The principal adverse effect of post-traumatic sepsis is endothelial cell damage leading to increased microvascular permeability, with ensuing influx of fluid and plasma protein to the interstitium, leading to acute respiratory, renal, and cardiac failure. Activated complement, and the cyclooxygenase and lipoxygenase products of arachidonic acid metabolism have been implicated as causative agents of these lesions. This project tests the hypothesis that, in physiologic concentrations, the lipoxygenase products of arachidonic acid metabolism (leukotrienes C and D) mediate the increased microvascular permeability of bacterial sepsis.
Specific aims of this research are to measure leukotrienes C and D, thromboxane B2, prostaglandin 6-KF1Alpha, activated complement component C5a, and their relationship to hemodynamic instability and permeability edema in sepsis. Subsequent infusions of each of these compounds to physiological levels into healthy animals will determine whether each is sufficient to produce the changes seen in systemic sepsis. Specific blockers of leukotriene synthesis, thromboxane synthesis, and depletion of complement stores will be used in septic animals to detemine if these substances are necessary for the production of increased capillary permeability in sepsis. A five hour graded infusion of Aeromonas Hydrophila into adult female pigs with full hemodynamic monitoring will be employed to observe changes in the above substances simultaneous with assessment of hemodynamic parameters. To identify the relationship of thromboxane, the leukotrienes, and activated complement to the changes in pulmonary, hepatic, renal, and cardial pathology during sepsis, awake unrestrained femoral artery cannulated male Sprague-Dawley rats will receive a 1 ml injection of Aermonas Hydrophila deep to the skin of the back, which results in progressive sepsis, fatal in 22-30 hours. Animals will be sacrificed 2,6,12,18,24, and 48 hours after inoculation of bacteria, with vital organs examined pathologically, and plasma levels of leukotrienes C and D, thromboxane B2, prostaglandin 6KF1Alpha, platelet and leukocyte aggregometry and functional assay for complement C5a will be performed. The results from these studies could suggest modifications of the lipoxygenase and cyclooxygenase arachidonic acid pathways, and of non-specific activation of complement, toward improved survival and lowered morbidity in severe post-traumatic sepsis.
