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Skin and lung tissue sections from patients with\n SS<\/jats:styled-content>\n c and healthy donors were immunostained for leukotriene A\n 4<\/jats:sub>\n hydrolase (\n LTA<\/jats:styled-content>\n 4<\/jats:sub>\n H), the critical enzyme for\n LTB<\/jats:styled-content>\n 4<\/jats:sub>\n synthesis, and BLT1, in combination with different cell markers. In mouse models of\n SS<\/jats:styled-content>\n c using bleomycin or angiotensin\n II<\/jats:styled-content>\n challenge or immunization with the\n DNA<\/jats:styled-content>\n topoisomerase I, genetic or pharmacologic interruption of the\n LTB<\/jats:styled-content>\n 4<\/jats:sub>\n \u2013\n BLT1<\/jats:styled-content>\n axis in mice was carried out to assess its effects on systemic disease features and myofibroblast markers. Immunoblotting was performed to examine the signaling pathway in fibroblasts and endothelial cells following stimulation with LTB\n 4<\/jats:sub>\n or with serum from SSc patients.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Serum\n LTB<\/jats:styled-content>\n 4<\/jats:sub>\n levels were 44.93% higher in patients with\n SS<\/jats:styled-content>\n c than in matched healthy controls (mean \u00b1\n SD<\/jats:styled-content>\n 220.3 \u00b1 74.75 pg\/ml versus 152.0 \u00b1 68.05 pg\/ml;\n P<\/jats:italic>\n < 0.0001), and this was associated with the patient subsets of\n SS<\/jats:styled-content>\n c\u2010associated interstitial lung disease and diffuse cutaneous\n SS<\/jats:styled-content>\n c. Levels of\n LTA<\/jats:styled-content>\n 4<\/jats:sub>\n H and BLT1 were increased in lesional areas of the skin and lungs of\n SS<\/jats:styled-content>\n c patients, and both were abundant in myofibroblasts and endothelial cells. Interruption of the\n LTB<\/jats:styled-content>\n 4<\/jats:sub>\n \u2013\n BLT1<\/jats:styled-content>\n axis in mouse models of\n SS<\/jats:styled-content>\n c significantly mitigated dermal and pulmonary fibrosis, with 54.00% and 52.65% fewer \u03b1\u2010smooth muscle actin\u2013positive myofibroblasts accumulating in the skin and lungs of mice, respectively, after bleomycin challenge. Immunoblotting of cultures with recombinant\n LTB<\/jats:styled-content>\n 4<\/jats:sub>\n \u2013stimulated fibroblasts and endothelial cells or with serum from\n SS<\/jats:styled-content>\n c patients showed that fibroblast\u2013myofibroblast and endothelial\u2013mesenchymal transitions were promoted via BLT1, and that this was dependent on activation of the phosphatidylinositol 3\u2010kinase (\n PI<\/jats:styled-content>\n 3K)\/Akt\/mechanistic target of rapamycin (\n mTOR<\/jats:styled-content>\n ) pathway but independent of the release of transforming growth factor \u03b2 (\n TGF<\/jats:styled-content>\n \u03b2) by fibroblasts or endothelial cells.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The\n LTB<\/jats:styled-content>\n 4<\/jats:sub>\n \u2013\n BLT1<\/jats:styled-content>\n axis may contribute to fibrosis in\n SS<\/jats:styled-content>\n c by directly promoting myofibroblast differentiation via the\n PI<\/jats:styled-content>\n 3K\/Akt\/\n mTOR<\/jats:styled-content>\n pathway, and this appears to operate independently of autocrine secretion of\n TGF<\/jats:styled-content>\n \u03b2.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.41192","type":"journal-article","created":{"date-parts":[[2019,12,24]],"date-time":"2019-12-24T02:55:52Z","timestamp":1577156152000},"page":"1013-1025","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Promotion of Myofibroblast Differentiation and Tissue Fibrosis by the Leukotriene B\n 4<\/sub>\n \u2013Leukotriene B\n 4<\/sub>\n Receptor Axis in Systemic Sclerosis"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7650-1237","authenticated-orcid":false,"given":"Minrui","family":"Liang","sequence":"first","affiliation":[{"name":"Huashan Hospital and Fudan University Shanghai 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