In this study, we first define a novel pathway that mediates ROS-dependent tight junction disruption upon particulate matter challenge. Tight junctions, or zonula occludens, are the most apical component of the intercellular junctional complex, which also includes adherens junctions, desmosomes, and gap junctions [36] . ZO-1 was the first tight junction protein to be identified, and ZO-2 and ZO-3 were later isolated as proteins that coimmunoprecipitated with ZO-1 [37, 38] . ZO-1 is a peripheral membrane-associated component of the cytoplasmic plaque of tight junctions and is found ubiquitously within tight junctions of epithelial and endothelial cells [39] . ZO-1 interacts with many cellular proteins via its multiple protein-binding domains. ZO-1 has been reported to interact with other ZO family members or claudins via the PDZ domains [40, 41] . ZO-1 interacts with the C-terminus of occludin with its GuK domain and the acidic domain [42] . The proline-rich C-terminus of ZO-1 mediates its binding to F-actin in vitro, and thus links it to the cytoskeleton [43] . Clearly, ZO-1 interacts with a wide variety of cell skeleton components and plays a central role in orchestrating tight junction complexes. Any dysregulation of ZO-1 in endothelial cells by extracellular stimuli, such as virus shell proteins or alcohol, leads to persistent tight junction disruption and vascular hyperpermeability.