Grants and Contracts Details
Sepsis and sepsis-associated multiple organ failure is a tremendous burden for health-care systems. Despite extensive basic research and clinical studies, the pathophysiology of sepsis is still poorly understood. Patients with sepsis often develop thrombocytopenia, a response that can be modeled in mice by Intraperitoneal injection of lipopolysaccharide (LPS) or in the clinically relevant cecal ligation and puncture (CLP) sepsis model. Septic patients with severe thrombocytopenia have a poor prognosis and unusually high mortality. However, the extent to which platelet activation contributes to the pathogenesis of sepsis has not been clear. The overall goal of this proposal is to determine the role of platelets in sepsis and systemic inflammation, and to explore molecular mechanisms by which platelets affect outcomes of septic shock. Previous studies reported that platelets interact with monocytes/macrophages and promote proinflammatory cytokine production by macrophages. However, our preliminary data indicate that although in agreement with the previous studies that platelets increased tumor necrosis factor-alpha (TNFá) production by macrophages in response to low-dose LPS, they attenuated TNFá production elicited by high concentrations of LPS. Furthermore, depletion of platelets by injection of an anti-GPIbá monoclonal antibody increased plasma TNFá and IL-6 levels in a mouse endotoxemia model and markedly increased mortality rate. In contrast, transfusion of platelets reduced the plasma pro-inflammatory cytokine levels and reduced mortality. Based on these novel observations, we hypothesize that platelets serve as a critical switch to regulate inflammatory response and that platelets inhibit inflammatory response thus play a beneficial role in severe septic shock. Data from in vitro experiments indicate that LPS- or thrombin-stimulated platelets inhibited TNFá and IL-6 production by macrophages, which was reversed by pre-incubation of platelets with a cyclooxygenase 1 (COX1) inhibitor aspirin. Stimulation of platelets with LPS or thrombin induced prostaglandin E2 (PGE2) production and inhibition of TNFá and IL-6 production by activated platelets was reversed by pre-incubation of macrophages with an antagonist of the PGE2 receptor EP4. Based on these compelling data, we further hypothesize that platelets protect against septic shock through inhibiting macrophage-dependent inflammation via the COX1/PGE2/EP4 pathway.
|Effective start/end date||7/1/14 → 6/30/16|
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