Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury.
Alpha-lipoic acid (1, 2-dithiolane-3-pentanoic acid; LA), synthesized in mitochondria by LA synthase (Lias), is a potent antioxidant and a cofactor for metabolic enzyme complexes. In this study, we examined the effect of genetic reduction of LA synthesis on its antioxidant and anti-inflammatory properties using a model of LPS-induced inflammation in Lias+/- mice. The increase of plasma proinflammatory cytokine, TNF-alpha, and NF-kappaB at an early phase following LPS injection was greater in Lias+/- mice compared with Lias+/+ mice. The circulating blood white blood cell (WBC) and platelet counts dropped continuously during the initial 4 h. The counts subsequently recovered partially in Lias+/+ mice, but the recovery was impaired totally in Lias+/- mice. Administration of exogenous LA normalized the recovery of WBC counts in Lias+/- mice but not platelets. Enhanced neutrophil sequestration in the livers of Lias+/- mice was associated with increased hepatocyte injury and increased gene expression of growth-related oncogene, E-selectin, and VCAM-1 in the liver and/or lung. Lias gene expression in tissues was 50% of normal expression in Lias+/- mice and reduced further by LPS treatment. Decreased Lias expression was associated with diminished hepatic LA and tissue oxidative stress. Finally, Lias+/- mice displayed enhanced mortality when exposed to LPS-induced sepsis. These data demonstrate the importance of endogenously produced LA for preventing leukocyte accumulation and tissue injury that result from LPS-induced inflammation.
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Bldg., Chapel Hill, NC 27599-7525, USA.
Xianwen
X
Yi
Kuikwon
K
Kim
Weiping
W
Yuan
Longquan
L
Xu
Hyung-Suk
HS
Kim
Jonathon W
JW
Homeister
Nigel S
NS
Key
Nobuyo
N
Maeda
D000818:Animals; D016207:Cytokines / Q000097:blood; D019040:E-Selectin / Q000378:metabolism; D004734:Energy Metabolism; D006579:Heterozygote; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D018805:Sepsis / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D013466:Sulfurtransferases / Q000235:genetics / Q000502:physiology*; D008063:Thioctic Acid / Q000378:metabolism* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D016207:Cytokines; D019040:E-Selectin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D008063:Thioctic Acid; D013466:Sulfurtransferases; C116435:lipoic acid synthase