Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM2.5

OBJECTIVE Exposure to air pollutants leads to the development of pulmonary and cardiovascular diseases, and thus air pollution is one of the major global threats to human health. Air pollutant particulate matter 2.5 (PM 2.5 )-induced cellular dysfunction impairs tissue homeostasis and causes vascular and cardiopulmonary damage. To test a hypothesis that elevated plasminogen activator inhibitor-1 (PAI-1) levels play a pivotal role in air pollutant-induced cardiopulmonary pathologies, we examined the efficacy of a drug-like novel inhibitor of PAI-1, TM5614, in treating PM 2.5 -induced vascular and cardiopulmonary pathologies. APPROACH AND RESULTS Results from biochemical, histological, and immunohistochemical studies revealed that PM 2.5 increases the circulating levels of PAI-1 and thrombin and that TM5614 treatment completely abrogates these effects in plasma. PM 2.5 significantly augments levels of pro-inflammatory cytokine IL-6 in bronchoalveolar lavage fluid, and this also can be reversed by TM5614, indicating its efficacy in amelioration of PM 2.5 -induced increases in inflammatory and pro-thrombotic factors. TM5614 reduces PM 2.5 -induced increased levels of inflammatory markers Mac3 and pSTAT3, adhesion molecule VCAM1, and apoptotic marker cleaved caspase 3. Longer exposure to PM 2.5 induces pulmonary and cardiac thrombosis, but TM5614 significantly ameliorates PM 2.5 -induced vascular thrombosis. TM5614 also reduces PM 2.5 -induced increased blood pressure and heart weight. In vitro cell culture studies revealed that PM 2.5 induces the levels of PAI-1, type I collagen, fibronectin, and SREBP-1/2, a transcription factor that mediates profibrogenic signaling, in cardiac fibroblasts. TM5614 abrogated that stimulation, indicating that it may block PM 2.5 -induced PAI-1 and profibrogenic signaling through suppression of SREBP-1. Furthermore, TM5614 blocked PM 2.5 -mediated suppression of Nrf2, a major antioxidant regulator in cardiac fibroblasts. CONCLUSIONS Pharmacological inhibition of PAI-1 with TM5614 is a promising therapeutic approach to control air pollutant PM 2.5 -induced cardiopulmonary and vascular pathologies. Abstract Figure