title: Characterization of LPS-induced lung inflammation in cftr-/- mice and the effect of docosahexaenoic acid.
abstract: The mechanism by which Pseudomonas causes excessive inflammation in the cystic fibrosis lung is unclear. We have reported that arachidonic acid is increased and docosahexaenoic acid (DHA) decreased in lung, pancreas, and ileum from cftr-/- mice. Oral DHA corrected this defect and reversed the pathology. To determine which mediators regulate inflammation in lungs from cftr-/- mice and whether inhibition occurs with DHA, cftr-/- and wild-type (WT) mice were exposed to aerosolized Pseudomonas lipopolysaccharide (LPS). After 2 days of LPS, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2, and KC levels in bronchoalveolar lavage fluid were increased in cftr-/- compared with WT mice and not suppressed by pretreatment with oral DHA. Neutrophil levels were not different between cftr-/- and WT mice. After 3 days of aerosolized LPS, neutrophil concentration, TNF-alpha, and the eicosanoids 6-keto-PGF1alpha, PGF2alpha, PGE2, and thromboxane B2 were all increased in bronchoalveolar lavage fluid from cftr-/- mice compared with WT controls. Oral DHA had no significant effect on TNF-alpha levels in cftr-/- mice. In contrast, neutrophils and eicosanoids were decreased in cftr-/- but not in WT mice treated with DHA, indicating that the effects of DHA on these inflammatory parameters may be related to correction of the membrane lipid defect.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. sfreedma@caregroup.harvard.edu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Freedman
authors.forename: Deborah
authors.initials: D
authors.lastname: Weinstein
authors.forename: Paola G
authors.initials: PG
authors.lastname: Blanco
authors.forename: Pedro
authors.initials: P
authors.lastname: Martinez-Clark
authors.forename: Serge
authors.initials: S
authors.lastname: Urman
authors.forename: Munir
authors.initials: M
authors.lastname: Zaman
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Juan G
authors.initials: JG
authors.lastname: Alvarez
mesh_terms: D000284:Administration, Oral; D000336:Aerosols; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002452:Cell Count; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000032:analysis; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000032:analysis; D003550:Cystic Fibrosis / Q000150:complications / Q000276:immunology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000032:analysis; D006133:Growth Substances / Q000032:analysis; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000032:analysis; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D018181:Mice, Inbred CFTR; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D011549:Pseudomonas; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000336:Aerosols; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D015777:Eicosanoids; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D004281:Docosahexaenoic Acids