Abstract
Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Reliable therapeutic options to reduce peritoneal adhesions are scarce. We investigated whether the formation of postsurgical adhesions can be affected by pharmacological interference with hypoxia-inducible factors (HIFs). Mice were treated with a small molecule HIF-inhibitor, YC-1 (3-[5′-Hydroxymethyl-2′-furyl]-1-benzyl-indazole), or vehicle three days before and seven days after induction of peritoneal adhesions or, alternatively, once during induction of peritoneal adhesions. Pretreatment or single intraperitoneal lavage with YC-1 significantly reduced postoperative adhesion formation without prompting systemic adverse effects. Expression analyses of cytokines in peritoneal tissue and fluid and in vitro assays applying macrophages and peritoneal fibroblasts indicated that this effect was cooperatively mediated by various putatively HIF-1α-dependent mechanisms, comprising attenuated pro-inflammatory activation of macrophages, impaired recruitment and activation of peritoneal fibroblasts, mitigated epithelial-mesenchymal-transition (EMT), as well as enhanced fibrinolysis and impaired angiogenesis. Thus, this study identifies prevention of postsurgical peritoneal adhesions as a novel and promising field for the application of HIF inhibitors in clinical practice.
Highlights
Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation
In a first approach to assess the effects of YC-1 on postoperative adhesion formation, treatment with YC-1 (20 mg/kg BW i.p.) was initiated three days prior to adhesion induction applying the ischemic buttons model, and continued until evaluation on postoperative day seven (“pretreatment” scheme, Fig. 1a, left)
We demonstrate that intraperitoneal treatment with a small molecule hypoxia-inducible factors (HIFs)-inhibitor, YC-1, reduces the formation of postoperative peritoneal adhesions in a preclinical rodent model
Summary
Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Development of permanent adhesions is a multistep process, comprising a macrophage-driven inflammatory response, formation of a fibrinous exudate, recruitment of fibroblasts which become activated to form myofibroblasts, excess collagen fibre deposition and subsequent vascularization[2,3,4,5]. These processes occur in a low oxygen environment (hypoxia), which critically modulates inflammation and healing[3,6,7].
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