Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
J Inflamm (Lond). 2009 Dec 10;6:34. doi: 10.1186/1476-9255-6-34.
The lanthanide cation, gadolinium (GdCl3) protects the myocardium against infarction following ischemia and reperfusion. Neutrophils and macrophages are the main leukocytes responsible for infarct expansion after reperfusion. GdCl3 interferes with macrophage and neutrophil function in the liver by decreasing macrophage secretion of inflammatory cytokines and neutrophil infiltration. We hypothesized that GdCl3 protects against ischemia and reperfusion injury by decreasing inflammation. We determined the impact of GdCl3 treatment for reperfusion injury on 1) circulating monoctye and neutrophil counts, 2) secretion of inflammatory cytokines, and 3) influx of monocytes and neutrophils into the myocardium.
Rats (n = 3-6/gp) were treated with saline or GdCl3 (20 mumol/kg) 15 min prior to a 30 min period of regional ischemia and 120 min reperfusion. Sham rats were not subject to ischemia. Blood was collected either after 30 min ischemia or 120 min reperfusion and hearts were harvested at 120 min reperfusion for tissue analysis. Blood was analyzed for leukocytes counts and cytokines. Tissue was analyzed for cytokines and markers of neutrophil and monocyte infiltration by measuring myeloperoxidase (MPO) and alpha-naphthyl acetate esterase (ANAE).
GdCl3 did not affect the number of circulating neutrophils prior to ischemia. Two hours reperfusion resulted in a 2- and 3- fold increase in circulating monocytes and neutrophils, respectively. GdCl3 decreased the number of circulating monocytes and neutrophils during reperfusion to levels below those present prior to ischemia. Furthermore, after 120 min of reperfusion, GdCl3 decreased ANAE and MPO activity in the myocardium by 1.9-fold and 6.5-fold respectively. GdCl3 decreased MPO activity to levels below those measured in the Sham group. Serum levels of the major neutrophil chemoattractant cytokine, IL-8 were increased from pre-ischemic levels during ischemia and reperfusion in both control and GdCl3 treated rats. Likewise, IL-8 levels increased throughout the 3 hour time period in the Sham group. There was no difference in IL-8 detected in the myocardium after 120 min reperfusion between groups. In contrast, after 120 min reperfusion GdCl3 decreased the myocardial tissue levels of macrophage secreted cytokines, GM-CSF and IL-1.
GdCl3 treatment prior to ischemia and reperfusion injury decreased circulating monocytes and neutrophils, macrophage secreted cytokines, and leukocyte infiltration into injured myocardium. These results suggest GdCl3 decreased monoctye and neutrophil migration and activation and may be a novel treatment for inflammation during ischemia and reperfusion.
镧系阳离子钆（GdCl3）可保护心肌免受缺血再灌注引起的梗塞。中性粒细胞和巨噬细胞是再灌注后梗死扩大的主要白细胞。GdCl3 通过减少巨噬细胞分泌的炎症细胞因子和中性粒细胞浸润来干扰肝内巨噬细胞和中性粒细胞的功能。我们假设 GdCl3 通过减少炎症来保护免受缺血再灌注损伤。我们确定了 GdCl3 治疗再灌注损伤对 1）循环单核细胞和中性粒细胞计数，2）炎症细胞因子的分泌以及 3）单核细胞和中性粒细胞流入心肌的影响。
在 30 分钟的局部缺血和 120 分钟的再灌注之前，将大鼠（n = 3-6/gp）用盐水或 GdCl3（20 mumol/kg）处理。假手术大鼠未进行缺血。在 30 分钟缺血后或 120 分钟再灌注后采集血液，并在再灌注 120 分钟时采集心脏以进行组织分析。血液分析白细胞计数和细胞因子。通过测量髓过氧化物酶（MPO）和α-萘乙酸酯酶（ANAE）来分析组织中中性粒细胞和单核细胞浸润的细胞因子和标志物。
GdCl3 对缺血前循环中的中性粒细胞数量没有影响。再灌注 2 小时导致循环中的单核细胞和中性粒细胞分别增加了 2 倍和 3 倍。GdCl3 使再灌注过程中的循环单核细胞和中性粒细胞数量减少至低于缺血前的水平。此外，再灌注 120 分钟后，GdCl3 将心肌中的 ANAE 和 MPO 活性分别降低了 1.9 倍和 6.5 倍。GdCl3 将 MPO 活性降低至低于 Sham 组测量的水平。在对照组和 GdCl3 处理组中，在缺血和再灌注过程中，主要中性粒细胞趋化因子细胞因子 IL-8 的血清水平从缺血前水平升高。同样，在 Sham 组中，IL-8 水平在整个 3 小时时间段内均升高。在再灌注 120 分钟后，两组之间在心肌中检测到的 IL-8 没有差异。相比之下，再灌注 120 分钟后，GdCl3 降低了巨噬细胞分泌的细胞因子 GM-CSF 和 IL-1 的心肌组织水平。
在缺血和再灌注损伤之前用 GdCl3 治疗可减少循环中的单核细胞和中性粒细胞，巨噬细胞分泌的细胞因子以及白细胞浸润到受损的心肌中。这些结果表明，GdCl3 减少了单核细胞和中性粒细胞的迁移和激活，可能是缺血再灌注期间炎症的一种新治疗方法。
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