title: Chronic endotoxin exposure produces airflow obstruction and lung dendritic cell expansion.
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.
authors.affiliation: Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Lai
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Fresco
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pinilla
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Macias
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Brown
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Englert
authors.forename: Oliver
authors.initials: O
authors.lastname: Hofmann
authors.forename: James A
authors.initials: JA
authors.lastname: Lederer
authors.forename: Winston
authors.initials: W
authors.lastname: Hide
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Manuela
authors.initials: M
authors.lastname: Cernadas
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Baron
mesh_terms: D000403:Airway Resistance / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004731:Endotoxins / Q000276:immunology / Q000494:pharmacology*; D015870:Gene Expression; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016273:Occupational Exposure; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D004731:Endotoxins; C556062:IL10 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016753:Interleukin-10