Inflammation and oxidative stress induced by cigarette smoke in Lewis rat brains
Introduction
Links between cigarette smoking and neurological complications have been demonstrated in disease states such as stroke and Alzheimer's disease, and more recently in MS (Sundstrom et al., 2008, Cataldo et al., 2010, Shah and Cole, 2010). Underlying these associations are animal studies which show that smoking can increase levels of circulating proinflammatory markers and markers of oxidative stress, including levels of reactive oxygen species (ROS), and decrease levels of antioxidants (Churg et al., 2002, D'Hulst et al., 2005, Moerloose et al., 2005, Khanna et al., 2009). Among studies performed in humans are those which have shown that urinary levels of nucleic acid and lipid oxidative products were increased with smoking and that serum and urine levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) correlated inversely with levels of the nicotine metabolite cotinine in smokers (Harman et al., 2003, Sobczak et al., 2004). In addition to activating proinflammatory responses and cellular stress, CS and nicotine have effects that can result in immunosuppression (Geng et al., 1995, Sopori and Kozak, 1998, Sopori et al., 1998, Chen et al., 2007). Therefore, using a Lewis rat model we examined these possible effects of cigarette smoke on the expression of markers of proinflammatory and anti-inflammatory responses. We also examined the effects on the expression of NADPH oxidase, pro-oxidant and antioxidant genes and on the activation of Nrf2. These studies showed that a number of these responses increased in brains of rats with significant CS exposure. This study, which represents the first demonstration of these effects from CS in the brain, provides a basis for future investigations of the specific mechanisms by which cigarette smoking may trigger the development of inflammatory and degenerative nervous system diseases.
Section snippets
Exposure of rats to cigarette smoke
This study was conducted according to the Guidelines for Animal Experiments of the NIH using CS-exposed and non-exposed Lewis rats (Harlan) (n = 8 rats/group). Rats were exposed to cigarette smoke in a specially constructed smoke chamber where the animals were restrained and ventilated by a smoking machine (Khanna et al., 2009). In the machine, smoke is sucked from lit cigarettes by syringes and pumped around a chamber, where the rats inhale the cigarette smoke. The smoking machine was set to
Cigarette smoke induced neuroinflammation detected in immunostained brain sections from exposed rats
Sections were stained for MHC class II, which is expressed by T cells, B cells, monocytes, macrophages, and, in the brain, also by microglia and astrocytes. These studies showed increased MCH class II staining in parenchymal and in perivascular regions of brain from the CS-exposed rats (Fig. 1). In contrast, no staining was noted in brain tissue from the control rats. Lysates of brain tissue from the CS-exposed and non-exposed rats were also examined by ELISA for levels of the proinflammatory
Discussion
Our studies demonstrate the presence of inflammatory involvement and increased expression of pro-oxidant markers in the brains of Lewis rats exposed to CS. It has been well documented that tobacco smoke exposure can lead to the development of diseases of a variety of organ systems. We found that there was increased proinflammatory and anti-inflammatory cytokine gene responses in the exposed rat brains. In particular, CS exposure elevated Th1 as well as Th17 and Treg cell-associated cytokine
Acknowledgments
Research supported by R01DA021556 (WR) and a donation from the Hills Family (WR).
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