Tumor necrosis factor-α and interleukin-1β synergistically depress human myocardial function
Tumor necrosis factor-α and interleukin-1β synergistically depress human myocardial function
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DOI：
10.1097/00003246-199907000-00018
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发表时间：
1999-07-01
影响因子：
8.8
通讯作者：
Harken, AH
中科院分区：
文献类型：
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作者：
Cain, BS;Meldrum, DR;Harken, AH
目的：肿瘤坏死因子α和白介素1β等促炎细胞因子参与了心肌缺血再灌注损伤、脓毒症、慢性心力衰竭、病毒性心肌炎和心脏移植排斥反应的发病机制。尽管脓毒症休克时循环中的肿瘤坏死因子-α和白介素1-β经常升高，但目前尚不清楚脓毒症时是否诱导了肿瘤坏死因子-α或白介素1-β直接抑制人类的心肌功能，如果是的话，两者是否协同抑制了心肌功能。此外，这些细胞因子导致人类心肌抑制的机制(S)仍不清楚。我们假设：a)TNF-α和IL-1β直接抑制人体心肌功能，b)两者协同作用抑制人体心肌功能；C)抑制神经酰胺酶或一氧化氮合酶，通过限制近端细胞因子信号或心肌一氧化氮(NO)的产生，减轻由TNF-α或IL-1β引起的心肌抑制。设计：前瞻性、随机、对照研究。地点：一所大学医院的实验实验室。对象：新鲜获得的人心肌小梁。干预：心脏手术时获取人心房小梁，悬浮在器官浴中，并以1 Hz的频率模拟电场，记录形成的力。平衡90min后，加入肿瘤坏死因子-α(1.25、12.5、125、250pg/mL20min)、白介素1-β(6.25、12.5、50、200pg/mL20min)、或肿瘤坏死因子-α(1.25pg/mL6.25pg/mL)+白介素1-β(6.25pg/mL)，在20min后的100min内进行功能测定。为了评估鞘磷脂和NO通路在肿瘤坏死因子-α和白介素1-β交叉信号中的作用，神经酰胺酶抑制剂N-油酰乙醇胺(1MU)或一氧化氮合酶抑制剂NG-单甲基-L-精氨酸(10MU)在肿瘤坏死因子-α(125pg/mL)或白介素β(50pg/mL)之前加入。测量和主要结果：肿瘤坏死因子-α和白介素1-β均以剂量依赖的方式抑制人体心肌功能(最大降幅分别为16.2±1.9%和25.7±6.3%)，对收缩功能的影响大于对舒张期的影响。.05)。然而，当肿瘤坏死因子-α和白介素1-β结合在一起时，没有单独导致抑郁的浓度(p>；0.05 vs对照)会导致收缩抑制(p<；0.05 vs对照)。抑制心肌鞘氨醇释放或NO释放可阻断肿瘤坏死因子-α或白介素1-β的心肌抑制作用。结论：肿瘤坏死因子-α和白介素1-β分别对人体心肌功能有协同抑制作用。鞘氨醇可能参与了导致人类心肌功能抑制的肿瘤坏死因子-α和白介素1-β信号。减少TNF-α或IL-1β的产生或信号的治疗策略可能会限制脓毒症患者的心肌功能障碍。
Objective: Proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (II)-1 beta have been implicated in the pathogenesis of myocardial dysfunction in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Although circulating TNF-alpha and IL-1 beta are both often elevated in septic shock, it remains unknown whether TNF-alpha or IL-1 beta are the factors induced during sepsis that directly depress human myocardial function, and if so, whether the combination synergistically depresses myocardial function. Furthermore, the mechanism(s) by which these cytokines induce human myocardial depression remain unknown. We hypothesized the following: a) TNF-alpha and IL-1 beta directly depress human myocardial function; b) together, TNF-alpha and IL-1 beta act synergistically to depress human myocardial function; and c) inhibition of ceramidase or nitric oxide synthase attenuates myocardial depression induced by TNF-alpha or IL-1 beta by limiting proximal cytokine signaling or production of myocardial nitric oxide (NO).Design:Prospective, randomized, controlled study.Setting: Experimental laboratory in a university hospital.Subjects: Freshly obtained human myocardial trabeculae.Interventions: Human atrial trabeculae were obtained at the time of cardiac surgery, suspended in organ baths, and field simulated at 1 Hz, and the developed force was recorded. After a 90-min equilibration, TNF-alpha (1.25, 12.5, 125, or 250 pg/mL for 20 mins), IL-1 beta (6.25, 12.5, 50, or 200 pg/mL for 20 mins), or TNF-alpha (1.25 pg/mL) plus IL-1 beta (6.25 pg/mL) were added to the bath, and function was measured for the subsequent 100 mins after the 20-min exposure. To assess the roles of the sphingomyelin and NO pathways in TNF-alpha and IL-1 beta cross-signaling, the ceramidase inhibitor N-oleoyl ethanolamine (1 mu M) or the NO synthase inhibitor NG-monomethyl-L-arginine (10 mu M) was added before TNF-alpha (125 pg/mL) or IL-beta (50 pg/mL).Measurements and Main Results:TNF-alpha and IL-1 beta each depressed human myocardial function in a dose-dependent fashion (maximally depressing to 16.2 + 1.9% baseline developed force for TNF-alpha and 25.7 + 6.3% baseline developed force for IL-1 beta), affecting systolic relatively more than diastolic performance teach p < .05). However, when combined, TNF-alpha and IL-1 beta at concentrations that did not individually result in depression (p >.05 vs, control) resulted in contractile depression (p < .05 vs. control). Inhibition of myocardial sphingosine or NO release abolished the myocardial depressive effects of either TNF-alpha or IL-1 beta.Conclusions:TNF-alpha and IL-1 beta separately and synergistically depress human myocardial function. Sphingosine likely participates in the TNF-alpha and IL-1 beta signal leading to human myocardial functional depression. Therapeutic strategies to reduce production or signaling of either TNF-alpha or IL-1 beta may limit myocardial dysfunction in sepsis.