Protective effects of pentoxifylline in pulmonary inflammation are adenosine receptor A2A dependent
Protective effects of pentoxifylline in pulmonary inflammation are adenosine receptor A2A dependent
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DOI：
10.1096/fj.13-228122
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发表时间：
2013-09-01
期刊：
影响因子：
4.8
通讯作者：
Reutershan, Joerg
中科院分区：
文献类型：
--
作者：
Konrad, Franziska M.;Neudeck, Gianna;Reutershan, Joerg
己酮茶碱（PTX）在实验性急性肺损伤中具有抗炎作用。然而，对人类的研究结果存在争议。最近的体外研究表明，PTX可能需要腺苷受体A（2A）才能有效。因此，我们在lps诱导的小鼠肺部炎症模型中研究了A（2A）与PTX之间的关系。PTX治疗（10 mg/kg）降低了细胞内流（40%）、微血管通透性（30%）和趋化细胞因子向肺泡间隙的释放（TNF- 60%、IL-6 60%和CXCL2/3分别为53%）。这些保护作用在A(2A)（-/-）小鼠和使用选择性A（2A）拮抗剂（1mg /kg）治疗的野生型小鼠中完全消失，但在腺苷水平改变的小鼠中效果没有差异。体外迁移实验显示内皮在PTX介导的PMN迁移中起关键作用，减少了50% （2 mM PTX）。这种效应也依赖于A（2A）。此外，PTX治疗后，人PMNs的氧化爆发依赖于A(2A)，减少了53%。综上所述，PTX通过A（2A）依赖途径在lps诱导的肺损伤中表现出抗炎作用。这些结果将有助于更好地理解之前关于PTX在炎症中的相互矛盾的数据，并将指导进一步研究考虑A的主要作用（2A）。Konrad， F. M, Neudeck， G., Vollmer， I., Ngamsri， K. C., Thiel， M., Reutershan， J.戊氧基茶碱对肺部炎症的保护作用是腺苷受体A（2A）依赖的。
Pentoxifylline (PTX) has been shown to exert anti-inflammatory effects in experimental acute lung injury. However, results in humans were controversial. Recent in vitro studies suggested that the adenosine receptor A(2A) may be required for PTX to be effective. Therefore, we studied the association between A(2A) and PTX in a murine model of LPS-induced pulmonary inflammation. PTX treatment (10 mg/kg) reduced cellular influx (by 40%), microvascular permeability (30%), and the release of chemotactic cytokines into the alveolar space (TNF- 60%, IL-6 60%, and CXCL2/3 53%, respectively). These protective effects were abolished completely in A(2A)(-/-) mice and in wild-type mice that had been treated with the selective A(2A) antagonist (1 mg/kg), but effects were not different in mice with altered adenosine levels. In vitro transmigration assays revealed a pivotal role of the endothelium in PTX-mediated PMN migration, with a reduction of 50% (2 mM PTX). This effect was also A(2A) dependent. Further, oxidative burst of human PMNs was A(2A)-dependently reduced by 53% after PTX treatment. In summary, PTX exhibits its anti-inflammatory effects in LPS-induced lung injury through an A(2A)-dependent pathway. These results will help to better understand previous conflicting data on PTX in inflammation and will direct further studies to consider the predominant role of A(2A).Konrad, F. M., Neudeck, G., Vollmer, I., Ngamsri, K. C., Thiel, M., Reutershan, J. Protective effects of pentoxifylline in pulmonary inflammation are adenosine receptor A(2A) dependent.