Crystalline silica-induced leukotrieneB4-dependent inflammation promotes lung tumor growth

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 tumor burden and genetic deletion of leukotriene B4 receptor1 (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 tumor model, CS exposure results in rapid tumor growth and decrease survival that is attenuated in the absence of BLT1. These results suggest that LTB4/BLT1 axis sets the pace of CS-induced sterile inflammation that promotes lung cancer progression. This knowledge will facilitate development of immunotherapeutic strategies to fight silicosis and lung cancer.