Published ahead of print on January 18, 2005, doi:10.1164/rccm.200409-1202OC Am. J. Respir. Crit. Care Med., Volume 171, Number 8, April 2005, 872-879 A more recent version of this article appeared on April 15, 2005
Submitted on September 14, 2004 Silica Particles Enhance Peripheral Thrombosis: Key Role of Lung Macrophage-neutrophil Cross-talkAbderrahim Nemmar1,1 Laboratory of Pneumology (Lung Toxicology), K.U.Leuven, Leuven, Belgium, 2 Department of Cell Biology, Vrije Universiteit Amsterdam, Faculty of Medicine, Amsterdam, The Netherlands, 3 Center for Molecular and Vascular Biology, K.U.Leuven, Leuven, Belgium * To whom correspondence should be addressed. E-mail: ben.nemery{at}med.kuleuven.ac.be.
Rationale- Inflammation and thrombosis are related via interactions between leukocytes, platelets, the vasculature and coagulation system. However, the mechanisms behind these interactions remain poorly understood. Objectives- 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 µ/hamster) were intratracheally instilled, and experimental thrombosis in photochemically induced femoral vein lesions was assessed 24 h later, in association with cellular infiltration in the lung. Measurements and Main Results- Intratracheally instilled silica particles (20 and 200 µ/hamster) triggered pulmonary inflammation, coupled to stimulation of peripheral platelet-rich thrombus formation. Both the selective depletion of lung macrophages by i.t. administration of clodronate-liposomes, and the combined depletion of circulating monocytes and neutrophils by i.p. injection of cyclophosphamide significantly reduced silica-induced influx of macrophages and neutrophils in BAL, and reduced peripheral thrombogenicity. Silica-induced lung inflammation was accompanied by increased neutrophil elastase levels in BAL and also 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. Key words: Silica particles, Lung, macrophage, neutrophil, Thrombosis.
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