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Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide‐induced tissue injury
Author(s) -
Yi Xianwen,
Kim Kuikwon,
Yuan Weiping,
Xu Longquan,
Kim HyungSuk,
Homeister Jonathon W.,
Key Nigel S.,
Maeda Nobuyo
Publication year - 2009
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0308161
Subject(s) - biology , inflammation , lipopolysaccharide , proinflammatory cytokine , oxidative stress , hepatocyte , endocrinology , medicine , lipoic acid , sepsis , gene expression , antioxidant , immunology , biochemistry , gene , in vitro
α‐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‐α, and NF‐κB 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.