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Nat Commun. 2015 Apr 29;6:7064. doi: 10.1038/ncomms8064.

Crystalline silica-induced leukotriene B4-dependent inflammation promotes lung tumour growth.

Author information

1
1] James Graham Brown Cancer Center, University of Louisville, Louisville 40202, Kentucky, USA [2] Department of Microbiology and Immunology, University of Louisville, Louisville 40202, Kentucky, USA.
2
Department of Environmental and Occupational Health Sciences, University of Louisville, Louisville 40202, Kentucky, USA.
3
Department of Pathology and Laboratory Medicine, University of Louisville, Louisville 40202, Kentucky, USA.
4
Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Chronic exposure to crystalline silica (CS) causes silicosis, an irreversible lung inflammatory disease that may eventually lead to lung cancer. In this study, we demonstrate that in K-ras(LA1) mice, CS exposure markedly enhances the lung tumour burden and genetic deletion of leukotriene B4 receptor-1 (BLT1(-/-)) attenuates this increase. Pulmonary neutrophilic inflammation induced by CS is significantly reduced in BLT1(-/-)K-ras(LA1) mice. CS exposure induces LTB4 production by mast cells and macrophages independent of inflammasome activation. In an air-pouch model, CS-induced neutrophil recruitment is dependent on LTB4 production by mast cells and BLT1 expression on neutrophils. In an implantable lung tumour model, CS exposure results in rapid tumour growth and decreased survival that is attenuated in the absence of BLT1. These results suggest that the LTB4/BLT1 axis sets the pace of CS-induced sterile inflammation that promotes lung cancer progression. This knowledge may facilitate development of immunotherapeutic strategies to fight silicosis and lung cancer.

PMID:
25923988
PMCID:
PMC4418220
DOI:
10.1038/ncomms8064
[Indexed for MEDLINE]
Free PMC Article

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