Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.

Clinical trials revealed beneficial effects of the broad-spectrum serine protease inhibitor aprotinin on the prevention of ischemia-reperfusion (I/R) injury. The underlying mechanisms remained largely unclear. Using in vivo microscopy on the cremaster muscle of male C57BL/6 mice, aprotinin as well a...

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Autores principales:	Christoph A Reichel, Max Lerchenberger, Bernd Uhl, Markus Rehberg, Nina Berberich, Stefan Zahler, Matthias P Wymann, Fritz Krombach
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9f20a55c123c4dfeae4eefe5ebad8b90
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spelling	oai:doaj.org-article:9f20a55c123c4dfeae4eefe5ebad8b902021-11-18T06:58:28ZPlasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.1932-620310.1371/journal.pone.0017229https://doaj.org/article/9f20a55c123c4dfeae4eefe5ebad8b902011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21364954/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Clinical trials revealed beneficial effects of the broad-spectrum serine protease inhibitor aprotinin on the prevention of ischemia-reperfusion (I/R) injury. The underlying mechanisms remained largely unclear. Using in vivo microscopy on the cremaster muscle of male C57BL/6 mice, aprotinin as well as inhibitors of the serine protease plasmin including tranexamic acid and ε-aminocaproic acid were found to significantly diminish I/R-elicited intravascular firm adherence and (subsequent) transmigration of neutrophils. Remodeling of collagen IV within the postischemic perivenular basement membrane was almost completely abrogated in animals treated with plasmin inhibitors or aprotinin. In separate experiments, incubation with plasmin did not directly activate neutrophils. Extravascular, but not intravascular administration of plasmin caused a dose-dependent increase in numbers of firmly adherent and transmigrated neutrophils. Blockade of mast cell activation as well as inhibition of leukotriene synthesis or antagonism of the platelet-activating-factor receptor significantly reduced plasmin-dependent neutrophil responses. In conclusion, our data suggest that extravasated plasmin(ogen) mediates neutrophil recruitment in vivo via activation of perivascular mast cells and secondary generation of lipid mediators. Aprotinin as well as the plasmin inhibitors tranexamic acid and ε-aminocaproic acid interfere with this inflammatory cascade and effectively prevent postischemic neutrophil responses as well as remodeling events within the vessel wall.Christoph A ReichelMax LerchenbergerBernd UhlMarkus RehbergNina BerberichStefan ZahlerMatthias P WymannFritz KrombachPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 2, p e17229 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christoph A Reichel Max Lerchenberger Bernd Uhl Markus Rehberg Nina Berberich Stefan Zahler Matthias P Wymann Fritz Krombach Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.
description	Clinical trials revealed beneficial effects of the broad-spectrum serine protease inhibitor aprotinin on the prevention of ischemia-reperfusion (I/R) injury. The underlying mechanisms remained largely unclear. Using in vivo microscopy on the cremaster muscle of male C57BL/6 mice, aprotinin as well as inhibitors of the serine protease plasmin including tranexamic acid and ε-aminocaproic acid were found to significantly diminish I/R-elicited intravascular firm adherence and (subsequent) transmigration of neutrophils. Remodeling of collagen IV within the postischemic perivenular basement membrane was almost completely abrogated in animals treated with plasmin inhibitors or aprotinin. In separate experiments, incubation with plasmin did not directly activate neutrophils. Extravascular, but not intravascular administration of plasmin caused a dose-dependent increase in numbers of firmly adherent and transmigrated neutrophils. Blockade of mast cell activation as well as inhibition of leukotriene synthesis or antagonism of the platelet-activating-factor receptor significantly reduced plasmin-dependent neutrophil responses. In conclusion, our data suggest that extravasated plasmin(ogen) mediates neutrophil recruitment in vivo via activation of perivascular mast cells and secondary generation of lipid mediators. Aprotinin as well as the plasmin inhibitors tranexamic acid and ε-aminocaproic acid interfere with this inflammatory cascade and effectively prevent postischemic neutrophil responses as well as remodeling events within the vessel wall.
format	article
author	Christoph A Reichel Max Lerchenberger Bernd Uhl Markus Rehberg Nina Berberich Stefan Zahler Matthias P Wymann Fritz Krombach
author_facet	Christoph A Reichel Max Lerchenberger Bernd Uhl Markus Rehberg Nina Berberich Stefan Zahler Matthias P Wymann Fritz Krombach
author_sort	Christoph A Reichel
title	Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.
title_short	Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.
title_full	Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.
title_fullStr	Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.
title_full_unstemmed	Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.
title_sort	plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/9f20a55c123c4dfeae4eefe5ebad8b90
work_keys_str_mv	AT christophareichel plasmininhibitorspreventleukocyteaccumulationandremodelingeventsinthepostischemicmicrovasculature AT maxlerchenberger plasmininhibitorspreventleukocyteaccumulationandremodelingeventsinthepostischemicmicrovasculature AT bernduhl plasmininhibitorspreventleukocyteaccumulationandremodelingeventsinthepostischemicmicrovasculature AT markusrehberg plasmininhibitorspreventleukocyteaccumulationandremodelingeventsinthepostischemicmicrovasculature AT ninaberberich plasmininhibitorspreventleukocyteaccumulationandremodelingeventsinthepostischemicmicrovasculature AT stefanzahler plasmininhibitorspreventleukocyteaccumulationandremodelingeventsinthepostischemicmicrovasculature AT matthiaspwymann plasmininhibitorspreventleukocyteaccumulationandremodelingeventsinthepostischemicmicrovasculature AT fritzkrombach plasmininhibitorspreventleukocyteaccumulationandremodelingeventsinthepostischemicmicrovasculature
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Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.

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