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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Thioredoxin-1 Ameliorates Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice

Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan (A.S., S.M., M.M.); Department of Respiratory Medicine, Ako City Hospital, Hyogo, Japan (A.S.); Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan (Y.H., H.N., J.Y.); and Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan (T.H., J.Y.)

Cigarette smoking is associated with the development of inflammatory lung diseases representing major health problems world-wide. We hypothesized that the redox-regulating molecule thioredoxin-1 (TRX), which shows anti-inflammatory, antioxidative, and antiapoptotic effects, could be induced by cigarette smoke (CS) and contribute to protect against CS-induced inflammation and lung destruction. In an acute study, human TRX transgenic mice and C57BL6/J mice were exposed to mainstream CS for 3 days. In the lungs of CS-exposed mice, bronchial epithelial injury and bronchoalveolar lavage neutrophilia were observed. Oxidative stress and apoptosis were enhanced, and the expression of cytokines macrophage inflammatory protein-2 and tumor necrosis factor (TNF)- was increased 15.3- and 2.4-fold, respectively. Compared with C57BL6/J mice, TRX-transgenic mice had significantly less inflammation, oxidative damage, and apoptosis, as well as decreased levels of matrix metalloprotease-12 mRNA and serum TNF-. When recombinant human TRX (40 µg/body/day, 3 days) was injected i.p. into CS-exposed C57BL6/J mice, a significant effect to offer protection against CS-induced lung injury was observed through suppression of neutrophil influx. In the chronic study, TRX-transgenic mice and C57BL6/J mice were exposed to CS for 6 months. This chronic exposure caused pulmonary emphysema in C57BL6/J mice accompanying prominent infiltration of macrophages and neutrophils to lung. These pathological changes were significantly suppressed in TRX-transgenic mice. In conclusion, TRX induction ameliorated CS-induced lung inflammation and emphysema in mice. TRX-1 may therefore play a preventive or therapeutic role in lung inflammatory disorders such as chronic obstructive pulmonary disease.

Address correspondence to: Dr. Yuma Hoshino, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507 Japan. E-mail: yuma{at}kuhp.kyoto-u.ac.jp

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