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

• Authors: Shuchismita R Satpathy, Venkatakrishna R Jala, Sobha R Bodduluri, Elangovan Krishnan, Bindu Hegde, Gary W Hoyle, Mostafa Fraig, Andrew D Luster, Bodduluri Haribabu
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 7064 (Apr 29 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25923988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokines
• Chemotactic Factors
• Inflammation Mediators
• Interleukin-1beta
• Receptors, Leukotriene B4
• Leukotriene B4
• Silicon Dioxide
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Cell Proliferation
• Chemokines (biosynthesis)
• Chemotactic Factors (metabolism)
• Crystallization
• Disease Progression
• Inflammation (pathology)
• Inflammation Mediators (metabolism)
• Interleukin-1beta (biosynthesis)
• Leukotriene B4 (metabolism)
• Lung Neoplasms (metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Biological
• Neutrophil Infiltration
• Proto-Oncogene Proteins p21(ras) (metabolism)
• Receptors, Leukotriene B4 (deficiency, metabolism)
• Silicon Dioxide (adverse effects)