title: A selective antagonist of histamine H₄ receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1.
abstract: OBJECTIVE
  Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H₄ receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators.
  
  
  METHODS
  Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg.kg⁻¹) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2 , LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured.
  
  
  RESULTS
  OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2 , LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2 , LTB4 and TNF-α in BAL fluid.
  
  
  CONCLUSIONS
  Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Somma
authors.forename: L
authors.initials: L
authors.lastname: Cinci
authors.forename: G
authors.initials: G
authors.lastname: Formicola
authors.forename: A
authors.initials: A
authors.lastname: Pini
authors.forename: R
authors.initials: R
authors.lastname: Thurmond
authors.forename: M
authors.initials: M
authors.lastname: Ennis
authors.forename: D
authors.initials: D
authors.lastname: Bani
authors.forename: E
authors.initials: E
authors.lastname: Masini
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D000941:Antigens / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects / Q000276:immunology; D003371:Cough / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000276:immunology; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017305:Annexin A1; D000941:Antigens; D006633:Histamine Antagonists; D007211:Indoles; D010879:Piperazines; D014409:Tumor Necrosis Factor-alpha; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D010047:Ovalbumin
keywords: JNJ 7777120; airway inflammation; apoptosis; asthma-like reaction; cytokines; histamine H4 receptors; lipocortin-1; oxidative stress; prostaglandins