Platelet-activating factor and arachidonic acid metabolites mediate tumor necrosis factor and eicosanoid kinetics and cardiopulmonary dysfunction during bacteremic shock

Abstract

Objective: Platelet-activating factor (PAF) and eicosanoids are putative mediators of septic shock that are associated with release of tumor necrosis factor (TNF). The purpose of this investigation was to a) examine temporal patterns of TNF and arachidonic acid metabolite release in a porcine model of bacteremic shock and b) selectively block PAF, thromboxane A2, prostacyclin, and leukotrienes to determine the relationships among these inflammatory response mediators and the alterations in cardiorespiratory dysfunction for which they are required.

Design: Prospective, nonrandomized, controlled trial.

Setting: Laboratory at a university medical center.

Subjects: Thirty-four female Yorkshire swine.

Interventions: Animals were divided into six experimental groups: five septic groups receiving an infusion of Aeromonas hydrophila at 0.2 mL/kg/hr, gradually increasing to 0.4 mL/kg/hr over 4 hrs. Each of four septic groups was pretreated with a specific mediator inhibitor (PAF receptor antagonist, n = 6; prostacyclin antibody, n = 5; leukotriene synthesis inhibitor, n = 5; and thromboxane receptor antagonist, n = 6). One septic group (n = 6) received no mediator inhibitor and served as a septic control, and one anesthesia control group (n = 6) received no intervention.

Measurements and main results: PAF receptor blockade significantly increased systemic hypotension and mixed venous oxygen saturation and decreased pulmonary artery pressure, oxygen extraction and consumption, hemoconcentration, and levels of TNF and eicosanoids. Leukotriene inhibition increased mean arterial pressure, pulmonary and systemic vascular resistance indices, and arterial and mixed venous oxygen saturation and reduced pulmonary hypertension, oxygen delivery, oxygen extraction, oxygen consumption, and all measured mediators. Thromboxane receptor blockade lowered TNF and leukotriene levels, ameliorated systemic and pulmonary vasoconstriction, and significantly increased arterial and tissue oxygenation compared with septic controls. Prostacyclin antagonism reduced prostacyclin plasma concentrations, arterial hypoxemia, and oxygen consumption during sepsis and increased circulating leukotriene B4.

Conclusions: Elevations in plasma TNF predictably precede peak levels of eicosanoids in this model. PAF, leukotrienes, and thromboxane A2 are necessary for pulmonary hypertension during bacteremia. Systemic hypotension and increased vascular permeability are mediated by both leukotrienes and PAF. There are complex interactions among mediators during sepsis and further studies are required to define these relationships.