Pharmacological Stabilization of Mast Cells Abrogates Late Thrombotic Events Induced by Diesel Exhaust Particles in Hamsters

Abstract

Background-Particulate air pollution is associated with cardiovascular diseases and myocardial infarction (MI). Methods and Results-We investigated the relationship between airway inflammation and thrombosis 24 hours after intratracheal (IT) instillation of diesel exhaust particles (DEP; 50 g/hamster). Mild thrombosis was induced in the femoral vein by endothelial injury, and the consequences of airway inflammation on thrombogenicity were studied via online video microscopy. Lung inflammation and histamine analysis in bronchoalveolar lavage (BAL) and plasma were performed after pretreatment with dexamethasone (DEX) or sodium cromoglycate (SC). DEP induced airway inflammation and histamine release in BAL and in plasma, and increased thrombosis, without elevating plasma von Willebrand factor (vWF) levels. The IT instillation of 400-nm positively charged polystyrene particles (500 g/hamster), serving as particles that do not penetrate into the circulation, equally produced airway inflammation, histamine release, and enhanced thrombosis. Histamine in plasma resulted from basophil activation. Intraperitoneal (IP) pretreatment with DEX (5 mg/kg) abolished the DEP-induced histamine increase in BAL and plasma and abrogated airway inflammation and thrombogenicity. The IT pretreatment with DEX (0.5 mg/kg) showed a partial but parallel inhibition of all of these parameters. Pretreatment with SC (40 mg/kg, IP) strongly inhibited airway inflammation, thrombogenicity, and histamine release. Conclusions-Our results are compatible with the triggering of mast cell degranulation and histamine release by DEP.Histamine plays an initial central role in airway inflammation, further release of histamine by circulating basophils, and peripheral thrombotic events. Antiinflammatory pretreatment can abrogate the peripheral thrombogenicity by preventing histamine release from mast cells.

Coagulation markers in healthy human subjects exposed to diesel exhaust

“…However, we did not directly test platelet activation, a more sensitive measure for which there is evidence in this hamster model. Finally, though the lack of DE-associated change in VWF is consistent with prior study [21] and suggests a lack of endothelial activation [22] under our experimental conditions, the role of endothelial dysfunction needs to be further addressed given others' findings of impaired vasomotor responses to both endothelium-dependent and -independent vasodilators at 6 hours [9].…”

Inhibition of mast cell-derived histamine secretion by cromolyn sodium treatment decreases biliary hyperplasia in cholestatic rodents

“…To support our findings, it has been demonstrated that cromolyn sodium treatment inhibits plasma histamine release in a model of airway inflammation and thrombosis. 54 Our in vitro studies demonstrated that treatment with cromolyn sodium did not affect cholangiocyte histamine secretion, suggesting that the in vivo effects of histamine secretion are directly related to the inhibition of mast cell-derived histamine.…”

Air Pollution and Cardiovascular Disease

“…Pretreatment of hamsters with a histamine H1-receptor antagonist, an anti-inflammatory drug, abolished pulmonary inflammation at all time points and reduced DEP-induced thrombosis at 6 and 24 hours post-instillation, indicating a crucial role for inflammation in thrombogenicity at these time points. Likewise, the administration of other anti-inflammatory drugs, such as dexamethasone and selective inhibitors of basophils, macrophages and neutrophils, also significantly reduced the PMinduced prothrombogenicity at 24 hours (Nemmar et al 2004, Nemmar et al 2005. In contrast, pretreatment with the histamine H1-receptor antagonist did not reduce thrombosis as soon as 1 hour after DEP exposure (Nemmar et al 2003c).…”