Abstract
Inhalation of particulate matter in polluted air causes direct, size-restricted passage in the circulation and pronounced lung inflammation, provoking platelet activation and (non)-fatal cardiovascular complications. To determine potency and mechanism of platelet sensitization via neutrophil enzymes, we performed in vitro aggregation studies in washed human platelets and in murine and human blood, in the presence of elastase, cathepsin G and regular platelet agonists, present in damaged arteries. The impact of both enzymes on in vivo thrombogenicity was studied in the same thrombosis mouse model, previously having demonstrated that neutrophil activation enhances peripheral thrombogenicity. At 0.05 U/mL, cathepsin G activated washed human platelets via PAR1, whereas at 0.35 U/mL, aggregation occurred via PAR4. In Swiss mouse platelet-rich plasma no aggregation occurred by cathepsin G at 0.4 U/mL. In human and murine blood, aggregations by 0.05–0.1 U/mL cathepsin G were similar and not PAR-mediated, but platelet aggregation was inhibited by ADP antagonists, advocating cathepsin G-released ADP in blood as the true agonist of sustained platelet activation. In the mouse thrombosis model, cathepsin G and elastase amplified mild thrombogenicity at blood concentrations that activated platelets in vitro. This study shows that cathepsin G and elastase secreted in the circulation during mild air pollution-induced lung inflammation lyse red blood cell membrane proteins, leading to ADP-leakage into plasma, sensitizing platelets and amplifying their contribution to cardiovascular complications of ambient particle inhalation.
Highlights
Exposure to particulate matter in polluted air for hours to weeks triggers cardiovascular disease-related mortality and non-fatal events, in conjunction with arterial thrombotic complications [1,2,3]
Via flow cytometry detection of platelet surface P-selectin, Figure 1a shows that 0.05 U/mL cathepsin G cannot activate platelets distinctly, in the absence of other platelet agonists
The relationship between tissue inflammation and thrombosis was investigated in vivo and in vitro, via studying platelet activation by the neutrophil-released proteases cathepsin G and elastase
Summary
Exposure to particulate matter in polluted air for hours to weeks triggers cardiovascular disease-related mortality and non-fatal events, in conjunction with arterial thrombotic complications [1,2,3]. Long-term exposure over years further increases the risk of cardiovascular mortality, as a result of vascular degenerative disease, caused by chronic inflammation, oxidative stress and atherosclerosis [1,4,5]. Experimental studies in animal models have reproduced the inhalation of particulate matter via intratracheal (i.t.) instillation and have demonstrated that instillation of a dose of diesel exhaust particles (DEP), representative of a 24 h inhalation interval in man causes rapid platelet activation, in turn eliciting arterial thrombogenicity of compromised arterial blood vessels [6]. Detailed studies in man and hamsters showed that the rapid sensitization of circulating platelets was due to the direct translocation of inhaled ultrafine particles into the blood stream within 1 h [6,7,8]. Histamine antagonism reduced arterial thrombogenicity, especially in the same 6–24 h time interval, linking lung inflammation and circulating platelet sensitization
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