Newman Walter H, Castresana Manuel R, Webb Jerry G, Detmer Kristina, Wang Zhongbiao
Department of Anesthesiology, Mercer University School of Medicine and Medical Center of Central Georgia, Macon, Georgia 31210, USA.
Anesthesiology. 2002 Apr;96(4):947-54. doi: 10.1097/00000542-200204000-00024.
Cytokines such as tumor necrosis factor alpha (TNF-alpha) are produced by the myocardium in heart disease and might be stimulated by reactive oxygen. In some cell types, cyclic adenosine monophosphate (AMP) inhibits TNF-alpha production. The authors tested the hypothesis that stimulation of cardiac beta-adrenergic receptors would inhibit cytokine gene transcription induced by reactive oxygen.
Rat hearts were perfused with buffer containing hypoxanthine. Reactive oxygen intermediates were generated by infusion of xanthine oxidase. Myocardial mRNA encoding 11 cytokines was determined. TNF-alpha, interleukin-6, and cyclic AMP were measured in the coronary effluent.
In control hearts, of the screened RNA, only mRNA encoding interleukin-1beta, -4, and -6 was detected. Stimulation with hypoxanthine-xanthine oxidase (HX-XO) induced detectable mRNA for TNF-alpha and interleukin-5 and increased mRNA band density for interleukin-1beta, -4, and -6. Simultaneous infusion of isoproterenol inhibited HX-XO-stimulated cytokine gene expression and caused release of cyclic AMP into the coronary effluent. In control hearts, TNF-alpha was not detected in the coronary effluent. After HX-XO administration, TNF-alpha was reliably detected at 60 min and interleukin-6 at 90 min. Simultaneous infusion of isoproterenol inhibited TNF-alpha and interleukin-6 release. Inclusion of propranolol in the perfusion buffer blocked the isoproterenol-induced inhibition of HX-XO-stimulated TNF-alpha release and release of cyclic AMP into the coronary effluent. In addition, elevating myocardial cyclic AMP with forskolin also blocked release of TNF-alpha stimulated by HX-XO. Finally, delaying infusion of isoproterenol until 30 min after HX-XO administration still suppressed release of TNF-alpha.
Reactive oxygen species activate cytokine gene transcription in the myocardium. The sympathetic nervous system, acting through beta-receptors to elevate myocardial cyclic AMP, regulates cardiac cytokine production by inhibition of transcription.
细胞因子如肿瘤坏死因子α（TNF-α）在心脏病时由心肌产生，可能受活性氧刺激。在某些细胞类型中，环磷酸腺苷（cAMP）可抑制TNF-α的产生。作者检验了如下假设：刺激心脏β-肾上腺素能受体会抑制活性氧诱导的细胞因子基因转录。
用含次黄嘌呤的缓冲液灌注大鼠心脏。通过注入黄嘌呤氧化酶产生活性氧中间体。测定编码11种细胞因子的心肌mRNA。检测冠状动脉流出液中的TNF-α、白细胞介素-6和环磷酸腺苷。
在对照心脏中，在所筛选的RNA中，仅检测到编码白细胞介素-1β、-4和-6的mRNA。用次黄嘌呤-黄嘌呤氧化酶（HX-XO）刺激可诱导出可检测到的TNF-α和白细胞介素-5的mRNA，并增加白细胞介素-1β、-4和-6的mRNA条带密度。同时注入异丙肾上腺素可抑制HX-XO刺激的细胞因子基因表达，并使环磷酸腺苷释放到冠状动脉流出液中。在对照心脏的冠状动脉流出液中未检测到TNF-α。给予HX-XO后，60分钟时可可靠检测到TNF-α，90分钟时可检测到白细胞介素-6。同时注入异丙肾上腺素可抑制TNF-α和白细胞介素-6的释放。在灌注缓冲液中加入普萘洛尔可阻断异丙肾上腺素诱导的对HX-XO刺激的TNF-α释放的抑制作用以及环磷酸腺苷释放到冠状动脉流出液中。此外，用福斯可林升高心肌环磷酸腺苷也可阻断HX-XO刺激的TNF-α释放。最后，将异丙肾上腺素的注入延迟至HX-XO给药后30分钟仍可抑制TNF-α的释放。
活性氧可激活心肌中的细胞因子基因转录。交感神经系统通过β受体作用升高心肌环磷酸腺苷，通过抑制转录来调节心脏细胞因子的产生。
