Effects of a selective histamine H?R antagonist on inflammation in a model of carrageenan-induced pleurisy in the rat.

摘要

The histamine H? receptor (H?R), 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 H?R antagonists can decrease airway inflammation and hyperreactivity in animal models of asthma. In the present study we evaluated the effect of the selective H?R 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, PgE? 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 H?R antagonists have anti-inflammatory effects and could have potential therapeutic application for the treatment of inflammatory diseases.