concanavalin-a and Shock

Systemic inflammatory response syndrome (SIRS) is a potentially lethal condition, as it can progress to shock, multi-organ failure, and death. It can be triggered by infection, tissue damage, or hemorrhage. The role of tissue injury in the progression from SIRS to shock is incompletely understood. Here, we show that treatment of mice with concanavalin A (ConA) to induce liver injury triggered a G-CSF-dependent hepatic infiltration of CD11b+Gr-1+Ly6G+Ly6C+ immature myeloid cells that expressed the orphan receptor myeloid DAP12-associated lectin-1 (MDL-1; also known as CLEC5A). Activation of MDL-1 using dengue virus or an agonist MDL-1-specific antibody in the ConA-treated mice resulted in shock. The MDL-1+ cells were pathogenic, and in vivo depletion of MDL-1+ cells provided protection. Triggering MDL-1 on these cells induced production of NO and TNF-α, which were found to be elevated in the serum of treated mice and required for MDL-1-induced shock. Surprisingly, MDL-1-induced NO and TNF-α production required eNOS but not iNOS. Activation of DAP12, DAP10, Syk, PI3K, and Akt was critical for MDL-1-induced shock. In addition, Akt physically interacted with and activated eNOS. Therefore, triggering of MDL-1 on immature myeloid cells and production of NO and TNF-α may play a critical role in the pathogenesis of shock. Targeting the MDL-1/Syk/PI3K/Akt/eNOS pathway represents a potential new therapeutic strategy to prevent the progression of SIRS to shock.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Differentiation; Concanavalin A; Disease Models, Animal; Disease Progression; Female; Humans; Immunity, Innate; Intracellular Signaling Peptides and Proteins; Lectins, C-Type; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Immunological; Myeloid Cells; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Receptors, Cell Surface; Receptors, Immunologic; Severe Dengue; Shock; Signal Transduction; Syk Kinase; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

We studied the ex vivo secretion of tumor necrosis factor (TNF) and interleukin 2 (IL-2) by splenocytes after circulatory shock induced by intestinal ischemia and reperfusion in rats. Shock was induced by total occlusion of the superior mesenteric artery followed by reperfusion. In a second group, vascular occlusion was maintained throughout the experimental protocol. A third group of sham rats and a fourth group of control rats with a negligible surgical procedure were also studied. "Spontaneous" (untriggered) secretion of TNF by splenocytes was higher in the ischemia-reperfusion group than in all other groups (p < 0.01), but did not increase significantly after stimulation with LPS. Splenocytes from control rats exhibited a marked increase in TNF secretion after stimulation with LPS to values similar to those in the ischemia-reperfusion group. A diminished, though statistically significant increase in LPS-stimulated secretion of TNF was detected in the sham and ischemia only groups of rats (p < 0.05) from untriggered values in each. Untriggered secretion of IL-2 was similar in all groups. However, when compared to control rats, splenocytes from the three surgically manipulated groups exhibited suppressed secretion of IL-2 in response to stimulation with Con A (p < 0.05). These results support the role played by TNF in mediation of shock and point to spleen macrophages as a source of TNF after intestinal ischemia and reperfusion. Our results also demonstrated postinjury alteration in immune function manifested by depressed ability of splenocytes to increase the production of IL-2 after stimulation with Con A.

Topics: Animals; Cells, Cultured; Concanavalin A; Interleukin-2; Intestines; Ischemia; Lipopolysaccharides; Macrophages; Male; Rats; Rats, Sprague-Dawley; Reperfusion; Shock; Spleen; Tumor Necrosis Factor-alpha