A selective antagonist of histamine H-4 receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1

作者：Somma T; Cinci L; Formicola G; Pini A; Thurmond R; Ennis M; Bani D; Masini E^*

来源：British Journal of Pharmacology, 2013, 170(1): 200-213.

DOI：10.1111/bph.12264

• histamine H-4 receptors
• JNJ 7777120
• asthma-like reaction
• airway inflammation
• lipocortin-1
• cytokines
• prostaglandins
• oxidative stress
• apoptosis

Background and Purpose Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H-4 receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H-4 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. %26lt;br%26gt;Experimental Approach Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10mgkg(-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 1h after antigen challenge. In BAL fluid, levels of LC-1, PGD(2), LTB4 and TNF- were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured. %26lt;br%26gt;Key Results OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD(2), LTB4 and TNF- levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD(2), LTB4 and TNF- in BAL fluid. %26lt;br%26gt;Conclusions and Implications Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF- and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation.

• 出版日期2013-9