Silica particles enhance peripheral thrombosis: key role of lung macrophage-neutrophil cross-talk.
BACKGROUND
Inflammation and thrombosis are related via interactions between leukocytes, platelets, the vasculature, and the coagulation system. However, the mechanisms behind these interactions remain poorly understood.


OBJECTIVE
We have investigated the effects of the well known pulmonary inflammation induced by silica for the development of peripheral thrombogenicity in a hamster model of thrombosis. In addition, the consequences of pulmonary macrophage and circulating monocyte and neutrophil depletion on the thrombogenicity were investigated.


METHODS
Silica particles (2-200 mug/hamster) were intratracheally instilled, and experimental thrombosis in photochemically induced femoral vein lesions was assessed 24 hours later, in association with cellular infiltration in the lung.


RESULTS
Intratracheally instilled silica particles (20 and 200 mug/hamster) triggered pulmonary inflammation, together with stimulation of peripheral platelet-rich thrombus formation. Both the selective depletion of lung macrophages by intratracheal administration of clodronate liposomes and the combined depletion of circulating monocytes and neutrophils by intraperitoneal injection of cyclophosphamide significantly reduced silica-induced influx of macrophages and neutrophils in bronchoalveolar lavage, and reduced peripheral thrombogenicity. Silica-induced lung inflammation was accompanied by increased neutrophil elastase levels in bronchoalveolar lavage and in plasma. Specific neutrophil elastase inhibition in the lung did not affect lung inflammation but reduced peripheral thrombogenicity.


CONCLUSIONS
These findings uncover pulmonary macrophage-neutrophil cross-talk releasing neutrophil elastase into the blood circulation. Elastase, triggering activation of circulating platelets, may then predispose platelets to initiate thrombotic events on mildly damaged vasculature.
Nemmar
Abderrahim
A
K.U. Leuven, Laboratory of Pneumology, Unit of Lung Toxicology, Herestraat 49, B-3000 Leuven, Belgium. ben.nemery@med.kuleuven.ac.be
Nemery
Benoit
B
Hoet
Peter H M
PH
Van Rooijen
Nico
N
Hoylaerts
Marc F
MF
D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D006224:Cricetinae; D005268:Femoral Vein / Q000276:immunology; D019272:Leukocyte Elastase / Q000097:blood; D016676:Macrophages, Alveolar / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D015539:Platelet Activation / Q000276:immunology; D020239:Receptor Cross-Talk / Q000276:immunology; D012822:Silicon Dioxide; D012829:Silicosis / Q000276:immunology*; D020246:Venous Thrombosis / Q000276:immunology*
D012822:Silicon Dioxide; D019272:Leukocyte Elastase