Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.

<h4>Purpose</h4>End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS), especially where platelets accumulate (e.g. spleen and lung). We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease...

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Autores principales:	Matthew Sharron, Claire E Hoptay, Andrew A Wiles, Lindsay M Garvin, Mayya Geha, Angela S Benton, Kanneboyina Nagaraju, Robert J Freishtat
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5c9106d15c094ce6b556f2e651753d48
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spelling	oai:doaj.org-article:5c9106d15c094ce6b556f2e651753d482021-11-18T07:10:55ZPlatelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.1932-620310.1371/journal.pone.0041549https://doaj.org/article/5c9106d15c094ce6b556f2e651753d482012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22844498/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Purpose</h4>End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS), especially where platelets accumulate (e.g. spleen and lung). We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease granzyme B. We now aim to define the site(s) of and mechanism(s) by which platelet granzyme B induces end-organ apoptosis in sepsis.<h4>Methods</h4>End-organ apoptosis in murine sepsis (i.e. polymicrobial peritonitis) was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90 minute ex vivo co-incubation with healthy murine splenocytes. Sepsis progression was measured via validated preclinical murine sepsis score.<h4>Measurements and main results</h4>There was evident apoptosis in spleen, lung, and kidney sections from septic wild type mice. In contrast, there was a lack of TUNEL staining in spleens and lungs from septic granzyme B null mice and these mice survived longer following induction of sepsis than wild type mice. In co-incubation experiments, physical separation of septic platelets from splenocytes by a semi-permeable membrane reduced splenocyte apoptosis to a rate indistinguishable from negative controls. Chemical separation by the platelet GPIIb/IIIa receptor inhibitor eptifibatide decreased apoptosis by 66.6±10.6% (p = 0.008). Mice treated with eptifibatide in vivo survived longer following induction of sepsis than vehicle control mice.<h4>Conclusions</h4>In sepsis, platelet granzyme B-mediated apoptosis occurs in spleen and lung, and absence of granzyme B slows sepsis progression. This process proceeds in a contact-dependent manner that is inhibited ex vivo and in vivo by the platelet GPIIb/IIIa receptor inhibitor eptifibatide. The GPIIb/IIIa inhibitors and other classes of anti-platelet drugs may be protective in sepsis.Matthew SharronClaire E HoptayAndrew A WilesLindsay M GarvinMayya GehaAngela S BentonKanneboyina NagarajuRobert J FreishtatPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e41549 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matthew Sharron Claire E Hoptay Andrew A Wiles Lindsay M Garvin Mayya Geha Angela S Benton Kanneboyina Nagaraju Robert J Freishtat Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.
description	<h4>Purpose</h4>End-organ apoptosis is well-described in progressive sepsis and Multiple Organ Dysfunction Syndrome (MODS), especially where platelets accumulate (e.g. spleen and lung). We previously reported an acute sepsis-induced cytotoxic platelet phenotype expressing serine protease granzyme B. We now aim to define the site(s) of and mechanism(s) by which platelet granzyme B induces end-organ apoptosis in sepsis.<h4>Methods</h4>End-organ apoptosis in murine sepsis (i.e. polymicrobial peritonitis) was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90 minute ex vivo co-incubation with healthy murine splenocytes. Sepsis progression was measured via validated preclinical murine sepsis score.<h4>Measurements and main results</h4>There was evident apoptosis in spleen, lung, and kidney sections from septic wild type mice. In contrast, there was a lack of TUNEL staining in spleens and lungs from septic granzyme B null mice and these mice survived longer following induction of sepsis than wild type mice. In co-incubation experiments, physical separation of septic platelets from splenocytes by a semi-permeable membrane reduced splenocyte apoptosis to a rate indistinguishable from negative controls. Chemical separation by the platelet GPIIb/IIIa receptor inhibitor eptifibatide decreased apoptosis by 66.6±10.6% (p = 0.008). Mice treated with eptifibatide in vivo survived longer following induction of sepsis than vehicle control mice.<h4>Conclusions</h4>In sepsis, platelet granzyme B-mediated apoptosis occurs in spleen and lung, and absence of granzyme B slows sepsis progression. This process proceeds in a contact-dependent manner that is inhibited ex vivo and in vivo by the platelet GPIIb/IIIa receptor inhibitor eptifibatide. The GPIIb/IIIa inhibitors and other classes of anti-platelet drugs may be protective in sepsis.
format	article
author	Matthew Sharron Claire E Hoptay Andrew A Wiles Lindsay M Garvin Mayya Geha Angela S Benton Kanneboyina Nagaraju Robert J Freishtat
author_facet	Matthew Sharron Claire E Hoptay Andrew A Wiles Lindsay M Garvin Mayya Geha Angela S Benton Kanneboyina Nagaraju Robert J Freishtat
author_sort	Matthew Sharron
title	Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.
title_short	Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.
title_full	Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.
title_fullStr	Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.
title_full_unstemmed	Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.
title_sort	platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by gpiib/iiia blockade.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/5c9106d15c094ce6b556f2e651753d48
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Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade.

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