The ability of inflammatory cytokines (IL-8, TNF-a and IL-10) to modulate PMN function is an important part of host defense mechanisms. To date, many of the clinical trials employing anti-cytokine therapy have been disappointing in part because previous in vitro studies have evaluated PMN function under conditions that do not mimic in vivo conditions (i.e. purified PMN, in the fluid phase, under strictly normoxic conditions). Studying PMN physiology under conditions that mimic the in vivo inflammatory situation is particularly important because reactive oxygen species released from activated PMN have been strongly implicated in the pathogenesis of both the systemic inflammatory response and sepsis syndromes. Nonetheless, a unifying paradigm that explains both increased oxidant production (with subsequent matrix protein injury) and the increased susceptibility to sepsis following trauma has not been determined. At inflammatory milieu in vivo, oxygen tension is often abnormal and to date, no studies have been performed investigating how cytokines regulate PMN function in nonnormoxic environments (hypoxemia + reoxygenation). Therefore, the long-term objective of these studies is to provide a cellular and molecular basis by which rational cytokine or anti-cytokine therapy might be used for inflammatory/infectious conditions. (i.e. SIRS, sepsis syndrome). To test this hypothesis, the investigators have utilized a methodology for dialyzing oxygen out of whole blood which has allowed for the preliminary investigation of how cytokines regulate PMN physiology under non-normoxic conditions. Further, these studies have been performed with PMN adherent to specific matrix proteins (fibronectin, laminin, RGDS). The rationale for this is that at sites of acute infection/inflammation PMNs migrate into the interstitium and adhere to matrix proteins. Our studies have allowed us to develop a dual-component central hypothesis - namely that exposure of whole blood PMNs to periods of hypoxemia + cytokines is a key pathophysiologic mechanism that contributes to increased oxidant production and matrix protein injury. Further, exposure of whole blood PMNs to periods of hypoxemia/reoxygenation and cytokines is a key pathophysiologic mechanism that contributes to the increased susceptibility to infection following tissue injury. These studies will determine the cellular and molecular mechanisms by which hypoxemia + reoxygenation plus cytokines causally explains both increased oxidant reduction and decreased bactericidal activity in whole blood granulocytes.
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