Polymorphonuclear Leukocyte-Mediated Lipid Peroxidation and Lung Injury (Complement, Free Radical, Hemolysis).

Abstract

It was demonstrated that systemic complement activation following thermal injury or intravenous injection of cobra venom factor causes acute lung microvascular injury, which is associated with the release of oxygen radicals from activated neutrophils. The present study investigated the pathophysiologic mechanisms of acute lung injury and intravascular hemolysis following systemic activation of the complement system. Evaluations of the leukocyte humoral responses and products of lipid peroxidation in both tissue and plasma were performed. The current study demonstrates that acute lung injury, measured by LDH-4 isoenzyme release and lung vascular permeability levels in complement-activated rats, is paralleled by the appearance of products of lipid peroxidation (conjugated dienes, lipid hydroperoxides, fluorochromic substances) in both plasma and tissue of lungs but not liver, kidney or spleen. Companion experiments in which animals were pre-treated with interventions found to protect against acute lung injury such as hydroxyl radical scavengers (dimethyl sulfoxide and dimethyl thiourea), or catalase, and the iron chelators (apolactoferrin and deferoxamine), also dramatically attenuated plasma and tissue levels of lipid hydroperoxides, conjugated dienes, and fluorochromic substances. Iron-saturated chelators provide no significant protection from both acute lung injury and preventing the appearance of lipid peroxidation products. Furthermore, an enhancement of lung injury is displayed by infusing FeCl(,3) into animals previously complement activated. Additional studies have shown that complement activation causes intravascular hemolysis and increased osmotic fragility of red cells. Both manifestations of red cell damage are markedly attenuated by the aforementioned interventions. These results suggest an important role of neutrophil-derived oxygen radicals in acute lung microvascular injury following systemic activation of the complement system.