Patients in septic shock, and patients following severe trauma, often develop serious pathophysiologic alterations which are difficult to manage. While important advances have been made in the supportive care of these patients, and in developing more potent antibiotics, there still exists a lack of understanding of the basic mechanisms that induce organ dysfunction. As a result, effective, target therapies for the multi-organ failure observed in sepsis and trauma are still not available. Recent data has indicated that much of the multi-organ failure is due to the host's own, overly vigorous immune response. Cytokines are soluble protein mediators of inflammation produced by inflammatory cells which have gained considerable attention as the potential initial inducing agents of sepsis and multi-organ failure. The evidence supporting this hypothesis is found in 3 lines of study a) cytokines are found in the serum of septic patients and the levels correlate with mortality, b) infusion of recombinant cytokines mimics much of the pathophysiology observed in sepsis or trauma, and c) anti-cytokine antibodies will prevent the lethality observed after injection of lipopolysaccharide (LPS) or live bacteria. In this grant proposal we intend to carefully dissect the roles of cytokines in the altered pathophysiology observed in sepsis by utilizing 2 established models of sepsis. The first of these involves injection of LPS into Freund's adjuvant primed mice, and in the second, sepsis is induced by performing cecal ligation and puncture (CLP). For both models we will analyze for the presence of the cytokines tumor necrosis factor (TNF), interleukin 1 (IL-1, both alpha and beta), and IL-6, since these are the cytokines most closely associated with sepsis. After we have carefully documented the temporal sequence of cytokine gene expression, at the bioactivity, immunohistochemical and mRNA levels in both models we will assess the multi-organ injury which invariably ensues. The relationship of cytokine production and organ injury will be evaluated by blocking bioactivity with highly specific anti-cytokine antibodies. Further studies will evaluate the LPS tolerant state in an attempt to inhibit cytokine production as well as block the damaging effects of cytokines on target organs. The successful execution of these studies will provide important insights into the mechanisms of injury observed in sepsis, and more fully evaluate the roles that cytokines play in the evolution of multi-organ failure. A clearer understanding of the basic events will allow the development and testing of more targeted, potentially clinically relevant therapies.
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