P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica

Silicosis is an occupational lung disease, characterized by irreversible and progressive fibrosis. Silica exposure leads to intense lung inflammation, reactive oxygen production, and extracellular ATP (eATP) release by macrophages. The P2X7 purinergic receptor is thought to be an important immunomod...

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Published in:	PloS one Vol. 9; no. 10; p. e110185
Main Authors:	Monção-Ribeiro, Leonardo C, Faffe, Débora S, Santana, Patrícia T, Vieira, Flávia S, da Graça, Carolyne Lalucha A L, Marques-da-Silva, Camila, Machado, Mariana N, Caruso-Neves, Celso, Zin, Walter A, Borojevic, Radovan, Takiya, Christina M, Coutinho-Silva, Robson
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 13-10-2014 Public Library of Science (PLoS)
Subjects:	Alveoli Analysis Animal models Animals Apoptosis Biology and Life Sciences Bronchoalveolar lavage Bronchoalveolar Lavage Fluid Bronchus Collagen Collagen - metabolism Cytokines Cytometry Disease Exposure Fibers Fibroblasts Fibroblasts - drug effects Fibroblasts - metabolism Fibrosis Flow cytometry IL-1β Immunophenotyping Infiltration Inflammation Inflammation - metabolism Inflammation - pathology Inflation (Economics) Interleukin-1beta - metabolism Laboratory animals Lung - metabolism Lung - pathology Lung - physiopathology Lung diseases Lungs Macrophages Macrophages, Alveolar - drug effects Macrophages, Alveolar - metabolism Mechanical properties Mechanics Mice Mice, Inbred C57BL NF-kappa B - metabolism NF-κB protein NIH 3T3 Cells Nitric oxide Nitric Oxide - metabolism Nitric Oxide Synthase Type II - metabolism Occlusion Occupational diseases Occupational exposure Oxidative stress Oxygen Oxygen production Parenchyma Peritoneum Phagocytosis Phagocytosis - drug effects Physiology Pressure transducers Pulmonary Fibrosis - pathology Pulmonary Fibrosis - physiopathology Purinergic P2X Receptor Antagonists - pharmacology Reactive oxygen species Reactive Oxygen Species - metabolism Receptors, Purinergic P2X7 - metabolism Rodents Rosaniline Dyes - metabolism Signal Transduction - drug effects Silica Silicon dioxide Silicon Dioxide - toxicity Silicosis Smad2 Protein - metabolism Smad3 Protein - metabolism Trachea Transforming Growth Factor beta - metabolism Transforming growth factors Tumor necrosis factor-TNF Brazil United States > US Rio de Janeiro Brazil
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Summary:	Silicosis is an occupational lung disease, characterized by irreversible and progressive fibrosis. Silica exposure leads to intense lung inflammation, reactive oxygen production, and extracellular ATP (eATP) release by macrophages. The P2X7 purinergic receptor is thought to be an important immunomodulator that responds to eATP in sites of inflammation and tissue damage. The present study investigates the role of P2X7 receptor in a murine model of silicosis. To that end wild-type (C57BL/6) and P2X7 receptor knockout mice received intratracheal injection of saline or silica particles. After 14 days, changes in lung mechanics were determined by the end-inflation occlusion method. Bronchoalveolar lavage and flow cytometry analyzes were performed. Lungs were harvested for histological and immunochemistry analysis of fibers content, inflammatory infiltration, apoptosis, as well as cytokine and oxidative stress expression. Silica particle effects on lung alveolar macrophages and fibroblasts were also evaluated in cell line cultures. Phagocytosis assay was performed in peritoneal macrophages. Silica exposure increased lung mechanical parameters in wild-type but not in P2X7 knockout mice. Inflammatory cell infiltration and collagen deposition in lung parenchyma, apoptosis, TGF-β and NF-κB activation, as well as nitric oxide, reactive oxygen species (ROS) and IL-1β secretion were higher in wild-type than knockout silica-exposed mice. In vitro studies suggested that P2X7 receptor participates in silica particle phagocytosis, IL-1β secretion, as well as reactive oxygen species and nitric oxide production. In conclusion, our data showed a significant role for P2X7 receptor in silica-induced lung changes, modulating lung inflammatory, fibrotic, and functional changes.
Bibliography:	Conceived and designed the experiments: LCMR DSF CCN CMT RCS. Performed the experiments: LCMR DSF PS FSV CMdS MNM CLALdG. Analyzed the data: LCMR DSF PS FSV CMdS MNM CLALdG CMT RCS. Contributed reagents/materials/analysis tools: WAZ LCMR DSF PS FSV CMT RCS. Wrote the paper: LCMR DSF WAZ RB CMT RCS. Competing Interests: The authors have declared that no competing interests exist.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0110185