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

Satpathy SR, Jala VR, Bodduluri SR, Krishnan E, Hegde B, Hoyle GW, Fraig M, Luster AD, Haribabu B - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus

CS-induced neutrophil recruitment into the air pouch is dependent on LTB4/BLT1 axisCS induced inflammation in an air pouch was analyzed. Six hours post CS particle exposure the air pouch was lavaged with 3ml of buffer to assess LTB4 levels and infiltrating immune cells. (a) LTB4 levels, (b) leukocytes on cytospin slides and (c) total leukocytes, neutrophils and macrophages as identified by flow cytometry of the air pouch lavage fluid from mice of the indicated genotypes. Data are representative of at least five mice per group. Error bars denote mean ± SEM. *P < 0.02, **P <0.009; Mann Whitney U-test.
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Figure 7: CS-induced neutrophil recruitment into the air pouch is dependent on LTB4/BLT1 axisCS induced inflammation in an air pouch was analyzed. Six hours post CS particle exposure the air pouch was lavaged with 3ml of buffer to assess LTB4 levels and infiltrating immune cells. (a) LTB4 levels, (b) leukocytes on cytospin slides and (c) total leukocytes, neutrophils and macrophages as identified by flow cytometry of the air pouch lavage fluid from mice of the indicated genotypes. Data are representative of at least five mice per group. Error bars denote mean ± SEM. *P < 0.02, **P <0.009; Mann Whitney U-test.

Mentions: The in vitro studies showed that mast cells are a major source of LTB4 production and the absence of BLT1 clearly reduced lung inflammation and neutrophil influx in vivo. Previous studies have shown that CS mediated lung inflammation is dependent on the presence of mast cells [26]. We adopted the murine air-pouch model [27] to assess the contribution of mast cells and the role of LTB4-BLT1 axis in neutrophil recruitment during CS-induced inflammation. In this model, CS exposure of BLT1+/+ mice induced the production of LTB4 (Fig 7a) accompanied by influx of neutrophils (Fig 7b, c). This response however was significantly dampened in the BLT1−/− as well as in mast cell deficient mice (Fig 7a-c). These data shows that neutrophil recruitment is an early event during CS exposure and is controlled by mast cell-mediated LTB4 production and expression of BLT1 on neutrophils.


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

Satpathy SR, Jala VR, Bodduluri SR, Krishnan E, Hegde B, Hoyle GW, Fraig M, Luster AD, Haribabu B - Nat Commun (2015)

CS-induced neutrophil recruitment into the air pouch is dependent on LTB4/BLT1 axisCS induced inflammation in an air pouch was analyzed. Six hours post CS particle exposure the air pouch was lavaged with 3ml of buffer to assess LTB4 levels and infiltrating immune cells. (a) LTB4 levels, (b) leukocytes on cytospin slides and (c) total leukocytes, neutrophils and macrophages as identified by flow cytometry of the air pouch lavage fluid from mice of the indicated genotypes. Data are representative of at least five mice per group. Error bars denote mean ± SEM. *P < 0.02, **P <0.009; Mann Whitney U-test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4418220&req=5

Figure 7: CS-induced neutrophil recruitment into the air pouch is dependent on LTB4/BLT1 axisCS induced inflammation in an air pouch was analyzed. Six hours post CS particle exposure the air pouch was lavaged with 3ml of buffer to assess LTB4 levels and infiltrating immune cells. (a) LTB4 levels, (b) leukocytes on cytospin slides and (c) total leukocytes, neutrophils and macrophages as identified by flow cytometry of the air pouch lavage fluid from mice of the indicated genotypes. Data are representative of at least five mice per group. Error bars denote mean ± SEM. *P < 0.02, **P <0.009; Mann Whitney U-test.
Mentions: The in vitro studies showed that mast cells are a major source of LTB4 production and the absence of BLT1 clearly reduced lung inflammation and neutrophil influx in vivo. Previous studies have shown that CS mediated lung inflammation is dependent on the presence of mast cells [26]. We adopted the murine air-pouch model [27] to assess the contribution of mast cells and the role of LTB4-BLT1 axis in neutrophil recruitment during CS-induced inflammation. In this model, CS exposure of BLT1+/+ mice induced the production of LTB4 (Fig 7a) accompanied by influx of neutrophils (Fig 7b, c). This response however was significantly dampened in the BLT1−/− as well as in mast cell deficient mice (Fig 7a-c). These data shows that neutrophil recruitment is an early event during CS exposure and is controlled by mast cell-mediated LTB4 production and expression of BLT1 on neutrophils.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus