A Novel Intravascular Hemolysis Mouse Model

Abstract

Intravascular hemolysis is a common manifestation of several clinical human diseases including hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria and sickle-cell disease. However, there is lack of simple, specific and practicable animal model to define the pathogenesis. Conditional targeted cell ablation is a powerful approach for investigating the pathogenesis of human diseases and in vivo cellular functions. Recently we reported a conditional targeted cell ablation model mediated by intermedilysin (ILY) in human CD59 transgenic mice (Nature Medicine, 2008, 14: 98–103). One of transgenic mouse strains that express human CD59 only on the erythrocytes was intravenously administrated by ILY, which subsequently induced acute intravascular hemolysis and rapid death (less than 1 minute). Using this mouse model, we further demonstrated that the acute intravascular hemolysis led to reduced nitric oxide bioavailability due to cell-free hemoglobin scavenging, endothelial dysfunction, increased platelet activation, renal failure, and pulmonary artery hypertension, a complication suspected to be a main cause of mortality resulted from human hemolytic diseases. Together, these results suggest that this novel hemolytic mouse model can be used to study the pathogenesis of sequelae of intravascular hemolysis and as a useful platform for drug test.