FR128998 (a PAF Receptor Antagonist) Counters the Increased Pulmonary Vascular Resistance Associated with Ischemia-Reperfusion Injury in the Canine Lung.

Abstract

Ischemia-reperfusion injury induces deterioration of pulmonary function following lung transplantation. The spiro-thiazepin derivative FR128998 (FR) is a novel PAF receptor antagonist. The effect of FR on ischemia-reperfusion injury was investigated in an in situ warm ischemia model of canine lungs. Fifteen adult mongrel dogs, weighing 6 to 12 kg, were divided into two groups. FR (1 mg/kg/hr) was administered from prior to ischemia until 2 hours after reperfusion (FR-treated group; n = 8), or vehicle was injected using the same technique (Control group; n = 7). Following hilar stripping of the left lung, the left pulmonary artery and veins were clamped for 3 hours to induce warm ischemia. The left main bronchus was bisected at the same time and anastomosed 3 hours later. Arterial oxygen saturation (SaO(2)), left pulmonary vascular resistance (L-PVR), and cardiac output (CO) were measured 30 minutes after reperfusion. The lungs were harvested for pathological study, and polymorphonuclear neutrophils (PMNs) were counted. The 2-day survival rate was also investigated. After reperfusion, SaO(2) L-PVR, and CO were significantly (p < 0.05) better in the FR-treated group than in the control group. Histological findings after 30 minutes of reperfusion showed alveolar damage with interstitial edema and hyaline membranes localized along the alveolar ducts in the control group, while there was only slight localized interstitial edema in the FR group. PMN infiltration was less extensive in the FR group than in the control group. FR appears to have a protective effect against lung ischemia-reperfusion injury. This might result from inhibition of the local release of PAF. </hea