Signaling mechanisms of altered cellular responses in trauma, burn, and sepsis: role of Ca2+.

Alterations in cellular responses in various organ systems contribute to trauma-, burn-, and sepsis-related multiple organ dysfunction syndrome. Such alterations in muscle contractile, hepatic metabolic, and neutrophil and T-cell inflammatory-immune responses have been shown to result from cell-signaling modulations and/or impairments in the respective cell types. Altered Ca(2+) signaling would seem to play an important role in the myocardial and vascular smooth muscle contractile dysfunction in the injury conditions; Ca(2+)-linked signaling derangement also plays a crucial role in sepsis-induced altered skeletal muscle protein catabolism and resistance to insulin-mediated glucose use. The injury-related increased hepatic gluconeogenesis and acute-phase protein response could also be caused by a pathophysiologic up-regulation of hepatocyte Ca(2+)-signal generation. The increased oxidant production by neutrophil, a potentially detrimental inflammatory response in early stages after burn or septic injuries, seems to result from an up-regulation of both the Ca(2+)-dependent as well as Ca(2+)-independent signaling pathways. The injury conditions would seem to cause an inappropriate up-regulation of Ca(2+)-signal generation in the skeletal myocyte, hepatocyte, and neutrophil, while they lead to a down-regulation of Ca(2+) signaling in T cells. The crucial signaling derangement that causes T-cell proliferation suppression seems to be a decrease in the activation of protein tyrosine kinases, which subsequently down-regulates Ca(2+) signaling. The delineation of cell-signaling derangements in trauma, burn, or sepsis conditions can lead to development of therapeutic interventions against the disturbed cellular responses in the vital organ systems.