Chronic endotoxin exposure produces airflow obstruction and lung dendritic cell expansion.
Lai PS; Fresco JM; Pinilla MA; Macias AA; Brown RD; Englert JA; Hofmann O; Lederer JA; Hide W; Christiani DC; Cernadas M; Baron RM
Am J Respir Cell Mol Biol 2012 Aug; 47(2):209-217
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.
Airway-obstruction; Airway-resistance; Endotoxins; Exposure-levels; Analytical-processes; Drugs; Drug-interaction; Genetics; Immunology; Animals; Metabolism; Pathology; Lung; Lung-function; Laboratory-animals; Pulmonary-disorders; Pulmonary-function; Pulmonary-function-tests; Pulmonary-system; Pulmonary-system-disorders; Inhalants;
Author Keywords: airway resistance; inhalation; neutrophils; macrophages; dendritic cells; endotoxin
Rebecca M. Baron, M.D., Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115
American Journal of Respiratory Cell and Molecular Biology