Abstract
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 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 Phd2+/–-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.
Highlights
Anastomotic leakage (AL) occurs in up to 7% of all patients undergoing colorectal surgery [1]
The present study demonstrates that prolyl hydroxylases (PHDs) inhibition by DMOG and Phd2+/– improve healing of colonic anastomoses under both ischemic and septic conditions in 2 relevant preclinical mouse models
Our in vitro findings suggest that PHD inhibition (PHI)- and Phd2+/–-induced M2 polarization of macrophages enhances wound healing capacities of intestinal epithelial cells and fibroblasts, which overall confers a favorable microenvironment within colonic anastomoses
Summary
Anastomotic leakage (AL) occurs in up to 7% of all patients undergoing colorectal surgery [1]. Sufficient oxygen supply to intestinal anastomoses is paramount for healing [4, 5], and ischemia represents one main cause for AL after colorectal surgery [6]. All metazoans that rely on sufficient oxygen supply are able to initiate a specific adaptive gene program, called the hypoxia-inducible factor (HIF) pathway [11]. This molecular response involves upregulation of numerous HIF target genes, which in concert either increase oxygen supply, for example, by forming new blood vessels (angiogenesis) and red blood cells (erythropoiesis), or adapt cellular metabolism to decrease oxygen consumption [11]. The first PHI has recently been approved to treat anemia in patients with chronic kidney diseases [14]
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