Abstract
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)-α 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-α. 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.
Footnotes
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This study was supported by funds from the Ministry of Education, Culture, Sports, Science and Technology, Japan and Redox Bioscience, Inc. (Kyoto, Japan).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.134007.
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ABBREVIATIONS: CS, cigarette smoke; COPD, chronic obstructive pulmonary disease; ROS, reactive oxygen species; TNF, tumor factor; MMP, matrix metalloprotease; TRX, thioredoxin-1; WT, wild-type; Tg, transgenic; rh, recombinant human; PCR, polymerase chain GSH, glutathione; ssDNA, single-stranded DNA; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; Lm, mean linear intercept(s); DI, destructive ASK1, apoptosis signal-regulating kinase 1: MIP, macrophage inflammatory protein.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received November 6, 2007.
- Accepted February 5, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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