression of pro-fibrotic genes was observed (P < 0.05). Expression of pro-fibrotic genes in HADFs stimulated with TGF-β1 were significantly (P < 0.05) reduced by dual inhibition strategy with complete amelioration of ACTA2 in comparison to their respective individual treatments. Ratio of anti-fibrotic genes (MMP2/TIMP1) was restored significantly (P < 0.05). Conclusion: Dual inhibition strategy with sildenafil plus SB204741 leads to near complete amelioration of conversion of fibroblasts to myofibroblasts and thus may have the potential to treat fibrosis in scleroderma.


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