Pini A, Somma T, Formicola G, Lucarini L, Bani D, Thurmond R, Masini E
Department of NEUROFARBA, Sect. of Pharmacology, University of Florence, Viale G. Pieraccini n.6, 50139 Florence (Italy).
Curr Pharm Des. 2014;20(9):1338-44. doi: 10.2174/13816128113199990553.
The histamine H₄ receptor (H₄R), recently cloned and identified, is a G-protein coupled histamine receptor family expressed in immune cells which plays an important role in inflammation. Recent data evidentiated that H₄R antagonists can decrease airway inflammation and hyperreactivity in animal models of asthma. In the present study we evaluated the effect of the selective H₄R antagonist JNJ7777120 (JNJ) in carrageenan-induced pleurisy, an in vivo model of inflammation, well characterized for cellular and molecular mechanisms. Intra-pleural administration of λ-carrageenan (1% w/v in 0.2 ml sterile saline) determined an intense recruitment of leucocytes in pleural exudates and in lung tissues, activated inducible nitric oxide (NO) synthase and cyclooxygenase-2, thus increasing the generation of harmful autacoids such as NO and pro-inflammatory prostaglandins, PgE₂ and 6-ketoPgF(1α), increased cellular and DNA oxidative stress, measured as malondialdehyde and 8-OH-deoxyguanosine and the local generation of IL-1β and TNF-α. Moreover, the activity of caspase-3, an early marker of apoptosis was also activated by λ-carrageenan injection. The pre-treatment with JNJ (5-10 mg Kg⁻¹ b.wt., given intrapleurally), 60 min before carrageenan markedly reduced all the studied parameters. This study clearly demonstrated that histamine H₄R antagonists have anti-inflammatory effects and could have potential therapeutic application for the treatment of inflammatory diseases.
组胺H₄受体（H₄R）是最近克隆和鉴定出的一种G蛋白偶联组胺受体家族，表达于免疫细胞中，在炎症过程中发挥重要作用。最近的数据表明，H₄R拮抗剂可减轻哮喘动物模型中的气道炎症和高反应性。在本研究中，我们评估了选择性H₄R拮抗剂JNJ7777120（JNJ）在角叉菜胶诱导的胸膜炎中的作用，角叉菜胶诱导的胸膜炎是一种体内炎症模型，其细胞和分子机制已得到充分表征。胸膜内注射λ-角叉菜胶（0.2 ml无菌盐水中1% w/v）可导致胸膜渗出液和肺组织中白细胞大量募集，激活诱导型一氧化氮（NO）合酶和环氧化酶-2，从而增加有害自分泌物质如NO和促炎前列腺素PgE₂和6-酮-PgF(1α)的生成，增加细胞和DNA氧化应激（以丙二醛和8-羟基脱氧鸟苷衡量）以及IL-1β和TNF-α的局部生成。此外，caspase-3（细胞凋亡的早期标志物）的活性也因注射λ-角叉菜胶而被激活。在注射角叉菜胶前60分钟，胸膜内给予JNJ（5 - 10 mg Kg⁻¹体重）预处理可显著降低所有研究参数。本研究清楚地表明，组胺H₄R拮抗剂具有抗炎作用，可能对炎症性疾病的治疗具有潜在的治疗应用价值。
