Leukotriene receptor antagonism prevents lung protein leakage and hypoxaemia in a septic cat model

Abstract

Products of the arachidonic acid cascade have been found to play an Important role in the pathophysiology in experimental shock and in ARDS. The effect of cysteinyl-leukotriene (cLT) blockade on the development of respiratory failure during septic shock was examined. Ventilated cats received an infusion of Escherichia coli bacteria. Pretreatment was given with diethylcarbamazine (DEC), a leukotriene synthetase inhibitor, or a new potent cLT receptor antagonist, ICI 198,615. With a gamma camera, the distributions of plasma transferrin radiolabelled with indium-113m chloride (113mIn) and erythrocytes radiolabelled with technetium-99m (99mTc) were measured over the lungs. A normalized slope index (NSI) reflecting protein leakage, based on the transferrin extravasation, was calculated. In the nonseptic control group (n=7) NSI was 4.4x10-4±0.7xlO-min-1 (mean+SEM). Unpretreated septic animals (n=7) showed a protein leakage after bacterial infusion, with a NSI of 34±3.5x10-4min-1. Pretreatment with DEC (n=6) significantly reduced NSI to 16±1.5x10-4min-1. In the group pretreated with ICI 198,615 (n=8), NSI was 9±1.2x10-4min-1. Arterial oxygen tension (Pa(O2)) remained at baseline level of 20±1.0 kPa during the experimental period in both the nonseptic control group and the ICI 198,615 pretreated group. In the unpretreated septic group, Pa(O2) fell progressively from a preseptic value of 21±0.9 to 12±1.5 kPa after 3 h. Pharmacological blockade of the cLTs could prevent the sepsis-induced development of progressive pulmonary microvascular protein leakage and the correlated fall in Pa(O2) in the cat.