title: Inhibition of early airway neutrophilia does not affect development of airway hyperresponsiveness.
abstract: The effect of modifying early neutrophil-mediated inflammation on the development of airway hyperresponsiveness (AHR) was investigated using an interleukin (IL)-1 receptor antagonist (IL-1Ra), an anti-IL-18 antibody (anti-IL-18) or a p38 mitogen-activated protein kinase (MAPK) inhibitor (M39). Balb/c mice were sensitized to ovalbumin (OVA) and challenged with a single intranasal dose of OVA. Treatment with the IL-1Ra or anti-IL-18 was initiated 20 min before challenge, whereas M39 was administered 4 h before the challenge. Eight hours after challenge, sensitized mice showed significantly higher numbers of neutrophils in bronchoalveolar lavage (BAL) fluid; treatment with IL-1Ra, anti-IL-18, or M39 significantly decreased the influx of neutrophils. At 48 h, none of the treatments affected eosinophil inflammation in BAL fluid and lung tissue, goblet cell hyperplasia, or cytokine levels (IL-4, IL-5, IL-12, IL-13, interferon-gamma) in BAL fluid. Anti-IL-18 or IL-1Ra had no effect on the development of AHR, whereas M39-treated mice showed a decrease in methacholine responsiveness. These results demonstrate that early neutrophil influx following allergen challenge is mediated by IL-1, IL-18, and p38 MAPK. However, neutralization of IL-1 and IL-18 did not affect the later development of AHR and eosinophilic airway inflammation. The effects of inhibiting p38 MAPK in decreasing AHR indicate activities independent of its prevention of neutrophil accumulation.
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Nick
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.forename: Catherine
authors.initials: C
authors.lastname: Duez
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.forename: Yeong-Ho
authors.initials: YH
authors.lastname: Rha
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Park
authors.forename: Anthony
authors.initials: A
authors.lastname: Joetham
authors.forename: Katie
authors.initials: K
authors.lastname: Poch
authors.forename: Azzeddine
authors.initials: A
authors.lastname: Dakhama
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054426:Chemokine CXCL2; D004791:Enzyme Inhibitors / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000276:immunology*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000276:immunology; D008168:Lung / Q000737:chemistry / Q000166:cytology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D015846:Monokines / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000906:Antibodies; D054426:Chemokine CXCL2; D004791:Enzyme Inhibitors; D020382:Interleukin-18; D015846:Monokines; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases