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Activation of the secretin (Sct)\/secretin receptor (SR) axis, expressed only by cholangiocytes, increases biliary proliferation, liver fibrosis, and bicarbonate secretion. We evaluated the effectiveness of SR antagonist treatment for early\u2010stage PBC. Male and female dominant\u2010negative TGF\u2010\u03b2 receptor II (dnTGF\u2010\u03b2RII) (model of PBC) and wild\u2010type mice at 12 wk of age were treated with saline or the SR antagonist, Sec 5\u201027, for 1 wk. dnTGF\u2010\u03b2RII mice expressed features of early\u2010stage PBC along with enhanced Sct\/SR axis activation and Sct secretion. dnTGF\u2010\u03b2RII mice had increased biliary proliferation or senescence, inflammation, and liver fibrosis. In dnTGF\u2010\u03b2RII mice, there was increased microRNA\u2010125b\/TGF\u2010\u03b21\/TGF\u2010\u03b2 receptor 1\/VEGF\u2010A signaling. Human early\u2010stage PBC patients had an increase in hepatobiliary Sct and SR expression and serum Sct levels. Increased biliary Sct\/SR signaling promotes biliary and hepatic damage during early\u2010stage PBC.\u2014Kennedy, L., Francis, H., Invernizzi, P., Venter, J., Wu, N., Carbone, M., Gershwin, M. E., Bernuzzi, F., Franchitto, A., Alvaro, D., Marzioni, M., Onori, P., Gaudio, E., Sybenga, A., Fabris, L., Meng, F., Glaser, S., Alpini, G. Secretin\/secretin receptor signaling mediates biliary damage and liver fibrosis in early\u2010stage primary biliary cholangitis. FASEB J. 33, 10269\u201310279 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201802606r","type":"journal-article","created":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T10:04:50Z","timestamp":1561716290000},"page":"10269-10279","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Secretin\/secretin receptor signaling mediates biliary damage and liver fibrosis in early\u2010stage primary biliary cholangitis"],"prefix":"10.1096","volume":"33","author":[{"given":"Lindsey","family":"Kennedy","sequence":"first","affiliation":[{"name":"Research, Central Texas Veterans Health Care System  Temple Texas USA"},{"name":"Department of Medical Physiology Texas A&amp;M University College of Medicine  Temple Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Francis","sequence":"additional","affiliation":[{"name":"Research, Central Texas Veterans Health Care System  Temple Texas USA"},{"name":"Department of Medical Physiology Texas A&amp;M University College of Medicine  Temple Texas USA"},{"name":"Baylor Scott &amp; 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