Tumor necrosis factor-alpha and interleukin-1 beta synergistically depress human myocardial function

作者：Brian S. Cain, Daniel R. Meldrum, Charles Anthony Dinarello, Xianzhong Meng, Kyung Sub Joo, Anirban M. Banerjee, Alden H. Harken · 发表于：Critical Care Medicine · 年份：1999 · DOI：10.1097/00003246-199907000-00018 · 被引用次数：425 · 研究领域：Cardiac Fibrosis and Remodeling、Cardiac Ischemia and Reperfusion、Atherosclerosis and Cardiovascular Diseases

OBJECTIVE: Proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta 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-1beta are both often elevated in septic shock, it remains unknown whether TNF-alpha or IL-1beta 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-1beta directly depress human myocardial function; b) together, TNF-alpha and IL-1beta 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-1beta 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, 1...