Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1-deficient mice

Background-Heme oxygenase (HO)-1 is an enzyme that degrades heme to generat e CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A di sease 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 admini stered LPS to mice that were wild-type (+/+), heterozygous (+/-), or homozy gous null (-/-) for targeted disruption of HO-1. LPS produced a similar ind uction 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 bloo d pressure (SBP) decreased in all the groups. However, SEP was significantl y 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 incr ease in endothelin-l contributed to this SEP response. Even though SEP was higher, mortality was increased in HO-1(-/-) mice, and they exhibited hepat ic and renal dysfunction that was not present in HO-1(+/+) and HO-1(+/-) mi ce. The end-organ damage and death in HO-1(-/-) mice was related to increas ed oxidative stress. Conclusions-These data suggest that the increased mortality during endotoxe mia in HO-1(-/-) mice is related to increased oxidative stress and end-orga n (renal and hepatic) damage, not to refractory hypotension.