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.
Highlights
Chronic exposure to crystalline silica (CS) causes silicosis, an irreversible lung inflammatory disease that may eventually lead to lung cancer
CS exposure leads to lung infiltration of neutrophils, macrophages and lymphocytes causing lung inflammation and the problem is further compounded by massive lung fibrosis leading to the disease silicosis[9,10]
We found that the K-rasLA1 mice showed distinctly visible lung tumours at the age of 105 days, whereas the BLT1 À / À K-rasLA1 mice showed fewer and smaller tumours (Supplementary Fig. 1a)
Summary
Chronic exposure to crystalline silica (CS) causes silicosis, an irreversible lung inflammatory disease that may eventually lead to lung cancer. 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 CSinduced sterile inflammation that promotes lung cancer progression. Chronic inflammation considered the seventh hallmark of cancer is promoted by a variety of intrinsic and extrinsic factors[1,2,3] Intrinsic factors such as activating mutation of K-ras, often associated with human lung adenocarcinomas[4] induces a pro-inflammatory microenvironment[5]. Extrinsic factors such as cigarette smoke or air-borne pollutants, commonly encountered in the environment, promote chronic lung inflammation and cancer[6,7]. The high-affinity LTB4 receptor, BLT1 is predominantly expressed on peripheral blood leukocytes and is known to modulate many chronic inflammatory diseases such as arthritis, atherosclerosis, allergic inflammation and insulin resistance during diet-induced obesity[17,18,19,20]
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