An important limitation of our study is the high dose of PM that we employed. With 10-30 μg/m 3 ambient PM level in the US or Europe, it is hardly to achieve a high level of acute PM exposure. While 100 μg/ml (in vitro) or 10 mg/kg (in vivo) are typical doses used in particulate matter toxicology studies [12, 13, 27, [54] [55] [56] . With an assumed ambient PM level of 20 μg/m 3 , one man with 70 kg body weight and 8 m 3 /minute respiration rate would receive a dose of 10 mg/kg corresponding to about 16 years of exposure with 50% deposition rate. As noted, a lot of cities in the developing countries still have high levels of ambient PM. A report by world bank [57] Extensive epidemiologic and experimental evidence has demonstrated that particulate air pollution directly causes cardiopulmonary damage. Our observations demonstrate a novel mechanism of PM-mediated disruption of endothelial barrier function which is attributable to ZO-1 degradation by calpain, which is activated by extracellular calcium leakage through oxidant-sensitive TRPM2 channels. Therefore, inhibition of ROS/TRPM2/calpain/ZO-1 degradation may provide useful therapeutic strategies for the treatment of endothelial barrier dysfunction and lung inflammation.