It is known that ozone stress can induce airway hyperresponsiveness (AHR). The underlying cellular and molecular mechanisms are not fully understood. We constructed a successive ozone-stressed rat model and showed that AHR caused by ozone stress presented as increased lung resistance (R-L) to inhaled histamine but not baseline RL. Meanwhile, structural disruption and decreased expression of integrin beta 4 on airway epithelia were observed. Further regression analysis revealed a significant negative correlation between increases in RL to histamine (at 0.32 mg/ml) and mRNA expression of integrin beta 4. Moreover, when integrin beta 4 on human bronchial epithelial cells was knocked down, we found that reactive oxygen species was increased and apoptosis rates were higher. Overall, this study suggests that downregulation of integrin beta 4 is important for the development ozone stress-induced AHR, presumably because it causes increased oxidative damage and epithelial apoptosis. (C) 2010 Elsevier Inc. All rights reserved.