Section of Pulmonary and Critical Care, Lung Injury Center, Department of Medicine, University of Chicago, IL, USA.
Crit Care Med. 2011 Dec;39(12):2711-21. doi: 10.1097/CCM.0b013e3182284a5f.
To test the hypothesis that preconditioning animals with amifostine improves ventilator-induced lung injury via induction of antioxidant defense enzymes. Mechanical ventilation at high tidal volume induces reactive oxygen species production and oxidative stress in the lung, which plays a major role in the pathogenesis of ventilator-induced lung injury. Amifostine attenuates oxidative stress and improves lipopolysaccharide-induced lung injury by acting as a direct scavenger of reactive oxygen and nitrogen species. This study tested effects of chronic amifostine administration on parameters of oxidative stress, lung barrier function, and inflammation associated with ventilator-induced lung injury.
Randomized and controlled laboratory investigation in mice and cell culture.
University laboratory.
C57BL/6J mice.
Mice received once-daily dosing with amifostine (10-100 mg/kg, intraperitoneal injection) 3 days consecutively before high tidal volume ventilation (30 mL/kg, 4 hrs) at day 4. Pulmonary endothelial cell cultures were exposed to pathologic cyclic stretching (18% equibiaxial stretch) and thrombin in a previously verified two-hit model of in vitro ventilator-induced lung injury.
Three-day amifostine preconditioning before high tidal volume attenuated high tidal volume-induced protein and cell accumulation in the alveolar space judged by bronchoalveolar lavage fluid analysis, decreased Evans Blue dye extravasation into the lung parenchyma, decreased biochemical parameters of high tidal volume-induced tissue oxidative stress, and inhibited high tidal volume-induced activation of redox-sensitive stress kinases and nuclear factor-kappa B inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 expression and increased superoxide dismutase and catalase enzymatic activities in the animal and endothelial cell culture models of ventilator-induced lung injury.
Amifostine preconditioning activates lung tissue antioxidant cell defense mechanisms and may be a promising strategy for alleviation of ventilator-induced lung injury in critically ill patients subjected to extended mechanical ventilation.
通过诱导抗氧化防御酶来检验预先使用氨磷汀预处理动物是否能改善机械通气引起的肺损伤这一假说。大潮气量机械通气会导致肺部活性氧和氮物质的产生和氧化应激，这在呼吸机相关性肺损伤的发病机制中起着主要作用。氨磷汀通过充当活性氧和氮物质的直接清除剂，减轻氧化应激并改善脂多糖引起的肺损伤。本研究检测了慢性氨磷汀给药对氧化应激、肺屏障功能和与呼吸机相关性肺损伤相关的炎症参数的影响。
在小鼠和细胞培养物中进行的随机对照实验室研究。
大学实验室。
C57BL/6J 小鼠。
小鼠在第 4 天进行大潮气量通气（30ml/kg，4 小时）前连续 3 天每天接受一次氨磷汀（10-100mg/kg，腹腔注射）给药。肺内皮细胞培养物在以前验证过的体外呼吸机相关性肺损伤两击模型中暴露于病理循环拉伸（18%等张拉伸）和凝血酶。
在大潮气量通气之前进行 3 天的氨磷汀预处理，通过支气管肺泡灌洗液分析来判断，可减轻大潮气量通气引起的肺泡空间中蛋白质和细胞的积聚，减少伊文思蓝染料向肺实质的渗出，降低与组织氧化应激相关的生化参数，并抑制大潮气量通气引起的氧化还原敏感应激激酶和核因子-κB 炎症级联的激活。氨磷汀的这些保护作用与动物和内皮细胞培养物模型中呼吸机相关性肺损伤的超氧化物歧化酶 2 表达增加以及超氧化物歧化酶和过氧化氢酶酶活性增加有关。
氨磷汀预处理激活了肺组织抗氧化细胞防御机制，可能是缓解接受长时间机械通气的危重病患者呼吸机相关性肺损伤的一种有前途的策略。
