A selective antagonist of histamine H4 receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1 |
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| Authors: | T Somma L Cinci G Formicola A Pini R Thurmond M Ennis D Bani E Masini |
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| Institution: | 1.Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy;2.Department of Anatomy, Histology and Forensic Medicine, Section of Histology, University of Florence, Florence, Italy;3.Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, CA, USA;4.Respiratory Medicine Research Group, The Queen''s University of Belfast, Belfast, UK |
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| Abstract: | Background and PurposeAmong 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.Experimental ApproachOvalbumin (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.Key ResultsOA 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 and ImplicationsAntigen-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.Linked ArticlesThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 |
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| Keywords: | histamine H4 receptors JNJ 7777120 asthma-like reaction airway inflammation lipocortin-1 cytokines prostaglandins oxidative stress apoptosis |
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