title: MD-2-dependent pulmonary immune responses to inhaled lipooligosaccharides: effect of acylation state.
abstract: Endotoxins represent one of the most potent classes of microbial immunoactive components that can cause pulmonary inflammation. The aim of this study was to compare the inflammatory potency of two types of Neisseria meningitidis endotoxins (lipooligosaccharides) in lungs: wild type (hexaacylated, LOS(wt)) and mutant type (pentaacylated, LOS(msbB)), and to determine the importance of MD-2 in endotoxin responses in lungs in vivo. Endotoxin-normoresponsive mice (BALB/c) were exposed to selected doses of penta- and hexaacylated lipooligosaccharides (LOS) by nasal aspiration. Cellular and cytokine/chemokine inflammatory responses in bronchoalveolar lavage were measured at 1-, 4-, 8-, 16-, 24-, and 48-hour time points. MD-2-null mice were exposed to one dose of hexaacylated LOS and inflammatory responses were measured after 4 and 24 hours. Inhalation of hexaacylated LOS resulted in strong inflammatory responses, while pentaacylated LOS was much less potent in inducing increases of neutrophils, TNF-alpha, macrophage inflammatory protein-1 alpha, IL-6, granulocyte colony-stimulating factor, and IL-1 beta concentration in bronchoalveolar lavage. Similar kinetics of inflammatory responses in lungs were found in both types of endotoxin exposures. Inhalation of hexaacylated LOS in MD-2-null mice resulted in significantly lower numbers of neutrophils in bronchoalveolar lavage than in normoresponsive mice. Markedly lower inflammatory potency of pentaacylated LOS was observed compared with hexaacylated LOS. Hyporesponsiveness in MD-2-null mice after nasal aspiration of wild-type LOS indicate its essential role in airway responsiveness to endotoxin.
authors.affiliation: Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA 52242-5000, USA.
authors.forename: Suzana
authors.initials: S
authors.lastname: Hadina
authors.forename: Jerrold P
authors.initials: JP
authors.lastname: Weiss
authors.forename: Paul B
authors.initials: PB
authors.lastname: McCray
authors.forename: Katarina
authors.initials: K
authors.lastname: Kulhankova
authors.forename: Peter S
authors.initials: PS
authors.lastname: Thorne
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D054405:Chemokine CCL3 / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology* / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038541:Neisseria meningitidis, Serogroup B / Q000737:chemistry / Q000276:immunology / Q000472:pathogenicity; D009504:Neutrophils / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D054405:Chemokine CCL3; D004731:Endotoxins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D014409:Tumor Necrosis Factor-alpha; C023023:lipid-linked oligosaccharides; D016179:Granulocyte Colony-Stimulating Factor