{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:36:13Z","timestamp":1792614973872,"version":"4.5.0"},"reference-count":53,"publisher":"American Society for Clinical Investigation","issue":"8","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"crossref","award":["031L0084"],"award-info":[{"award-number":["031L0084"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["SCHN 947\/4-2"],"award-info":[{"award-number":["SCHN 947\/4-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["STR 1570\/1-1"],"award-info":[{"award-number":["STR 1570\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010345","name":"B. Braun-Stiftung","doi-asserted-by":"crossref","award":["BBST-D-18-00018"],"award-info":[{"award-number":["BBST-D-18-00018"]}],"id":[{"id":"10.13039\/100010345","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,22]]},"abstract":"<jats:p>\n                    Anastomotic leakage (AL) accounts for a major part of in-house mortality in patients undergoing colorectal surgery. Local ischemia and abdominal sepsis are common risk factors contributing to AL and are characterized by upregulation of the hypoxia-inducible factor (HIF) pathway. The HIF pathway is critically regulated by HIF-prolyl hydroxylases (PHDs). Here, we investigated the significance of PHDs and the effects of pharmacologic PHD inhibition (PHI) during anastomotic healing. Ischemic or septic colonic anastomoses were created in mice by ligation of mesenteric vessels or lipopolysaccharide-induced abdominal sepsis, respectively. Genetic PHD deficiency (\n                    <jats:italic>Phd1<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    ,\n                    <jats:italic>\n                      Phd2\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    , and\n                    <jats:italic>Phd3<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    ) or PHI were applied to manipulate PHD activity. Pharmacologic PHI and genetic PHD2 haplodeficiency (\n                    <jats:italic>\n                      Phd2\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    ) significantly improved healing of ischemic or septic colonic anastomoses, as indicated by increased bursting pressure and reduced AL rates. Only\n                    <jats:italic>\n                      Phd2\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    (but not PHI or\n                    <jats:italic>Phd1<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    ) protected from sepsis-related mortality. Mechanistically, PHI and\n                    <jats:italic>\n                      Phd2\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    induced immunomodulatory (M2) polarization of macrophages, resulting in increased collagen content and attenuated inflammation-driven immune cell recruitment. We conclude that PHI improves healing of colonic anastomoses in ischemic or septic conditions by\n                    <jats:italic>\n                      Phd2\n                      <jats:sup>+\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    -mediated M2 polarization of macrophages, conferring a favorable microenvironment for anastomotic healing. Patients with critically perfused colorectal anastomosis or abdominal sepsis could benefit from pharmacologic PHI.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.139191","type":"journal-article","created":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T12:00:38Z","timestamp":1617105638000},"source":"Crossref","is-referenced-by-count":21,"title":["Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6967-9283","authenticated-orcid":true,"given":"Moritz J.","family":"Strowitzki","sequence":"first","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."},{"name":"School of Medicine and Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendolyn","family":"Kimmer","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Wehrmann","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina S.","family":"Ritter","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa M.","family":"Opitz","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Tuffs","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Biller","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Kugler","sequence":"additional","affiliation":[{"name":"School of Medicine and Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Keppler","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."},{"name":"Department of Anaesthesiology, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Harnoss","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7289-2891","authenticated-orcid":true,"given":"Johannes","family":"Klose","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7166-3675","authenticated-orcid":true,"given":"Thomas","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery, Heidelberg University, Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0439-0838","authenticated-orcid":true,"given":"Alfonso","family":"Blanco","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core Technology. 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