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 microg 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.
Nemmar
A
A
Laboratory of Pneumology (Lung Toxicology), K.U. Leuven, Leuven, Belgium.
Hoet
P H M
PH
Vandervoort
P
P
Dinsdale
D
D
Nemery
B
B
Hoylaerts
M F
MF
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006098:Granulocytes / Q000502:physiology; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D037742:Nanotubes, Carbon / Q000633:toxicity; D019007:P-Selectin / Q000097:blood*; D015539:Platelet Activation; D011014:Pneumonia / Q000097:blood* / Q000150:complications* / Q000209:etiology; D013925:Thromboplastin / Q000096:biosynthesis; D013927:Thrombosis / Q000097:blood* / Q000209:etiology*
D037742:Nanotubes, Carbon; D019007:P-Selectin; D013925:Thromboplastin