Pathogenesis and Therapy for Ventilator-Induced Lung Injury (VILI)

呼吸机可引起动物急性肺损伤(ALI)，常加重人类ALI(呼吸机诱发肺损伤[VILI])的肺损伤。肺泡上皮II型细胞(AEC-II)释放的多种炎性细胞因子和AEC-II的凋亡被认为在VILI的发病机制中起重要作用。我们首先研究了机械拉伸对AEC-II产生趋化因子的影响。机械应激对培养的大鼠AEC-II本身没有刺激Gro/CINC-1的释放，但增加了内毒素诱导的Gro/CINC-1的产生。其次，我们研究了高碳酸血症对AEC-II产生趋化因子和肺泡细胞凋亡的影响。EL ISA法检测高二氧化碳浓度(PCO2：70-80 mm Hg)刺激A549细胞产生AEC-II、IL-8。IL-8的产生通过诱导mRNA的表达而增加。高碳酸盐酸中毒也增加了内毒素诱导的IL-8的产生。这些数据表明，高碳酸血症在转录水平上上调了炎性细胞因子。最后，我们评价了高碳酸血症是否会改变AEC-II细胞的凋亡。高碳酸本身轻微诱导A549细胞的凋亡(根据APOPercentage凋亡率试剂盒评估)，尽管不是很明显。高碳酸血症对过氧化氢诱导的A549细胞凋亡无明显影响。这些发现提示低潮气机不能诱导或加强AEC-II的凋亡。

Ventilation is known to cause acute lung injury (ALI) in animals and often worsens lung damages in human ALI (ventilator-induced lung injury [VILI]). Many inflammatory cytokines released from alveolar epithelial type II cells (AEC-II) and apoptosis of AEC-II are thought to play an important role in the pathogenesis of VILI. We first investigated the effects of mechanical stretch on production of chemokine from AEC-II. Mechanical stress on rat cultured AEC-II per se did not stimulate release of GRO/CINC-1 but increased endotoxin-induced production of GRO/CINC-1. Secondly, we examined the effects of hypercapnic acidosis on chemokine production from AEC-II and apoptosis of the pneumocytes. Hypercapnia in the culture medium (PCO2 : 70-80mmHg) stimulated A549 cells, human AEC-II, IL-8 production as assessed by ELISA. IL-8 production was increased by inducing mRNA expression. Hypercapnic acidosis also multiplied endotoxin-induced IL-8 production. These data suggest that hypercapnic acidosis up-regulates inflammatory cytokines at the transcriptional level. Finally, we evaluated whether hypercapnia can change apoptosis of AEC-II. Hypercapnic acidosis per se slightly induced apoptosis of A549 cells (as assessed by APOPercentage Apoptosis Kit) although not significantly. Hypercapnic acidosis had no effect on apoptosis of A549 cells induced by hydrogen peroxide. These findings suggest that low tidal ventilation does not induce or potentiate apoptosis of AEC-II