Identifying the Molecular Mechanisms of Air Pollution-Induced Cardiovascular Disease
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An estimated 3.5-million people die annually from air pollution-induced cardiovascular disease (API-CVD). API-thrombosis (API-T) is a main contributor of these mortalities; however, the molecular mechanisms driving API-T are unclear. To identify these mechanisms we developed an in vitro model that represents the interface of the respiratory and cardiovascular system, the alveolar capillary region (ACR). This organotypic model includes human alveolar-like epithelial cells (H441), human lung fibroblasts, and human lung microvascular endothelial cells (HULEC). We hypothesized that air pollutant exposure of the H441 cells would initiate the onset of a pro-thrombotic state in the HULEC. To test this, we exposed H441 cells to the ubiquitous air pollutant, diesel exhaust particulates (DEP), and investigated the effect of this trans-alveolar exposure (TA-DEP) on the underlying HULEC. TA-DEP exposure induced expression of anti-oxidants such as heme oxygenase 1 and NAD(P)H dehydrogenase [quinone] 1, increased nuclear factor erythoid-2 related factor (NRF2) protein, and reduced glutathione redox potential in the HULEC. Concurrently, decreased expression of the endothelial fibrinolytic and anti-coagulant genes, tissue-type plasminogen activator, plasminogen activator urokinase, and thrombomodulin, and increased expression of the procoagulant gene, coagulation factor III occurred in the HULEC. These data suggest that TA-DEP exposure induces redox dysfunction and an endothelial pro-thrombotic profile in the ACR. We conclude that redox dysfunction and pro-thrombotic activation in the capillary beds of the ACR may be critical initiation steps of API-T. Data from this model can help develop intervention strategies against API-T and can encourage the development of organotypic models resulting in a reduction of animal testing. This does not reflect EPA policy.