| First Author | Freishtat RJ | Year | 2009 |
| Journal | Am J Respir Crit Care Med | Volume | 179 |
| Issue | 6 | Pages | 467-73 |
| PubMed ID | 19136373 | Mgi Jnum | J:164996 |
| Mgi Id | MGI:4835864 | Doi | 10.1164/rccm.200807-1085OC |
| Citation | Freishtat RJ, et al. (2009) Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity. Am J Respir Crit Care Med 179(6):467-73 |
| abstractText | 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 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. 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. |
