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1 PLATELET GRANZYME B INDUCES CONTACT-DEPENDENT END-ORGAN APOPTOSIS DURING MURINE SEPSIS
Matthew Sharron1,2, Andrew A. Wiles1, Claire E. Hoptay2, Kanneboyina Nagaraju1,2, Robert J. Freishtat1,2 1Children’s National Medical Center, Washington, DC, United States. 2George Washington University School of Medicine, Washington, DC, United States.
Purpose of Study: The objective of this study is to define the site(s) of and mechanism(s) by which platelet GzmB induces end-organ apoptosis in sepsis, and evaluate the effect of GzmB knockout on sepsis progression, mortality and MODS.
Methods Used: End-organ apoptosis in a murine cecal ligation and puncture (CLP) model of sepsis was analyzed by immunohistochemistry. Platelet cytotoxicity was measured by flow cytometry following 90-minute ex vivo co-incubation experiments with healthy murine splenocytes. Progression of sepsis was measured by a validated preclinical murine sepsis score.
Summary of Results: 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 lungs and spleens from septic GzmB null mice [Apoptotic index per mm2 (Wild Type (WT) vs. GzmB null) for lung = 3776+/-139 vs. 678+/-181 (p<0.001) and for spleen =2,682+/-191 vs. 622+/-120 (p<0.001)] despite similar levels of endotoxin and platelet aggregation. GzmB null mice had lower sepsis scores at all time points post-CLP than WT mice. At 24 hours post-CLP, the mortality rate of the GzmB null mice was 0% while the mortality rate of the WT mice 100%. Kaplan-Meier survival analysis showed that GzmB null mice survived longer following CLP than WT mice (P=0.0019 by Cox Proportional Hazard Regression). In cell culture co-incubation experiments, physical separation of septic platelets from healthy 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 …
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