{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:10:47Z","timestamp":1789063847124,"version":"build-2803163510"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T00:00:00Z","timestamp":1651276800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>In extrahepatic bile duct (EHBD) cholangiopathies, including primary sclerosing cholangitis, a reactive cholangiocyte phenotype is associated with inflammation and epithelial hyperproliferation. The signaling pathways involved in EHBD injury response are poorly understood. In this study, we investigated the role of Hedgehog (HH) signaling and its downstream effectors in controlling biliary proliferation and inflammation after EHBD injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      Using mouse bile duct ligation as an acute EHBD injury model, we used inhibitory paradigms to uncover mechanisms promoting the proliferative response. HH signaling was inhibited genetically in\n                      <jats:italic toggle=\"yes\">Gli1\u2212\/\u2212<\/jats:italic>\n                      mice or by treating wild\u2010type mice with LDE225. The role of neutrophils was tested using chemical (SB225002) and biological (lymphocyte antigen 6 complex locus G6D [Ly6G] antibodies) inhibitors of neutrophil recruitment. The cellular response was defined through morphometric quantification of proliferating cells and CD45+ and Ly6G+ immune cell populations. Key signaling component expression was measured and localized to specific EHBD cellular compartments by\n                      <jats:italic toggle=\"yes\">in situ<\/jats:italic>\n                      hybridization, reporter strain analysis, and immunohistochemistry. Epithelial cell proliferation peaked 24 h after EHBD injury, preceded stromal cell proliferation, and was associated with neutrophil influx. Indian HH ligand expression in the biliary epithelium rapidly increased after injury. HH\u2010responding cells and neutrophil chemoattractant C\u2010X\u2010C motif chemokine ligand 1 (CXCL1) expression mapped to EHBD stromal cells. Inhibition of HH signaling blocked CXCL1 induction, diminishing neutrophil recruitment and the biliary proliferative response to injury. Directly targeting neutrophils by inhibition of the CXCL1\/C\u2010X\u2010C motif chemokine receptor 2\/Ly6G signaling axis also decreased biliary proliferation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HH\u2010regulated CXCL1 orchestrates the early inflammatory response and biliary proliferation after EHBD injury through complex cellular crosstalk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32492","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T03:58:19Z","timestamp":1649303899000},"page":"936-950","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":11,"title":["C\u2010X\u2010C motif chemokine ligand 1 induced by Hedgehog signaling promotes mouse extrahepatic bile duct repair after acute injury"],"prefix":"10.1097","volume":"76","author":[{"given":"Nureen H.","family":"Mohamad Zaki","sequence":"first","affiliation":[{"name":"1259,Department of Internal Medicine,University of Michigan,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Shiota","sequence":"additional","affiliation":[{"name":"1259,Department of Internal Medicine,University of Michigan,Ann Arbor,Michigan,USA"},{"name":"12961,Department of Gastroenterology and Hepatology,Nagasaki University,Nagasaki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley N.","family":"Calder","sequence":"additional","affiliation":[{"name":"1259,Department of Internal Medicine,University of Michigan,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa M.","family":"Keeley","sequence":"additional","affiliation":[{"name":"1259,Department of Molecular and Integrative Physiology,University of Michigan,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin L.","family":"Allen","sequence":"additional","affiliation":[{"name":"1259,Department of Cell and Developmental Biology,University of Michigan,Ann Arbor,Michigan,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Nakao","sequence":"additional","affiliation":[{"name":"12961,Department of Gastroenterology and Hepatology,Nagasaki University,Nagasaki,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda C.","family":"Samuelson","sequence":"additional","affiliation":[{"name":"1259,Department of Internal Medicine,University of Michigan,Ann Arbor,Michigan,USA"},{"name":"1259,Department of Molecular and Integrative Physiology,University of Michigan,Ann 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