El-Hashim Ahmed Z, Abduo Heba T, Rachid Ousama M, Luqmani Yunus A, Al Ayadhy Bushra Y, Alkhaledi Ghanim M
Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
Pulm Pharmacol Ther. 2009 Jun;22(3):243-52. doi: 10.1016/j.pupt.2008.12.012. Epub 2008 Dec 27.
The role of adenosine in allergic inflammation is unclear. This study investigated the effects of the non-selective adenosine receptor agonist, 5-N-ethylcarboxamidoadenosine (NECA), on immunized only and immunized and airway challenged mice. The adenosine receptor sub-type(s) mediating the NECA effects and the A(2A) receptor mRNA expression were also investigated. In mice that were only immunized, intranasal NECA (1 mM) administration caused a significant increase in bronchoalveolar lavage total cell count (TCC), neutrophils and eosinophils (>1.5-, >6 and >60-fold, respectively). Two and four intranasal ovalbumin (OVA) challenges induced a significant (P < 0.05) increase in TCC (>2.1- and >4-fold, respectively) and eosinophils (>350- and >1700-fold, respectively). Real-time PCR analysis showed that the A(2A) receptor sub-type mRNA was significantly increased (P < 0.05) in the lung tissue of immunized mice following both two and four OVA challenges. NECA (0.3 mM) treatment caused a significant reduction in the increase induced by the two and four OVA challenges in the TCC by 46.1% and 56.6%, respectively, eosinophils by 70.1% and 75.6%, respectively, and in the A(2A) receptor sub-type mRNA by 43.2% and 41.0%, respectively. Treatment with the A(2A) receptor antagonist, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine), SCH-58261, completely reversed both the NECA-mediated reduction in TCC and eosinophilia. Moreover, OVA challenge of immunized mice, over 2 consecutive days, resulted in a significant (P < 0.05) increase in TCC (4.5-fold) and eosinophils (>2000-fold) that was detected 72 h later. NECA (0.3 mM) treatment, at 24 and 48 h post OVA challenge, significantly reduced the increase in both TCC and eosinophils by 45.0% and 74.8%, respectively. Our data show that in immunized, but not OVA-challenged mice, high dose of NECA (1 mM) induces an inflammatory airway response. In contrast, in models of inflammation, NECA, at mainly 0.3 mM, induces a significant anti-inflammatory effect when administered prior to the induction of airway inflammation or therapeutically following its establishment. The data also indicate that the anti-inflammatory action of NECA seems to be mediated via the A(2A) receptor sub-type and hence the use of selective A(2A) receptor agonists as potential therapeutic agents in the treatment of inflammatory diseases such as asthma should be investigated further.
腺苷在过敏性炎症中的作用尚不清楚。本研究调查了非选择性腺苷受体激动剂5-N-乙基甲酰胺基腺苷（NECA）对仅免疫以及免疫并气道激发的小鼠的影响。还研究了介导NECA效应的腺苷受体亚型以及A(2A)受体mRNA表达。在仅免疫的小鼠中，鼻内给予NECA（1 mM）导致支气管肺泡灌洗总细胞数（TCC）、中性粒细胞和嗜酸性粒细胞显著增加（分别增加>1.5倍、>6倍和>60倍）。两次和四次鼻内给予卵清蛋白（OVA）激发导致TCC（分别增加>2.1倍和>4倍）和嗜酸性粒细胞（分别增加>350倍和>1700倍）显著（P < 0.05）增加。实时PCR分析表明，两次和四次OVA激发后，免疫小鼠肺组织中A(2A)受体亚型mRNA显著增加（P < 0.05）。NECA（0.3 mM）处理分别使两次和四次OVA激发诱导的TCC增加显著降低46.1%和56.6%，嗜酸性粒细胞增加分别降低70.1%和75.6%，A(2A)受体亚型mRNA增加分别降低43.2%和41.0%。用A(2A)受体拮抗剂7-(2-苯乙基)-5-氨基-2-(2-呋喃基)-吡唑并-[4,3-e]-1,2,4-三唑并[1,5-c]嘧啶（SCH-58261）处理完全逆转了NECA介导的TCC和嗜酸性粒细胞增多的减少。此外，连续2天对免疫小鼠进行OVA激发，导致72小时后检测到TCC显著（P < 0.05）增加（4.5倍）和嗜酸性粒细胞增加（>2000倍）。在OVA激发后24小时和48小时给予NECA（0.3 mM）处理，分别使TCC和嗜酸性粒细胞增加显著降低45.0%和74.8%。我们的数据表明，在免疫但未OVA激发的小鼠中，高剂量的NECA（1 mM）诱导气道炎症反应。相反，在炎症模型中，主要为0.3 mM的NECA在气道炎症诱导前给药或在其形成后进行治疗性给药时，诱导显著的抗炎作用。数据还表明，NECA的抗炎作用似乎是通过A(2A)受体亚型介导 的，因此应进一步研究使用选择性A(2A)受体激动剂作为治疗哮喘等炎症性疾病的潜在治疗药物。
