Adrenomedullin reduces Staphylococcus aureus α-toxin-induced rat ileum microcirculatory damage
Adrenomedullin reduces Staphylococcus aureus α-toxin-induced rat ileum microcirculatory damage
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DOI：
10.1097/01.ccm.0000159194.53695.7a
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发表时间：
2005-04-01
影响因子：
8.8
通讯作者：
Hippenstiel, S
中科院分区：
文献类型：
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作者：
Brell, B;Temmesfeld-Wollbrück, B;Hippenstiel, S
Objective.微血管通透性增加和灌注不匹配是脓毒症或脓毒性休克的标志。肠粘膜对组织缺氧非常敏感。肠粘膜功能障碍可使细菌及其产物移位，从而使脓毒症和炎症持续存在。金黄色葡萄球菌α-毒素是该细菌的主要致病性决定因素，引起心血管衰竭。目前的证据表明，内源性肽肾上腺髓质素在全身炎症反应中稳定循环稳态。使用a-毒素作为一个定义明确的炎症反应的强启动剂，我们测试的假设，外源性应用肾上腺髓质素稳定肠道microcirculation.Design：前瞻性，实验study.Setting：研究实验室在一所大学hospital.Subjects：分离，灌注回肠从雄性Sprague-Dawley大鼠和人脐静脉内皮细胞。干预。S.肾上腺髓质素输注前后的金黄色葡萄球菌a毒素。测量和主要结果。在大鼠回肠的恒定流血液灌注制备物中，在上级肠系膜动脉中注射1 μ g α-毒素，可增加灌注压和相对血红蛋白浓度，并降低粘膜血红蛋白氧饱和度。连续输注肾上腺髓质素（0.1 μ mol/L）显着降低这些α-毒素相关的影响。肾上腺髓质素预处理可消除α毒素暴露回肠中观察到的严重微血管通透性过高。此外，肾上腺髓质素在体外阻断α-毒素诱导的内皮肌球蛋白轻链磷酸化、内皮细胞收缩和随后的内皮屏障功能丧失。在开始应用毒素后10分钟开始用肾上腺髓质素（0.1 μ mol/L）处理α毒素（输注0.05 μ g/mL）暴露的回肠，也显著降低了上级肠系膜动脉压和通透性增加。总之，这些数据表明，外源性肾上腺髓质素通过减少α毒素诱导的微循环障碍和稳定内皮屏障功能来保护回肠。
Objective. Increased microvascular permeability and perfusion mismatch are hallmarks of sepsis or septic shock. The intestinal mucosa is very sensitive to tissue hypoxia. Intestinal mucosa dysfunction may allow translocation of bacteria and their products, thereby perpetuating sepsis and inflammation. Staphylococcus aureus alpha-toxin is a major pathogenicity determinant of this bacterium, provoking cardiovascular collapse. Current evidence suggests that the endogenous peptide adrenomedullin stabilizes circulatory homeostasis in systemic inflammatory response. Using a-toxin as a well-defined strong initiator of an inflammatory reaction, we tested the hypothesis that exogenously applied adrenomedullin stabilizes gut microcirculation.Design: Prospective, experimental study.Setting: Research laboratory at a university hospital.Subjects: Isolated, perfused ileum from male Sprague-Dawley rats and human umbilical vein endothelial cells. Interventions. Administration of S. aureus a-toxin before or after infusion of adrenomedullin.Measurements and Main Results. Injection of a bolus of 1 mu g of alpha-toxin in the superior mesenteric artery in a constant-flow, blood-perfused preparation of rat ileum increased perfusion pressure and relative hemoglobin concentration and decreased mucosal hemoglobin oxygen saturation. Continuous infusion of adrenomedullin (0.1 mu mol/L) significantly reduced these alpha-toxin-related effects. Severe microvascular hyperpermeability observed in alpha-toxin-exposed ileum was abolished by adrenomedullin pretreatment. In addition, adrenomedullin blocked alpha-toxin-induced endothelial myosin light chain phosphorylation, endothelial cell contraction, and subsequent loss of endothelial barrier function in vitro. Treatment of alpha-toxin (infusion of 0.05 mu g/mL)-exposed ileum with adrenomedullin (0.1 mu mol/L) started 10 mins after onset of toxin application also significantly reduced superior mesenteric artery pressure and permeability increase.Conclusions. In summary, these data suggest that exogenous adrenomedullin protects ileum by reducing alpha-toxin-induced microcirculatory disturbances and by stabilizing endothelial barrier function.