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Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM_2.5.

ABSTRACT: Numerous studies have established that acute or chronic exposure to environmental pollutants like particulate matter (PM) leads to the development of accelerated aging related pathologies including 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. 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 the levels of pro-inflammatory cytokine interleukin-6 (IL-6) in bronchoalveolar lavage fluid (BALF), 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 cluster of differentiation 107 b (Mac3) and phospho-signal transducer and activator of transcription-3 (pSTAT3), adhesion molecule vascular cell adhesion molecule 1 (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 (Millipore), and sterol regulatory element binding protein-1 and 2 (SREBP-1 and SREBP-2), transcription factors that mediate 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 and 2. Furthermore, TM5614 blocked PM_2.5-mediated suppression of nuclear factor erythroid related factor 2 (Nrf2), a major antioxidant regulator, in cardiac fibroblasts. Pharmacological inhibition of PAI-1 with TM5614 is a promising therapeutic approach to control air pollutant PM_2.5-induced cardiopulmonary and vascular pathologies.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC8434953 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rapid urbanization and consuming lifestyles have intensified air pollution in urban areas. Air pollution in megacities has imposed severe environmental damages to human health. Proper management of the issue necessitates identification of the share of emission sources. Therefore, numerous research works have studied the apportionment of the total emissions and observed concentrations among different emissions sources. In this research, a comprehensive review is conducted to compare the source apportioning results for ambient air PM2.5 in the megacity of Tehran, the capital of Iran. One hundred seventy-seven pieces of scientific literatures, published between 2005 and 2021, were reviewed. The reviewed research are categorized according to the source apportioning methods: emission inventory (EI), source apportionment (SA), and sensitivity analysis of the concentration to the emission sources (SNA). The possible reasons for inconsistency among the results are discussed according to the scope of the studies and the implemented methods. Although 85% of the reviewed original estimates identify that mobile sources contribute to more thant 60% of Tehran air pollution, the distribution of vehicle types and modes are clearly inconsistent among the EI studies. Our review suggests that consistent results in the SA studies in different locations in central Tehran may indicate the reliability of this method for the identification of the type and share of the emission sources. In contrast, differences among the geographical and sectoral coverage of the EI studies and the disparities among the emission factors and activity data have caused significant deviations among the reviewed EI studies. Also, it is shown that the results of the SNA studies are highly dependent on the categorization type, model capabilities and EI presumptions and data input to the pollutant dispersion modelings. As a result, integrated source apportioning in which the three methods complement each other's results is necessary for consistent air pollution management in megacities.Supplementary informationThe online version contains supplementary material available at 10.1007/s40201-023-00855-0.

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Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM_2.5.

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

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OmicsDI is part of the ELIXIR infrastructure

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Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM_2.5.