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

Shuchismita R. Satpathy, Venkatakrishna R. Jala, Sobha R. Bodduluri, Elangovan Krishnan, Bindu Hegde, Gary W. Hoyle, Mostafa Fraig, Andrew D. Luster and Bodduluri Haribabu ()
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Shuchismita R. Satpathy: James Graham Brown Cancer Center, University of Louisville
Venkatakrishna R. Jala: James Graham Brown Cancer Center, University of Louisville
Sobha R. Bodduluri: James Graham Brown Cancer Center, University of Louisville
Elangovan Krishnan: James Graham Brown Cancer Center, University of Louisville
Bindu Hegde: James Graham Brown Cancer Center, University of Louisville
Gary W. Hoyle: University of Louisville
Mostafa Fraig: University of Louisville
Andrew D. Luster: Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School
Bodduluri Haribabu: James Graham Brown Cancer Center, University of Louisville

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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-rasLA1 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-rasLA1 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.

Date: 2015
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DOI: 10.1038/ncomms8064

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