Dokladny Karol, Moseley Pope L, Ma Thomas Y
Internal Medicine-Gastroenterology and Hepatology, University of New Mexico, Albuquerque, New Mexico 87131-0001, USA.
Am J Physiol Gastrointest Liver Physiol. 2006 Feb;290(2):G204-12. doi: 10.1152/ajpgi.00401.2005.
The effects of physiologically relevant increase in temperature (37-41 degrees C) on intestinal epithelial tight junction (TJ) barrier have not been previously studied. Additionally, the role of heat-shock proteins (HSPs) in the regulation of intestinal TJ barrier during heat stress remains unknown. Because heat-induced disturbance of intestinal TJ barrier could lead to endotoxemia and bacterial translocation during physiological thermal stress, the purpose of this study was to investigate the effects of modest, physiologically relevant increases in temperature (37-41 degrees C) on intestinal epithelial TJ barrier and to examine the protective role of HSPs on intestinal TJ barrier. Filter-grown Caco-2 intestinal epithelial cells were used as an in vitro intestinal epithelial model system to assess the effects of heat exposure on intestinal TJ barrier. Exposure of filter-grown Caco-2 monolayers to modest increases in temperatures (37-41 degrees C) resulted in a significant time- and temperature-dependent increases in Caco-2 TJ permeability. Exposure to modest heat (39 or 41 degrees C) resulted in rapid and sustained increases in HSP expression; and inhibition of HSP expression produced a marked increase in heat-induced increase in Caco-2 TJ permeability (P < 0.001). Heat exposure (41 degrees C) resulted in a compensatory increase in Caco-2 occludin protein expression and an increase in junctional localization. Inhibition of HSP expression prevented the compensatory upregulation of occludin protein expression and produced a marked disruption in junctional localization of occludin protein during heat stress. In conclusion, our findings demonstrate for the first time that a modest, physiologically relevant increase in temperature causes an increase in intestinal epithelial TJ permeability. Our data also show that HSPs play an important protective role in preventing the heat-induced disruption of intestinal TJ barrier and suggest that HSP mediated upregulation of occludin expression may be an important mechanism involved in the maintenance of intestinal epithelial TJ barrier function during heat stress.
生理相关温度升高（37 - 41摄氏度）对肠道上皮紧密连接（TJ）屏障的影响此前尚未有研究。此外，热休克蛋白（HSPs）在热应激期间对肠道TJ屏障调节中的作用仍不清楚。由于生理热应激期间热诱导的肠道TJ屏障紊乱可导致内毒素血症和细菌移位，本研究的目的是探讨适度的、生理相关温度升高（37 - 41摄氏度）对肠道上皮TJ屏障的影响，并研究HSPs对肠道TJ屏障的保护作用。将滤膜培养的Caco - 2肠道上皮细胞用作体外肠道上皮模型系统，以评估热暴露对肠道TJ屏障的影响。将滤膜培养的Caco - 2单层细胞暴露于适度温度升高（37 - 41摄氏度）会导致Caco - 2 TJ通透性出现显著的时间和温度依赖性增加。暴露于适度热（39或41摄氏度）会导致HSP表达迅速且持续增加；抑制HSP表达会使热诱导的Caco - 2 TJ通透性增加显著升高（P < 0.001）。热暴露（41摄氏度）导致Caco - 2闭合蛋白表达代偿性增加以及连接定位增加。抑制HSP表达可阻止闭合蛋白表达的代偿性上调，并在热应激期间导致闭合蛋白的连接定位出现显著破坏。总之，我们的研究结果首次表明，适度的、生理相关温度升高会导致肠道上皮TJ通透性增加。我们的数据还表明，HSPs在防止热诱导的肠道TJ屏障破坏中起重要保护作用，并提示HSP介导的闭合蛋白表达上调可能是热应激期间维持肠道上皮TJ屏障功能的重要机制。
