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 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.
Wiesel
P
P
Program of Developmental Cardiovascular Biology, the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Patel
A P
AP
DiFonzo
N
N
Marria
P B
PB
Sim
C U
CU
Pellacani
A
A
Maemura
K
K
LeBlanc
B W
BW
Marino
K
K
Doerschuk
C M
CM
Yet
S F
SF
Lee
M E
ME
Perrella
M A
MA
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
D019332:Endothelin-1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse