NAD(P)H oxidase contributes to the progression of remote hepatic parenchymal injury and endothelial dysfunction, but not microvascular perfusion deficits.
Oxidative stress occurs in remote liver injury, but the origin of the oxidant generation has yet to be thoroughly delineated. Some reports suggest that the source of the distant oxidative stress originates from the site of initial insult [i.e., xanthine oxidase (XO)]; however, it could also be derived from sources such as phagocytic and/or vascular NAD(P)H oxidase (Nox) enzymes. With a murine model of bilateral hindlimb ischemia-reperfusion, we describe here a mechanism for Nox-dependent oxidant production that contributes, at least in part, to remote hepatic parenchymal injury and sinusoidal endothelial cell (SEC) dysfunction. To determine whether Nox enzymes were the source of oxidants, mice were treated immediately after the onset of hindlimb ischemia with specific inhibitors to XO (50 mg/kg ip allopurinol) or Nox (10 mg/kg ip gp91ds-tat and 3 mg/kg ip apocynin). After 1 h of ischemia, hindlimbs were reperfused for either 3 or 6 h. Inhibition of XO failed to provide any improvement in parenchymal injury, SEC dysfunction, neutrophil accumulation, or microvascular dysfunction. In contrast, the inhibition of Nox enzymes prevented the progression (6 h) of parenchymal injury, significantly protected against SEC dysfunction, and completely prevented signs of neutrophil-derived oxidant stress. At the same time, however, inhibition of Nox failed to protect against the early parenchymal injury and microvascular dysfunction at 3 h of reperfusion. These data confirm that microvascular perfusion deficits are not essential for the pathogenesis of remote hepatic parenchymal injury. The data also suggest that Nox enzymes, not XO, are involved in the progression of compromised hepatic parenchymal and endothelial integrity during a systemic inflammatory response.
Dorman
Robert B
RB
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham Street 638, Little Rock, AR 72205-7199, USA.
Wunder
Christian
C
Saba
Hamida
H
Shoemaker
Jennifer L
JL
MacMillan-Crow
Lee Ann
LA
Brock
Robert W
RW
D000818:Animals; D018450:Disease Progression; D004727:Endothelium / Q000473:pathology*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000503:physiopathology; D008954:Models, Biological; D019255:NADPH Oxidases / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D014443:Tyrosine; D009195:Peroxidase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases