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Neurotropin Demonstrates Cytoprotective Effects in Lung Cells through the Induction of Thioredoxin-1

Yuma Hoshino¹, Takayuki Nakamura^2,, Atsuyasu Sato³, Michiaki Mishima³, Junji Yodoi⁴ and Hajime Nakamura¹

¹ Thioredoxin Project, Department of Experimental Therapeutics, Translational Research Center; ² Department of Organ Preservation Technology, Graduate School of Medicine, Kyoto University Hospital; ³ Department of Respiratory Medicine, Graduate School of Medicine; and ⁴ Laboratory of Infection and Prevention, Department of Biological Response, Institute for Virus Research, Kyoto University, Kyoto, Japan

Correspondence and requests for reprints should be addressed to Yuma Hoshino, M.D., Ph.D., 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507 Japan. E-mail: yuma{at}kuhp.kyoto-u.ac.jp

Neurotropin, a nonprotein extract from inflamed rabbit skin inoculated with vaccinia virus, is well known as an analgesic drug, but its cytoprotective effects have not been explored. Because infection by viruses, such as human T-cell leukemia virus type I and Epstein-Barr virus, induces expression of the redox-regulating molecule, thioredoxin (TRX), we hypothesized that neurotropin would also be capable of regulating the redox balance and could be applied for the therapeutics of lung diseases caused by oxidative stress, such as chronic obstructive pulmonary disease. Neurotropin enhanced mRNA expression of the redox-regulating molecules, glutathione peroxidase and catalase and, particularly, TRX, in human lung adenocarcinoma A549 cells. Neurotropin also increased the cellular TRX content and regulated TRX release from cells. The cytoprotective effects of neurotropin against hydrogen peroxide and cigarette smoke extracts was demonstrated by an attenuation of lactate dehydrogenase release from oxidant-exposed A549 cells and the inhibition of apoptosis. This cytoprotection was linked with reduced activity of intracellular oxidants. Furthermore, neurotropin enhanced TRX expression in mouse lungs and ameliorated cigarette smoke–induced lung injury in mice, suggesting that its cytoprotective effects in lung epithelial cells are mediated through the induction of redox-regulating molecules that reduce intracellular oxidative activity.

Key Words: antioxidants • chronic obstructive pulmonary disease • cytoprotection • therapeutics

CLINICAL RELEVANCE The authors demonstrate antioxidative and cytoprotective properties of an analgesic drug, neurotropin, and associated them with thioredoxin induction. Neurotropin could provide another option for chronic obstructive pulmonary disease therapeutics.