BCL-2 inhibits gut epithelial apoptosis induced by acute lung injury in mice but has no effect on survival
BCL-2 inhibits gut epithelial apoptosis induced by acute lung injury in mice but has no effect on survival
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DOI：
10.1097/01.shk.0000094559.76615.1c
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发表时间：
2003-11-01
期刊：
影响因子：
3.1
通讯作者：
Coopersmith, CM
中科院分区：
文献类型：
--
作者：
Husain, KD;Stromberg, PE;Coopersmith, CM
在人类研究和非感染性炎症和脓毒症的动物模型中，肠上皮细胞凋亡增加。肠细胞死亡增加似乎在脓毒症中具有生理学意义。先前的研究表明，抗凋亡蛋白Bcl-2在转基因小鼠肠上皮细胞中的过表达与铜绿假单胞菌肺炎和盲肠结扎和穿孔的存活率提高有关。非感染性炎症中肠道细胞凋亡增加的功能意义尚未研究。我们假设肠细胞凋亡对非感染性危重病患者的生存率是有害的。为了解决这个问题，在野生型（WT）FVB/N小鼠和在肠上皮中过表达Bcl-2的转基因小鼠中，通过气管内注射脂多糖（LPS，800 μ g）诱导急性肺损伤（ALI）。在12、24、48和72小时收获肠，并通过苏木精和伊红以及活性半胱天冬酶-3染色评估100个连续隐窝中的细胞凋亡。与假手术组相比，ALI组肠上皮细胞凋亡明显增加（P < 0.01），而Bcl-2过表达组肠上皮细胞凋亡明显减少（P < 0.05）。WT和转基因ALI动物的血浆肿瘤坏死因子α、白细胞介素（IL）-6和IL-10水平相似，与假手术动物相比，两者在12 h时IL-10水平升高，24 h时IL-6水平升高。在另一项实验中，对患有ALI的转基因和WT动物的死亡率进行了跟踪，以确定肠道Bcl-2过表达是否赋予了生存优势。WT动物（n = 33）和Bcl-2动物（n = 23，P = ns）在10天时的存活率分别为73%和65%。这些结果表明，虽然肠上皮细胞凋亡在多种危重病模型中升高，但通过Bcl-2过表达预防肠细胞死亡与脓毒症和非感染性炎症之间的不同生存效应相关。
Gut epithelial apoptosis is increased in human studies and animal models of noninfectious inflammation and sepsis. Elevated intestinal cell death appears to be physiologically significant in sepsis. Previous studies demonstrate that overexpression of the antiapoptotic protein Bcl-2 in the gut epithelium of transgenic mice is associated with improved survival from Pseudomonas aeruginosa pneumonia and cecal ligation and puncture. The functional significance of elevated gut apoptosis in noninfectious inflammation has not been examined. We hypothesized that intestinal apoptosis would be detrimental to survival in noninfectious critical illness. To address this issue, acute lung injury (ALI) was induced with intratracheal injection of lipopolysaccharide (LPS, 800 mug) in wild-type (WT) FVB/N mice and transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Guts were harvested at 12, 24, 48, and 72 h and assessed for apoptosis by both hematoxylin and eosin and active caspase-3 staining in 100 contiguous crypts. ALI increased gut epithelial apoptosis 12 h after LPS instillation compared with shams (P < 0.01), whereas overexpression of Bcl-2 decreased intestinal apoptosis compared with WT animals with ALI when assayed by active caspase-3 (P < 0.05). Plasma levels of tumor necrosis factor alpha, interleukin (IL)-6, and IL-10 were similar between WT and transgenic animals with ALI, both of which had elevated IL-10 levels at 12 h and elevated IL-6 levels at 24 h compared with sham animals. In a separate experiment, transgenic and WT animals with ALI were followed for mortality to determine whether gut overexpression of Bcl-2 conferred a survival advantage. Survival at 10 days was 73% in WT animals (n = 33) and 65% in Bcl-2 animals (n = 23, P = ns). These results indicate that while gut epithelial apoptosis is elevated in multiple models of critical illness, prevention of intestinal cell death by overexpression of Bcl-2 is associated with a disparate survival effect between sepsis and noninfectious inflammation.