Cigarette smoke has been widely investigated in terms of epidemiology and pathological endpoints in relation to human lung diseases and animal study. In this study we exposed Wistar rats to cigarette smoke at concentrations of 20% and 60% to explore potential molecular mechanisms at the protein level. Exposures were conducted twice a day, 5 days a week for 43 weeks. As a major metabolite of nicotine in cigarette, cotinine level in rat urine was determined by HPLC-MS. A dose-dependent analysis indicated that cotinine may be used as an exposure marker of cigarette smoke. Expression of receptor for advanced glycation endproducts (RAGE), an immunoglobulin super family that triggers the intracellular signal cascade reaction leading to inflammation and its ligand S100A6 (calgranulin) in bronchial epithelial cells and lung tissues of rats, were found to be positive correlated with cotinine levels, indicating that RAGE and S100A6 may be attributable to inflammation and oxidative damage caused by cigarette smoke.