Il-1β and Il-6 act synergistically with TNF-α to alter cardiac contractile function after burn trauma
Il-1β and Il-6 act synergistically with TNF-α to alter cardiac contractile function after burn trauma
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DOI：
10.1097/00024382-200210000-00012
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发表时间：
2002-10-01
期刊：
影响因子：
3.1
通讯作者：
Horton, JW
中科院分区：
文献类型：
--
作者：
Maass, DL;White, J;Horton, JW
尽管大量研究已经提供证据表明炎性细胞因子TNF-α和IL-1 β具有显著的负性肌力作用，但白细胞介素在烧伤介导的心功能障碍中的作用尚未确定。此外，大多数检查炎性细胞因子的心脏毒性作用的研究都忽略了在患有创伤、败血症或缺血性心脏病的完整受试者中发生的复杂的炎性环境。因此，本研究检测了烧伤创伤后心肌细胞分泌IL-1 β和IL-6的时间进程，另外的研究检测了这些细胞因子单独或与TNF-α联合对心脏收缩性能的影响（Langendorff）。Sprague-Dawley大鼠给予超过全身表面积40%的全层烧伤;液体复苏为乳酸林格氏液，每烧伤面积百分比4 mL/kg。假烧伤动物接受相同的麻醉和处理，但没有烧伤。在烧伤后的几个不同时间处死大鼠，用含胶原酶的缓冲液灌注离体心脏（n = 4-5只大鼠/组/时间段）以制备心肌细胞或体外灌注以检查心脏收缩功能（n = 5-6只大鼠/组/时间段）。包括额外的幼稚对照大鼠（n = 10）以制备心肌细胞，依次用不同浓度的IL-1 β、IL-6或TNF-α单独或组合攻击几个时间段（37 ℃ CO2培养箱1-3 h）。最后，将单独或组合的炎性细胞因子加入到从另外的对照大鼠（n = 6-7只/组）分离的心脏的灌注液中，以评估细胞因子激发的心脏收缩和舒张作用。尽管进行了积极的液体复苏，但烧伤创伤导致心肌细胞分泌IL-1 β、IL-6和TNF-α的时间相关性增加。暴露的幼稚心肌细胞制备的对照大鼠每种细胞因子单独或组合的细胞因子的挑战产生了时间依赖性和浓度依赖性的细胞活力下降和上清液肌酸激酶水平的增加。当单独加入Langendorff灌注心脏时，IL-1 β或TNF-α产生的心脏缺陷比IL-6更大;联合细胞因子激发（IL-1 β + TNF-α + IL-6）时功能障碍最大。这些数据证实，烧伤创伤上调心肌细胞的炎性细胞因子分泌，并表明这些炎性细胞因子协同作用，产生烧伤介导的心脏收缩功能障碍。
Although numerous studies have provided evidence that the inflammatory cytokines TNF-alpha and IL-1beta have significant negative inotropic effects, the role of the interleukins in burn-mediated cardiac dysfunction has not been defined. Furthermore, most studies examining the cardiotoxic effects of inflammatory cytokines have ignored the complex inflammatory milieu that occurs in the intact subject with trauma, sepsis, or ischemic heart disease. Therefore, this study examined the time course of IL-1beta and IL-6 secretion by cardiomyocytes after burn trauma, and additional studies examined the effects of these cytokines alone or in combination with TNF-alpha on cardiac contractile performance (Langendorff). Sprague-Dawley rats were given a full thickness burn injury over 40% of the total body surface area; fluid resuscitation was lactated Ringer's solution, 4 mL/kg per burn percentage of burn area. Sham burn animals received identical anesthesia and handling, but no burn injury. Rats were sacrificed at several different times postburn, and isolated hearts (n = 4-5 rats/group/time period) were perfused with collagenase-containing buffer to prepare cardiomyocytes or were perfused in vitro to examine cardiac contractile function (n = 5-6 rats/group/time period). Additional naive control rats (n = 10) were included to prepare cardiomyocytes that, in turn, were challenged with different concentrations of either IL-1beta, IL-6, or TNF-alpha alone or in combination for several time periods (CO2 incubator at 37degreesC for 1-3 h). Finally, inflammatory cytokines alone or in combination were added to the perfusate of hearts isolated from additional control rats (n = 6-7/group) to assess the cardiac contraction and relaxation effects of cytokine challenge. Despite aggressive fluid resuscitation, burn trauma produced a time-related increase in cardiomyocyte secretion of IL-1beta, IL-6, and TNF-alpha. Exposure of naive cardiomyocytes prepared from control rats to each cytokine alone or combined cytokine challenge produced a time-dependent and concentration-dependent decrease in cell viability and an increase in supernatant creatine kinase levels. Either IL-1beta or TNF-alpha produced greater cardiac defects than IL-6 when added separately to Langendorff-perfused hearts; dysfunction was maximal with combined cytokine challenge (IL-1beta plus TNF-alpha plus IL-6). The data confirm that burn trauma upregulates inflammatory cytokine secretion by cardiomyocytes and suggest that these inflammatory cytokines act in concert to produce burn-mediated cardiac contractile dysfunction.