Endotoxin-Induced Mortality Is Related to Increased Oxidative Stress and End-Organ Dysfunction, Not Refractory Hypotension, in Heme Oxygenase-1–Deficient Mice

Abstract

Background —Heme oxygenase (HO)-1 is an enzyme that degrades heme to generate CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A disease process characterized by decreases in vascular tone and increases in oxidative stress is endotoxic shock. Moreover, HO-1 is markedly induced in multiple organs after the administration of endotoxin (lipopolysaccharide [LPS]) to mice. Methods and Results —To determine the role of HO-1 in endotoxemia, we administered LPS to mice that were wild-type (+/+), heterozygous (±), or homozygous null (−/−) for targeted disruption of HO-1. LPS produced a similar induction of HO-1 mRNA and protein in HO-1 +/+ and HO-1 +/− mice, whereas HO-1 − /− mice showed no HO-1 expression. Four hours after LPS, systolic blood pressure (SBP) decreased in all the groups. However, SBP was significantly higher in HO-1 − /− mice (121±5 mm Hg) after 24 hours, compared with HO-1 +/+ (96±7 mm Hg) and HO-1 +/− (89±13 mm Hg) mice. A sustained increase in endothelin-1 contributed to this SBP response. Even though SBP was higher, mortality was increased in HO-1 − /− mice, and they exhibited hepatic and renal dysfunction that was not present in HO-1 +/+ and HO-1 +/− mice. The end-organ damage and death in HO-1 − /− mice was related to increased oxidative stress. Conclusions —These data suggest that the increased mortality during endotoxemia in HO-1 − /− mice is related to increased oxidative stress and end-organ (renal and hepatic) damage, not to refractory hypotension.