(Circulation. 2000;102:3015.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Endotoxin-Induced Mortality Is Related to Increased Oxidative Stress and End-Organ Dysfunction, Not Refractory Hypotension, in Heme Oxygenase-1–Deficient Mice
From the Program of Developmental Cardiovascular Biology, the Cardiovascular Division (P.W., A.P.P., A.P., K. Maemura., S.-F.Y., M.-E.L., M.A.P.) and the Pulmonary and Critical Care Division (M.A.P.), Brigham and Women’s Hospital; the Department of Medicine (A.P., S.-F.Y., M.-E.L., M.A.P.) Harvard Medical School; and the Cardiovascular Biology Laboratory (P.W., A.P.P., N.D., P.B.M., C.U.S., A.P., K. Maemura, S.-F.Y., M.-E.L., M.A.P.) and the Physiology Program (B.W.L., K. Marino, C.M.D.), Harvard School of Public Health, Boston, Mass. Dr Doerschuk is now at the Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio.
Correspondence to Mark A. Perrella, MD, Program of Developmental Cardiovascular Biology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail mperrella{at}rics.bwh.harvard.edu
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.
Key Words: endotoxin • shock • vasoconstriction • perfusion
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