Abello P A, Buchman T G
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-5612, USA.
Shock. 1994 Nov;2(5):320-3. doi: 10.1097/00024382-199411000-00004.
We previously reported that sequential exposure of cultured porcine aortic endothelial cells to lipopolysaccharide (LPS) and then to inducers of the heat shock response resulted in lethal injury by programmed cell death. In these present experiments, we evaluated the ability of other mediators of sepsis to prime endothelial cells for subsequent injury upon heat shock induction. We used SVEC4-10 microvascular endothelial cells, a cloned SV40-transformed cell line derived from LPS-resistant C3H/HeJ mice. When these endothelial cells were treated first with tumor necrosis factor-alpha followed by induction of the heat shock response with either heat or sodium arsenite (As), a standard chemical inducer of the heat shock response in vitro, a tumor necrosis factor dose-dependent cytotoxicity was observed, similar to that which we had seen previously in porcine endothelial cells primed with LPS. Subsequent experiments found that priming with interferon-gamma produced a similar dose-dependent toxicity upon heat shock with either heat or As. The reducing agents dithiothreitol and n-acetylcysteine, which we have previously shown to inhibit heat shock-induced programmed cell death in LPS-primed porcine endothelial cells, were also effective in protecting against heat shock-induced death following cytokine-priming in this microvascular cell line, suggesting that the intracellular signaling pathways of these priming agents are somewhere convergent. These data suggest that both exogenous and endogenous mediators of inflammation can prime endothelial cells for subsequent injury upon induction of the heat shock response, and are consistent with the emerging concept of redundancy in inflammatory signaling.
我们先前报道，培养的猪主动脉内皮细胞先后暴露于脂多糖（LPS），然后再暴露于热休克反应诱导剂，会导致程序性细胞死亡引起的致命损伤。在目前的这些实验中，我们评估了脓毒症的其他介质使内皮细胞对热休克诱导后的后续损伤产生预处理的能力。我们使用了SVEC4-10微血管内皮细胞，这是一种从对LPS有抗性的C3H/HeJ小鼠衍生而来的克隆的SV40转化细胞系。当这些内皮细胞先用肿瘤坏死因子-α处理，随后用热或亚砷酸钠（As，体外热休克反应的标准化学诱导剂）诱导热休克反应时，观察到了肿瘤坏死因子剂量依赖性细胞毒性，这与我们之前在用LPS预处理的猪内皮细胞中所看到的情况相似。随后的实验发现，用干扰素-γ进行预处理，在热或As诱导热休克时会产生类似的剂量依赖性毒性。我们先前已证明能抑制LPS预处理的猪内皮细胞中热休克诱导的程序性细胞死亡的还原剂二硫苏糖醇和N-乙酰半胱氨酸，在这种微血管细胞系中，对细胞因子预处理后热休克诱导的死亡也有保护作用，这表明这些预处理剂的细胞内信号通路在某处是趋同的。这些数据表明，炎症的外源性和内源性介质都能使内皮细胞对热休克反应诱导后的后续损伤产生预处理，并且与炎症信号传导中冗余这一新兴概念相一致。
