1. Chronic endotoxin exposure produces airflow obstruction and lung dendritic cell expansion.
- Author
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Lai PS, Fresco JM, Pinilla MA, Macias AA, Brown RD, Englert JA, Hofmann O, Lederer JA, Hide W, Christiani DC, Cernadas M, and Baron RM
- Subjects
- Airway Resistance drug effects, Airway Resistance genetics, Airway Resistance immunology, Animals, Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Antigen-Presenting Cells pathology, Bronchial Hyperreactivity genetics, Bronchial Hyperreactivity immunology, Bronchial Hyperreactivity metabolism, Bronchial Hyperreactivity pathology, Bronchoalveolar Lavage Fluid immunology, Dendritic Cells immunology, Dendritic Cells metabolism, Dendritic Cells pathology, Endotoxins immunology, Gene Expression, Interleukin-10 genetics, Interleukin-10 immunology, Interleukin-10 metabolism, Interleukin-6 genetics, Interleukin-6 immunology, Interleukin-6 metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear pathology, Lipopolysaccharides immunology, Lipopolysaccharides pharmacology, Lung immunology, Lung metabolism, Lung pathology, Macrophages immunology, Macrophages metabolism, Macrophages pathology, Male, Mice, Mice, Inbred C57BL, Models, Animal, Myeloid Cells drug effects, Myeloid Cells immunology, Myeloid Cells metabolism, Myeloid Cells pathology, Neutrophils drug effects, Neutrophils immunology, Neutrophils metabolism, Neutrophils pathology, Occupational Exposure, Pneumonia genetics, Pneumonia immunology, Pneumonia metabolism, Pneumonia pathology, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, Up-Regulation, Dendritic Cells drug effects, Endotoxins pharmacology, Lung drug effects, Pulmonary Disease, Chronic Obstructive immunology
- Abstract
Little is known about the mechanisms of persistent airflow obstruction that result from chronic occupational endotoxin exposure. We sought to analyze the inflammatory response underlying persistent airflow obstruction as a result of chronic occupational endotoxin exposure. We developed a murine model of daily inhaled endotoxin for periods of 5 days to 8 weeks. We analyzed physiologic lung dysfunction, lung histology, bronchoalveolar lavage fluid and total lung homogenate inflammatory cell and cytokine profiles, and pulmonary gene expression profiles. We observed an increase in airway hyperresponsiveness as a result of chronic endotoxin exposure. After 8 weeks, the mice exhibited an increase in bronchoalveolar lavage and lung neutrophils that correlated with an increase in proinflammatory cytokines. Detailed analyses of inflammatory cell subsets revealed an expansion of dendritic cells (DCs), and in particular, proinflammatory DCs, with a reduced percentage of macrophages. Gene expression profiling revealed the up-regulation of a panel of genes that was consistent with DC recruitment, and lung histology revealed an accumulation of DCs in inflammatory aggregates around the airways in 8-week-exposed animals. Repeated, low-dose LPS inhalation, which mirrors occupational exposure, resulted in airway hyperresponsiveness, associated with a failure to resolve the proinflammatory response, an inverted macrophage to DC ratio, and a significant rise in the inflammatory DC population. These findings point to a novel underlying mechanism of airflow obstruction as a result of occupational LPS exposure, and suggest molecular and cellular targets for therapeutic development.
- Published
- 2012
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