Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses
| Autor: | Julian S. Wehrmann, Christopher Tuffs, Marvin Biller, Cormac T. Taylor, Gwendolyn Kimmer, Alfonso Blanco, Alina S. Ritter, Jonathan M. Harnoss, Thomas Schmidt, Martin Schneider, Moritz J. Strowitzki, Johannes Klose, Vanessa M. Opitz, Praveen Radhakrishnan, Julia Kugler, Ulrich Keppler |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Colon Ischemia Anastomotic Leak Inflammation Anastomosis Gastroenterology Prolyl Hydroxylases Hypoxia-Inducible Factor-Proline Dioxygenases Mice 03 medical and health sciences 0302 clinical medicine Immune system Downregulation and upregulation Sepsis Internal medicine Abdomen medicine Animals Humans RNA Messenger Hypoxia Wound Healing business.industry Macrophages Anastomosis Surgical General Medicine Hypoxia (medical) medicine.disease Colorectal surgery Amino Acids Dicarboxylic 030104 developmental biology 030220 oncology & carcinogenesis Medicine Female Collagen Caco-2 Cells medicine.symptom Ligation business Collagens Research Article |
| Zdroj: | JCI Insight, Vol 6, Iss 8 (2021) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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 (Phd1-/-, Phd2+/-, and Phd3-/-) or PHI were applied to manipulate PHD activity. Pharmacologic PHI and genetic PHD2-haplodeficiency (Phd2+/-) significantly improved healing of ischemic or septic colonic anastomoses, as indicated by increased bursting pressure and reduced AL rates. Only Phd2+/- (but not PHI or Phd1-/-) protected from sepsis-related mortality. Mechanistically, PHI and Phd2+/- induced immuno-modulatory (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 Phd2+/--mediated M2 polarization of macrophages, conferring a favourable microenvironment for anastomotic healing. Patients with critically perfused colorectal anastomosis or abdominal sepsis could benefit from pharmacologic PHI. |
| Databáze: | OpenAIRE |
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