ArticleJCI insight2021
Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 15 citations in OpenAlex.
- Immunomodulatory thermosensitive hydroxypropyl chitin hydrogel platform maintains cartilage-synovium homeostasis for enhanced osteoarthritis therapy.Bioactive materials · 2026Article
- Macrophages in Intestinal Wound Healing: Dichotomous Effects and Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- IMMUNOREACT 4: Peritumoral Microenvironment Associated with Anastomotic Leaks After Surgery for Rectal Cancer.Cancers · 2026Article
- Microenvironment-Responsive Nanomaterials for Colorectal Anastomotic Healing: A Signal-Threshold-Response Framework for Stage-Adaptive Repair.International journal of nanomedicine · 2026Review
- Comparison of the effects of stent-based diversion technique versus prophylactic double-lumen ileostomy on intestinal flora in postoperative patients with rectal cancer.Frontiers in microbiology · 2026Article
- Bioinspired injectable hydrogels for bone regeneration.Journal of advanced research · 2025Review
- Layer-specific molecular signatures of colon anastomotic healing and leakage in mice.Molecular medicine (Cambridge, Mass.) · 2025Article
- Targeting hypoxia-inducible factor-1 alpha suppressesGut microbes · 2023Article
- Enhancement of Collagen-I Levels in Human Gingival Fibroblasts by Small Molecule Activation of HIF-1α.Journal of agricultural and food chemistry · 2023Article
- Bacterial Lysate from the Multi-Strain Probiotic SLAB51 Triggers Adaptative Responses to Hypoxia in Human Caco-2 Intestinal Epithelial Cells under Normoxic Conditions and Attenuates LPS-Induced Inflammatory Response.International journal of molecular sciences · 2023Article
- Hydrogel Drug Delivery Systems for Bone Regeneration.Pharmaceutics · 2023Review
- Article
- Immunometabolic Signature during Respiratory Viral Infection: A Potential Target for Host-Directed Therapies.Viruses · 2023Review
- Perspectives on Hypoxia Signaling in Tumor Stroma.Cancers · 2021Review
- Healing of colonic anastomosis in rats under obstructive ileus conditions.Discoveries (Craiova, Romania)Article
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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