title: 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.
  
  
  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.
authors: Program of Developmental Cardiovascular Biology, the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: P
authors: P
authors: Wiesel
authors: A P
authors: AP
authors: Patel
authors: N
authors: N
authors: DiFonzo
authors: P B
authors: PB
authors: Marria
authors: C U
authors: CU
authors: Sim
authors: A
authors: A
authors: Pellacani
authors: K
authors: K
authors: Maemura
authors: B W
authors: BW
authors: LeBlanc
authors: K
authors: K
authors: Marino
authors: C M
authors: CM
authors: Doerschuk
authors: S F
authors: SF
authors: Yet
authors: M E
authors: ME
authors: Lee
authors: M A
authors: MA
authors: Perrella
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics; D019446:Endotoxemia / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007022:Hypotension / Q000139:chemically induced / Q000209:etiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009026:Mortality; D009102:Multiple Organ Failure / Q000201:enzymology / Q000401:mortality* / Q000503:physiopathology; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D019332:Endothelin-1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse