Heat Shock Protein 72 Enhances Autophagy as a Protective Mechanism in Lipopolysaccharide-Induced Peritonitis in Rats
Heat Shock Protein 72 Enhances Autophagy as a Protective Mechanism in Lipopolysaccharide-Induced Peritonitis in Rats
复制标题
热休克蛋白 72 增强自噬作为脂多糖诱导的大鼠腹膜炎的保护机制
DOI：
10.1016/j.ajpath.2011.08.013
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发表时间：
2011-12-01
影响因子：
6
通讯作者：
Mao, Haiping
中科院分区：
文献类型：
--
作者：
Li, Shu;Zhou, Yi;Mao, Haiping
腹膜透析相关性腹膜炎导致间皮细胞剥脱，最终导致膜完整性改变和腹膜功能障碍。由于热休克蛋白72（HSP 72）赋予保护细胞凋亡，因为自噬介导的生存响应细胞应激，我们研究是否自噬有助于HSP 72介导的细胞保护脂多糖（LPS）诱导的腹膜炎。培养的腹膜间皮细胞暴露于LPS首先导致自噬，然后导致凋亡。3-甲基腺嘌呤或Beclin-1小干扰RNA抑制自噬使细胞对凋亡敏感，并消除了HSP 72的抗凋亡作用，表明自噬激活是一种促生存机制。HSP 72的过表达通过c-Jun N-末端激酶（JNK）磷酸化和Be-clin-1上调而增强自噬。JNK活性的抑制逆转了HSP 72介导的Beclin-1上调和自噬，表明HSP 72介导的自噬是JNK依赖的。在LPS相关性腹膜炎大鼠模型中，自噬发生在腹膜细胞凋亡之前。香叶基香叶基丙酮上调HSP 72可增加自噬，抑制细胞凋亡，减轻腹膜损伤，而槲皮素下调HSP 72可减弱这些作用。此外，阻断自噬氯喹促进细胞凋亡和加重LPS相关的腹膜功能障碍。因此，HSP 72保护腹膜免受LPS诱导的间皮细胞损伤，至少部分通过增强JNK活化依赖性自噬和抑制凋亡。这些结果表明，HSP 72诱导可能是一种潜在的治疗腹膜炎。(Am J Pathol 2011，179：2822-2834; DOI：10.1016/j.ajpath.2011.08.013）
Peritoneal dialysis related peritonitis causes the denudation of mesothelial cells and, ultimately, membrane integrity alterations and peritoneal dysfunction. Because heat shock protein 72 (HSP72) confers protection against apoptosis and because autophagy mediates survival in response to cellular stresses, we examined whether autophagy contributes to HSP72-mediated cytoprotection in lipopolysaccharide (LPS)-induced peritonitis. Exposure of cultured peritoneal mesothelial cells to LPS resulted first in autophagy and later, apoptosis. Inhibition of autophagy by 3-methyladenine or Beclin-1 small-interfering RNA sensitized cells to apoptosis and abolished the antiapoptotic effect of HSP72, suggesting that autophagy activation acts as a prosurvival mechanism. Overexpression of HSP72 augmented autophagy through c-Jun N-terminal kinase (JNK) phosphorylation and Be-clin-1 up-regulation. Suppression of JNK activity reversed HSP72-mediated Beclin-1 up-regulation and autophagy, indicating that HSP72-mediated autophagy is JNK dependent. In a rat model of LPS-associated peritonitis, autophagy occurred before apoptosis in peritoneum. Up-regulation of HSP72 by geranylgeranylacetone increased autophagy, inhibited apoptosis, and attenuated peritoneal injury, and these effects were blunted by down-regulation of HSP72 with quercetin. Additionally, blocking autophagy by chloroquine promoted apoptosis and aggravated LPS-associated peritoneal dysfunction. Thus, HSP72 protects peritoneum from LPS-induced mesothelial cells injury, at least in part by enhancing JNK activation dependent autophagy and inhibiting apoptosis. These findings imply that HSP72 induction might be a potential therapy for peritonitis. (Am J Pathol 2011, 179:2822-2834; DOI: 10.1016/j.ajpath.2011.08.013)