NEUTROPHILS, CYTOKINES AND CYTOKINE RECEPTORS IN SEPTIC SHOCK

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Human polymorphonuclear leukocytes (PMNL) synthesize, secrete, contain specific membrane receptors for, and respond to the cytokines IL-1 alpha and beta and TNF beta. Both of these cytokines and PMNL play an essential role in the pathogenesis of acute disseminated inflammation with organ failure which may follow microbial infection (septic shock). Our objective is to show that septic shock in humans is consistently associated with amplified expression of receptors for IL-1 on blood PMNL, and tolerance of these PMNL to LPS- and IL-1 alpha-induced expression of the IL-1 beta gene, and that such phenotypic changes play an important role in acquisition, severity, or outcome of highly lethal septic shock. This research will: 1. Determine if the phenotypic changes typical of sepsis-PMNL are also found in other inflammatory pathologies: A. acute disseminated microbial-induced inflammation without organ failure; B. acute disseminated inflammation not caused by infection and with or without organ failure; C. localized infection without fever or leukocytosis; D. viral infection. 2. Prospectively study patients at high risk for developing septic shock (trauma-patients) to test the hypothesis that the phenotypic alterations found in sepsis-PMNL correlate with risk, severity, or outcome of septic shock. 3. Test the hypothesis that increased synthesis of receptor protein is responsible for increased expression of IL-1 R on sepsis-PMNL by evaluating transcriptional and translational processes. 4. Determine the site responsible for the adaptation of sepsis-PMNL to IL-1 beta gene expression. Our findings should provide insight into cellular events which regulate the human response to severe inflammation, and have implications for risk, prognosis, and therapy of septic shock.