Enhanced peripheral thrombogenicity after lung inflammation is mediated by platelet–leukocyte activation: role of P-selectin
Background: Inhaled ultrafine particles trigger peripheral thrombotic complications. Methods: We have analyzed the systemic prothrombotic risk following lung inflammation induced by pulmonary carbon nanotubes (CNTs). Results: Intratracheal instillation in Swiss mice of 200 and 400 μg of multiwall ground CNTs triggered substantial lung neutrophil, but not macrophage influx, 24 h later. The detection of circulating platelet–leukocyte conjugates exclusively 6 h after CNT instillation pointed to early but transient activation of circulating platelets. At 24 h, elevated plasma procoagulant microvesicular tissue factor activity was found in CNT-exposed but not in saline-exposed mice. However, at 24 h, both the tail and jugular vein bleeding times were prolonged in CNT-exposed but not in saline-exposed mice, arguing against strong CNT-induced platelet activation at this point. Nevertheless, at 24 h, enhanced peripheral thrombogenicity was detected in CNT-exposed but not in saline-exposed mice, via quantitative photochemically induced carotid artery thrombosis measurements. P-selectin neutralization abrogated platelet–leukocyte conjugate formation and microvesicular tissue factor generation, and abolished the CNT-induced thrombogenicity amplification. In contrast, the weak vascular injury-triggered thrombus formation in saline-treated mice was not affected by P-selectin neutralization at 24 h. Conclusions: The mild CNT-induced lung inflammation translates via rapid but mild and transient activation of platelets into P-selectin-mediated systemic inflammation. Leukocyte activation leads to tissue factor release, in turn eliciting inflammation-induced procoagulant activity and an associated prothrombotic risk.
Document Type: Research Article
Affiliations: 1: Laboratory of Pneumology (Lung Toxicology), K.U. Leuven, Leuven, Belgium 2: Medical Research Council Toxicology Unit, Leicester, UK 3: Department of Physiology, College of Medicine, Sultan Qaboos University, Al-khod, Sultanate of Oman
Publication date: 2007-06-01