Published ahead of print on January 8, 2009, doi:10.1164/rccm.200807-1085OC Am. J. Respir. Crit. Care Med., Volume 179, Number 6, March 2009, 467-473 A more recent version of this article appeared on March 15, 2009
Submitted on July 14, 2008 Sepsis Alters the Megakaryocyte-Platelet Transcriptional Axis Resulting in Granzyme B-mediated LymphotoxicityRobert J Freishtat1*,1 Division of Emergency Medicine, Department of Pediatrics , Children's National Medical Center, Washington, District of Columbia, United States; Research Center for Genetic Medicine, Children's National Medical Center, Washington, District of Columbia, United States; George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States, 2 Division of Critical Care Medicine, Department of Pediatrics, University of California at Davis Medical Center, Sacramento, California, United States; School of Medicine, University of California at Davis Medical Center, Sacramento, California, United States, 3 Research Center for Genetic Medicine, Children's National Medical Center, Washington, District of Columbia, United States, 4 Division of Emergency Medicine, Department of Pediatrics , Children's National Medical Center, Washington, District of Columbia, United States; George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States, 5 Division of Critical Care Medicine, Children's National Medical Center, Washington, District of Columbia, United States, 6 George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States, 7 University of California at Davis, Davis, California, United States, 8 George Washington University, Washington, District of Columbia, United States, 9 Research Center for Genetic Medicine, Children's National Medical Center, Washington, District of Columbia, United States; George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States * To whom correspondence should be addressed. E-mail: rfreishtat{at}cnmcresearch.org.
Rationale: Sepsis-related mortality results in part from immunodeficiency secondary to profound lymphoid apoptosis. The biological mechanisms responsible are not understood. Objectives: Because recent evidence shows platelets are involved in microvascular inflammation and that they accumulate in lymphoid microvasculature in sepsis, we hypothesized a direct role for platelets in sepsis-related lymphoid apoptosis. Methods: We studied megakaryocytes and platelets from a murine induced-sepsis model, with validation in septic children, which showed induction of the cytotoxic serine protease granzyme B. Measurements and Main Results: Platelets from septic mice induced marked apoptosis of healthy splenocytes ex vivo. In addition, platelets from septic granzyme B null (-/-) mice showed no lymphotoxicity. Conclusions: Our findings establish a conceptual advance in sepsis: septic megakaryocytes produce platelets with acutely altered mRNA profiles and these platelets mediate lymphotoxicity via granzyme B. Given the contribution of lymphoid apoptosis to sepsis-related mortality, modulation of platelet granzyme B becomes an important new target for investigation and therapy. Key words: Blood platelets • Sepsis • Granzyme B • Apoptosis
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