Opposite Effects of Mepyramine on JNJ 7777120-Induced Amelioration of Experimentally Induced Asthma in Mice in Sensitization and Provocation

BACKGROUND: Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, JNJ 7777120, an antagonist at the histamine H(4) receptor, reduces asthmatic symptoms, while the histamine H(1) receptor-selective antagonist mepyramine is virtually without effect. In the present study, we analyzed the effect of combined antagonism at the histamine H(1) and H(4) receptors in a murine asthma model in relation to the timing of their application, i.e. sensitization or provocation. METHODOLOGY/PRINCIPAL FINDINGS: Asthma was induced in mice by sensitization and provocation with ovalbumin. JNJ 7777120 and/or mepyramine were injected subcutaneously either during sensitization or during provocation, and typical asthma parameters were analyzed. JNJ 7777120, but not mepyramine, reduced serum concentrations of anti-OVA IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar-lavage (BAL)-fluids independently of the timing of application. Upon application of JNJ 7777120 plus mepyramine in combination during provocation, mepyramine inhibited the effects of JNJ 7777120. In contrast, when applied during sensitization, mepyramine enhanced the disease-ameliorating effects of JNJ 7777120. CONCLUSIONS/SIGNIFICANCE: Our study indicates that both histamine H(1) and H(4) receptors play important roles in the course of murine experimental asthma. Unexpectedly, the contribution of these receptors to the pathogenesis differs between the two phases, sensitization or provocation. Since in human asthma, repeated contact to the allergen is not only provocation but also a boost of sensitization, a combined pharmacological targeting of histamine H(1) and H(4) receptors could be taken into consideration as an option for the prevention of asthma and maybe other allergic diseases.