A selective antagonist of histamine H4 receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1
Version of Record online: 15 AUG 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Issue: Histamine Pharmacology Update. Guest Editor: Paul L Chazot
Volume 170, Issue 1, pages 200–213, September 2013
How to Cite
Somma, T., Cinci, L., Formicola, G., Pini, A., Thurmond, R., Ennis, M., Bani, D. and Masini, E. (2013), A selective antagonist of histamine H4 receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1. British Journal of Pharmacology, 170: 200–213. doi: 10.1111/bph.12264
- Issue online: 15 AUG 2013
- Version of Record online: 15 AUG 2013
- Accepted manuscript online: 4 JUN 2013 07:37AM EST
- Manuscript Accepted: 24 MAY 2013
- Manuscript Revised: 20 MAY 2013
- Manuscript Received: 29 OCT 2012
- Ente Cassa di Risparmio di Firenze
- histamine H4 receptors;
- JNJ 7777120;
- asthma-like reaction;
- airway inflammation;
- oxidative stress;
Background and Purpose
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.
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.
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 and Implications
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.
This 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