Pharmacological HIF-inhibition attenuates postoperative adhesion formation

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...

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Autores principales:	Moritz J. Strowitzki, Alina S. Ritter, Praveen Radhakrishnan, Jonathan M. Harnoss, Vanessa M. Opitz, Marvin Biller, Julian Wehrmann, Ulrich Keppler, Jana Scheer, Markus Wallwiener, Thomas Schmidt, Alexis Ulrich, Martin Schneider
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/43eac480f7274873bf568b3a53b3ff8a
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spelling	oai:doaj.org-article:43eac480f7274873bf568b3a53b3ff8a2021-12-02T15:05:31ZPharmacological HIF-inhibition attenuates postoperative adhesion formation10.1038/s41598-017-13638-z2045-2322https://doaj.org/article/43eac480f7274873bf568b3a53b3ff8a2017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-13638-zhttps://doaj.org/toc/2045-2322Abstract 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.Moritz J. StrowitzkiAlina S. RitterPraveen RadhakrishnanJonathan M. HarnossVanessa M. OpitzMarvin BillerJulian WehrmannUlrich KepplerJana ScheerMarkus WallwienerThomas SchmidtAlexis UlrichMartin SchneiderNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Moritz J. Strowitzki Alina S. Ritter Praveen Radhakrishnan Jonathan M. Harnoss Vanessa M. Opitz Marvin Biller Julian Wehrmann Ulrich Keppler Jana Scheer Markus Wallwiener Thomas Schmidt Alexis Ulrich Martin Schneider Pharmacological HIF-inhibition attenuates postoperative adhesion formation
description	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.
format	article
author	Moritz J. Strowitzki Alina S. Ritter Praveen Radhakrishnan Jonathan M. Harnoss Vanessa M. Opitz Marvin Biller Julian Wehrmann Ulrich Keppler Jana Scheer Markus Wallwiener Thomas Schmidt Alexis Ulrich Martin Schneider
author_facet	Moritz J. Strowitzki Alina S. Ritter Praveen Radhakrishnan Jonathan M. Harnoss Vanessa M. Opitz Marvin Biller Julian Wehrmann Ulrich Keppler Jana Scheer Markus Wallwiener Thomas Schmidt Alexis Ulrich Martin Schneider
author_sort	Moritz J. Strowitzki
title	Pharmacological HIF-inhibition attenuates postoperative adhesion formation
title_short	Pharmacological HIF-inhibition attenuates postoperative adhesion formation
title_full	Pharmacological HIF-inhibition attenuates postoperative adhesion formation
title_fullStr	Pharmacological HIF-inhibition attenuates postoperative adhesion formation
title_full_unstemmed	Pharmacological HIF-inhibition attenuates postoperative adhesion formation
title_sort	pharmacological hif-inhibition attenuates postoperative adhesion formation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/43eac480f7274873bf568b3a53b3ff8a
work_keys_str_mv	AT moritzjstrowitzki pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT alinasritter pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT praveenradhakrishnan pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT jonathanmharnoss pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT vanessamopitz pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT marvinbiller pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT julianwehrmann pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT ulrichkeppler pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT janascheer pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT markuswallwiener pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT thomasschmidt pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT alexisulrich pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation AT martinschneider pharmacologicalhifinhibitionattenuatespostoperativeadhesionformation
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Pharmacological HIF-inhibition attenuates postoperative adhesion formation

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