Abstract
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 that platelets are involved in microvascular inflammation and that they accumulate in lym- phoid 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. 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.
Original language | English (US) |
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Pages (from-to) | 467-473 |
Number of pages | 7 |
Journal | American Journal of Respiratory and Critical Care Medicine |
Volume | 179 |
Issue number | 6 |
DOIs | |
State | Published - Mar 15 2009 |
Keywords
- Apoptosis
- Blood platelets
- Granzyme B
- Sepsis
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine