PMID- 33941248 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20231111 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 23 IP - 1 DP - 2021 May 3 TI - Soluble guanylate cyclase stimulator reduced the gastrointestinal fibrosis in bleomycin-induced mouse model of systemic sclerosis. PG - 133 LID - 10.1186/s13075-021-02513-y [doi] LID - 133 AB - BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune-mediated connective tissue disorder. Although the etiology of the disease remains undetermined, SSc is characterized by fibrosis and proliferative vascular lesions of the skin and internal organs. SSc involves the gastrointestinal tract in more than 90 % of patients. Soluble guanylate cyclase (sGC) stimulator is used to treat pulmonary artery hypertension (PAH) and has been shown to inhibit experimental skin fibrosis. METHODS: Female C57BL/6J mice were treated with BLM or normal saline by subcutaneous implantation of osmotic minipump. These mice were sacrificed on day 28 or day 42. Gastrointestinal pathologies were examined by Masson Trichrome staining. The expression of fibrosis-related genes in gastrointestinal tract was analyzed by real-time PCR, and the levels of collagen in the tissue were measured by Sircol collagen assay. To evaluate peristaltic movement, the small intestinal transport (ITR%) was calculated as [dyeing distance x (duodenum - appendix)] - 1 x 100 (%). We treated BLM-treated mice with sGC stimulator or DMSO orally and analyzed them on day 42. RESULTS: Histological examination revealed that fibrosis from lamina propria to muscularis mucosa in the esophagus was significantly increased in BLM-treated mice, suggesting that BLM induces esophageal hyperproliferative and prefibrotic response in C57BL/6J mice. In addition, the gene expression levels of Col3a1, CCN2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in the esophagus were significantly increased in BLM-treated mice. More severe hyperproliferative and prefibrotic response was observed in the mice sacrificed on day 42 than the mice sacrificed on day 28. The ITR% was found to be significantly lower in BLM-treated mice, suggesting that gastrointestinal peristaltic movement was reduced in BLM-treated mice. Furthermore, we demonstrated that sGC stimulator treatment significantly reduced hyperproliferative and prefibrotic response of esophagus and intestine in BLM-treated mice, by histological examination and Sircol collagen assay. CONCLUSIONS: These findings suggest that BLM induces gastrointestinal hyperproliferative and prefibrotic response in C57BL/6J mice, and treatment with sGC stimulator improves the BLM-induced gastrointestinal lesion. FAU - Yamamoto, Yuzuru AU - Yamamoto Y AD - Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. FAU - Okano, Takaichi AU - Okano T AD - Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. AD - Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan. FAU - Yamada, Hirotaka AU - Yamada H AD - Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. FAU - Akashi, Kengo AU - Akashi K AD - Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. FAU - Sendo, Sho AU - Sendo S AD - Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. FAU - Ueda, Yo AU - Ueda Y AD - Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. FAU - Morinobu, Akio AU - Morinobu A AD - Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. FAU - Saegusa, Jun AU - Saegusa J AUID- ORCID: 0000-0001-7606-3743 AD - Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. jsaegusa@med.kobe-u.ac.jp. AD - Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan. jsaegusa@med.kobe-u.ac.jp. LA - eng PT - Journal Article DEP - 20210503 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 11056-06-7 (Bleomycin) RN - EC 4.6.1.2 (Soluble Guanylyl Cyclase) SB - IM MH - Animals MH - Bleomycin MH - Disease Models, Animal MH - Female MH - Fibrosis MH - Gastrointestinal Tract MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - *Pulmonary Fibrosis MH - *Scleroderma, Systemic/chemically induced/drug therapy MH - Soluble Guanylyl Cyclase PMC - PMC8091711 OTO - NOTNLM OT - Gastrointestinal fibrosis OT - Soluble guanylate cyclase stimulator OT - Systemic sclerosis COIS- The authors declare that they have no competing interests. EDAT- 2021/05/05 06:00 MHDA- 2021/06/22 06:00 PMCR- 2021/05/03 CRDT- 2021/05/04 05:55 PHST- 2020/12/23 00:00 [received] PHST- 2021/04/15 00:00 [accepted] PHST- 2021/05/04 05:55 [entrez] PHST- 2021/05/05 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2021/05/03 00:00 [pmc-release] AID - 10.1186/s13075-021-02513-y [pii] AID - 2513 [pii] AID - 10.1186/s13075-021-02513-y [doi] PST - epublish SO - Arthritis Res Ther. 2021 May 3;23(1):133. doi: 10.1186/s13075-021-02513-y.