Innate immune cell response in sepsis

Abstract: Leukocyte recruitment is known to be a key feature at sites of inflammation and important in the combat against infectious agents. However, the mechanisms of leukocyte recruitment in the pulmonary microvasculature in response to local and systemic inflammation remain elusive. Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. We hypothesized that leukocytes might exhibit different spatial patterns of accumulation in the pulmonary microvasculature in local versus systemic inflammation induced by injection lipopolysaccharide (LPS) intratracheally (i.t.) or intravenously (i.v.), monocytes and platelets might be important regulators of thrombin generation in abdominal sepsis induced by cecal ligation and puncture (CLP). We observed that systemic LPS caused more leukocytes trapping in capillaries compared to local LPS. The ratio of adherent leukocytes in venules compared to capillaries was higher in response to local LPS, suggesting that leukocytes were more prone to accumulate in venules in local inflammation and in capillaries in systemic inflammation. Alveolar accumulation of leukocytes was more efficient in local compared to systemic inflammation. Rho-kinase signaling appears to regulate both adhesive and mechanical aspects of endotoxin-induced leukocyte infiltration in the lung. In study II, It was found that dynamic changes in the coagulation system characterized by a hypercoagulable phase followed by a hypocoagulable phase in response to a septic insult. In addition, we found peripheral blood monocytes regulate sepsis-induced thrombin generation and consumption of coagulation factors. Moreover, monocytes are critical for formation of pro-inflammatory compounds and neutrophil accumulation in the lung in abdominal sepsis. We also found platelets regulate thrombin generation in abdominal sepsis and platelet-derived microparticles (PMPs) have the capacity to trigger thrombin formation and that this effect could be due to PS-mediated activation of the coagulation system. Moreover, our data demonstrated that Rac1 signaling is critical for the formation of PMPs and thrombin generation in sepsis. Taken together, these findings increase our understanding of the important role of neutrophils, monocytes and platelets in the pathophysiology of sepsis and data of this thesis may help to develop potential therapies in management of patients with sepsis.