PHOSPHODIESTERASE 4 INHIBITION DOSE DEPENDENTLY STABILIZES MICROVASCULAR BARRIER FUNCTIONS AND MICROCIRCULATION IN A RODENT MODEL OF POLYMICROBIAL SEPSIS
PHOSPHODIESTERASE 4 INHIBITION DOSE DEPENDENTLY STABILIZES MICROVASCULAR BARRIER FUNCTIONS AND MICROCIRCULATION IN A RODENT MODEL OF POLYMICROBIAL SEPSIS
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DOI：
10.1097/shk.0000000000000152
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发表时间：
2014-06-01
期刊：
影响因子：
3.1
通讯作者：
Schick, Martin Alexander
中科院分区：
文献类型：
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作者：
Flemming, Sven;Schlegel, Nicolas;Schick, Martin Alexander
背景：微血管内皮屏障功能的破坏可导致败血症患者微循环紊乱、器官衰竭和死亡。通过全身应用磷酸二酯酶4抑制剂（PD-4-I）增加内皮细胞cAMP水平，先前已被证明在全身性炎症模型（全身性炎症反应综合征）中保护微血管屏障特性，这表明一种新的治疗选择可以克服这一问题。然而，在临床相关的多微生物脓毒症长期影响模型中，PD-4-I的免疫调节作用和稳定微血管屏障功能和微循环的有效性尚未得到探索。方法：采用结肠上升支架腹膜炎（CASP）模型诱导多微生物脓毒症，在系统静脉注射不同剂量PD-4-I罗利普兰和不全身静脉注射不同剂量PD-4-I罗利普兰的情况下，对Sprague-Dawley大鼠进行大血流动力学和微血流动力学监测26 h。结果：所有CASP动物均出现脓毒症和腹膜炎的临床和实验室症状。虽然大血流动力学不良反应不明显，但PD-4-I的应用导致内皮屏障特性的稳定，正如异硫氰酸荧光素白蛋白外渗减少所显示的那样。然而，只有每小时1 mg/kg体重的低剂量PD-4-I改善了CASP模型的微循环流量，而每小时3 mg/kg体重的高剂量PDI-4-I有不良反应。因此，PD-4-I治疗可预防脓毒症引起的急性肾损伤和肺水肿。此外，PD-4-I治疗后，白细胞介素1 （IL-1）、IL-1、IL-12和肿瘤坏死因子水平降低，显示出PD-4-I的免疫调节作用，这似乎与罗利普兰的屏障稳定作用无关。结论：这些数据进一步证明，全身应用PD-4-I可适用于脓毒症的微血管屏障稳定治疗和微循环血流改善。
Background: Breakdown of microvascular endothelial barrier functions contributes to disturbed microcirculation, organ failure, and death in sepsis. Increased endothelial cAMP levels by systemic application of phosphodiesterase 4 inhibitors (PD-4-I) have previously been demonstrated to protect microvascular barrier properties in a model of systemic inflammation (systemic inflammatory response syndrome) suggesting a novel therapeutic option to overcome this problem. However, in a clinically relevant model of polymicrobial sepsis long-term effects, immunomodulatory effects and effectivity of PD-4-I to stabilize microvascular barrier functions and microcirculation remained unexplored. Methods: We induced polymicrobial sepsis using the colon ascendens stent peritonitis (CASP) model in which we performed macrohemodynamic and microhemodynamic monitoring with and without systemic intravenous application of different doses of PD-4-I rolipram in Sprague-Dawley rats over 26 h. Results: All animals with CASP showed clinical and laboratory signs of sepsis and peritonitis. Whereas macrohemodynamic adverse effects were not evident, application of PD-4-I led to stabilization of endothelial barrier properties as revealed by reduced extravasation of fluorescein isothiocyanate-albumin. However, only low-dose application of 1 mg/kg body weight per hour of PD-4-I improved microcirculatory flow in the CASP model, whereas high-dose therapy of 3 mg/kg BW per hour PDI-4-I had adverse effects. Accordingly, sepsis-induced acute kidney injury and lung edema were prevented by PD-4-I treatment. Furthermore, PD-4-I showed immunomodulatory effects as revealed by decreased interleukin 1 (IL-1), IL-1, IL-12, and tumor necrosis factor levels following PD-4-I treatment, which appeared not to correlate with barrier-stabilizing effects of rolipram. Conclusions: These data provide further evidence that systemic application of PD-4-I could be suitable for therapeutic microvascular barrier stabilization and improvement of microcirculatory flow in sepsis.