{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T16:34:38Z","timestamp":1781282078496,"version":"3.54.1"},"reference-count":61,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,18]],"date-time":"2024-02-18T00:00:00Z","timestamp":1708214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of University and Research","award":["MIRKOMANETTIRICATEN23"],"award-info":[{"award-number":["MIRKOMANETTIRICATEN23"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Conjunctival fibrosis is a serious clinical concern implicated in a wide spectrum of eye diseases, including outcomes of surgery for pterygium and glaucoma. It is mainly driven by chronic inflammation that stimulates conjunctival fibroblasts to differentiate into myofibroblasts over time, leading to abnormal wound healing and scar formation. Soluble guanylate cyclase (sGC) stimulation was found to suppress transforming growth factor \u03b2 (TGF\u03b2)-induced myofibroblastic differentiation in various stromal cells such as skin and pulmonary fibroblasts, as well as corneal keratocytes. Here, we evaluated the in vitro effects of stimulation of the sGC enzyme with the cell-permeable pyrazolopyridinylpyrimidine compound BAY 41-2272 in modulating the TGF\u03b21-mediated profibrotic activation of human conjunctival fibroblasts. Cells were pretreated with the sGC stimulator before challenging with recombinant human TGF\u03b21, and subsequently assayed for viability, proliferation, migration, invasiveness, myofibroblast marker expression, and contractile properties. Stimulation of sGC significantly counteracted TGF\u03b21-induced cell proliferation, migration, invasiveness, and acquisition of a myofibroblast-like phenotype, as shown by a significant downregulation of FAP, ACTA2, COL1A1, COL1A2, FN1, MMP2, TIMP1, and TIMP2 mRNA levels, as well as by a significant reduction in \u03b1-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein expression. In addition, pretreatment with the sGC stimulator was capable of significantly dampening TGF\u03b21-induced acquisition of a contractile phenotype by conjunctival fibroblasts, as well as phosphorylation of Smad3 and release of the proinflammatory cytokines IL-1\u03b2 and IL-6. Taken together, our findings are the first to demonstrate the effectiveness of pharmacological sGC stimulation in counteracting conjunctival fibroblast-to-myofibroblast transition, thus providing a promising scientific background to further explore the feasibility of sGC stimulators as potential new adjuvant therapeutic compounds to treat conjunctival fibrotic conditions.<\/jats:p>","DOI":"10.3390\/cells13040360","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T11:23:57Z","timestamp":1708341837000},"page":"360","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pharmacological Stimulation of Soluble Guanylate Cyclase Counteracts the Profibrotic Activation of Human Conjunctival Fibroblasts"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9275-7593","authenticated-orcid":false,"given":"Bianca Saveria","family":"Fioretto","sequence":"first","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6352-0175","authenticated-orcid":false,"given":"Irene","family":"Rosa","sequence":"additional","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3980-3073","authenticated-orcid":false,"given":"Elena","family":"Andreucci","sequence":"additional","affiliation":[{"name":"Section of Experimental Pathology and Oncology, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, Viale Morgagni 50, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1856-6363","authenticated-orcid":false,"given":"Rita","family":"Mencucci","sequence":"additional","affiliation":[{"name":"Eye Clinic, Careggi Hospital, Department of Neurosciences, Psychology, Pharmacology and Child Health (NEUROFARBA), University of Florence, Largo Brambilla 3, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1934-0414","authenticated-orcid":false,"given":"Mirca","family":"Marini","sequence":"additional","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2744-8625","authenticated-orcid":false,"given":"Eloisa","family":"Romano","sequence":"additional","affiliation":[{"name":"Section of Internal Medicine, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3956-8480","authenticated-orcid":false,"given":"Mirko","family":"Manetti","sequence":"additional","affiliation":[{"name":"Section of Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy"},{"name":"Imaging Platform, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,18]]},"reference":[{"key":"ref_1","unstructured":"Shumway, C.L., Motlagh, M., and Wade, M. 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