Coletta Ciro, Módis Katalin, Oláh Gábor, Brunyánszki Attila, Herzig Daniela S, Sherwood Edward R, Ungvári Zoltán, Szabo Csaba
Crit Care. 2014 Sep 16;18(5):511. doi: 10.1186/s13054-014-0511-3.
The goal of the current study was to investigate the effect of aging on the development of endothelial dysfunction in a murine model of sepsis, and to compare it with the effect of genetic deficiency of the endothelial isoform of nitric oxide synthase (eNOS).
Cecal ligation and puncture (CLP) was used to induce sepsis in mice. Survival rates were monitored and plasma indices of organ function were measured. Ex vivo studies included the measurement of vascular function in thoracic aortic rings, assessment of oxidative stress/cellular injury in various organs and the measurement of mitochondrial function in isolated liver mitochondria.
eNOS deficiency and aging both exacerbated the mortality of sepsis. Both eNOS-deficient and aged mice exhibited a higher degree of sepsis-associated multiple organ dysfunction syndrome (MODS), infiltration of tissues with mononuclear cells and oxidative stress. A high degree of sepsis-induced vascular oxidative damage and endothelial dysfunction (evidenced by functional assays and multiple plasma markers of endothelial dysfunction) was detected in aortae isolated from both eNOS(-/-) and aged mice. There was a significant worsening of sepsis-induced mitochondrial dysfunction, both in eNOS-deficient mice and in aged mice. Comparison of the surviving and non-surviving groups of animals indicated that the severity of endothelial dysfunction may be a predictor of mortality of mice subjected to CLP-induced sepsis.
Based on the studies in eNOS mice, we conclude that the lack of endothelial nitric oxide production, on its own, may be sufficient to markedly exacerbate the severity of septic shock. Aging markedly worsens the degree of endothelial dysfunction in sepsis, yielding a significant worsening of the overall outcome. Thus, endothelial dysfunction may constitute an early predictor and independent contributor to sepsis-associated MODS and mortality in aged mice.
本研究的目的是在脓毒症小鼠模型中研究衰老对内皮功能障碍发展的影响，并将其与一氧化氮合酶内皮型（eNOS）基因缺陷的影响进行比较。
采用盲肠结扎穿孔术（CLP）诱导小鼠脓毒症。监测存活率并测量器官功能的血浆指标。体外研究包括测量胸主动脉环的血管功能、评估各器官的氧化应激/细胞损伤以及测量分离的肝线粒体的线粒体功能。
eNOS缺陷和衰老均加剧了脓毒症的死亡率。eNOS缺陷小鼠和老年小鼠均表现出更高程度的脓毒症相关多器官功能障碍综合征（MODS）、单核细胞浸润组织和氧化应激。在从eNOS（-/-）小鼠和老年小鼠分离的主动脉中检测到高度的脓毒症诱导的血管氧化损伤和内皮功能障碍（通过功能测定和多种内皮功能障碍血浆标志物证明）。在eNOS缺陷小鼠和老年小鼠中，脓毒症诱导的线粒体功能障碍均显著恶化。对存活和未存活动物组的比较表明，内皮功能障碍的严重程度可能是CLP诱导的脓毒症小鼠死亡率的预测指标。
基于对eNOS小鼠的研究，我们得出结论，内皮一氧化氮生成的缺乏本身可能足以显著加剧脓毒性休克的严重程度。衰老显著加重脓毒症中内皮功能障碍的程度，导致总体结局显著恶化。因此，内皮功能障碍可能是老年小鼠脓毒症相关MODS和死亡率的早期预测指标和独立因素。
