Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0308161 on October 9, 2008

Published online before print October 9, 2008
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(Journal of Leukocyte Biology. 2009;85:146-153.)
© 2009 by Society for Leukocyte Biology

Mice with heterozygous deficiency of lipoic acid synthase have an increased sensitivity to lipopolysaccharide-induced tissue injury

Xianwen Yi*, Kuikwon Kim{dagger}, Weiping Yuan{ddagger}, Longquan Xu*, Hyung-Suk Kim*, Jonathon W. Homeister*, Nigel S. Key§ and Nobuyo Maeda*,1

* Departments of Pathology and Laboratory Medicine and
{ddagger} Biochemistry/Biophysics,
{dagger} Curriculum of Genetics and Molecular Biology, and
§ Division of Hematology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

1 Correspondence: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Bldg., Chapel Hill, NC 27599-7525, USA. E-mail: nobuyo{at}med.unc.edu

{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-{kappa}B 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.

Key Words: antioxidant • neutrophil • inflammation • sepsis • knockout mice