Abstract
BackgroundExposure of human populations to ambient particulate matter (PM) air pollution significantly contributes to the mortality attributable to ischemic cardiovascular events. We reported that mice treated with intratracheally instilled PM develop a prothrombotic state that requires the release of IL-6 by alveolar macrophages. We sought to determine whether exposure of mice to PM increases the levels of PAI-1, a major regulator of thrombolysis, via a similar or distinct mechanism.Methods and Principal FindingsAdult, male C57BL/6 and IL-6 knock out (IL-6−/−) mice were exposed to either concentrated ambient PM less than 2.5 µm (CAPs) or filtered air 8 hours daily for 3 days or were exposed to either urban particulate matter or PBS via intratracheal instillation and examined 24 hours later. Exposure to CAPs or urban PM resulted in the IL-6 dependent activation of coagulation in the lung and systemically. PAI-1 mRNA and protein levels were higher in the lung and adipose tissue of mice treated with CAPs or PM compared with filtered air or PBS controls. The increase in PAI-1 was similar in wild-type and IL-6−/− mice but was absent in mice treated with etanercept, a TNF-α inhibitor. Treatment with etanercept did not prevent the PM-induced tendency toward thrombus formation.ConclusionsMice exposed to inhaled PM exhibited a TNF-α-dependent increase in PAI-1 and an IL-6-dependent activation of coagulation. These results suggest that multiple mechanisms link PM-induced lung inflammation with the development of a prothrombotic state.
Highlights
There is a well-defined link between acute exposure to ambient particulate matter (PM) and morbidity and mortality from ischemic cardiovascular events including acute myocardial infarction and ischemic stroke [1]
These results suggest that multiple mechanisms link PM-induced lung inflammation with the development of a prothrombotic state
In mice exposed to concentrated ambient PM less than 2.5 mm (CAPs), we found small but significant elevations in the levels of the proinflammatory cytokines IL-6, MCP-1 and TNF-a in the bronchoalveolar lavage (BAL) fluid (Figure 1A–C)
Summary
There is a well-defined link between acute exposure to ambient particulate matter (PM) and morbidity and mortality from ischemic cardiovascular events including acute myocardial infarction and ischemic stroke [1]. Several groups of investigators have reported that humans and rodents exposed to PM develop an enhanced tendency toward thrombosis and impaired fibrinolysis in the first 24 hours after the exposure [3,4,5,6,7,8,9]. This time course is consistent with the lag time of PM-induced mortality reported in population based cohort studies [1]. We sought to determine whether exposure of mice to PM increases the levels of PAI-1, a major regulator of thrombolysis, via a similar or distinct mechanism
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