Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan.
Perit Dial Int. 2011 Jul-Aug;31(4):466-76. doi: 10.3747/pdi.2010.00157. Epub 2011 Apr 30.
Peritoneal fibrosis is an essential precursor condition to the development of encapsulating peritoneal sclerosis (EPS). This serious complication leads to a high mortality rate in peritoneal dialysis (PD) patients. Although several factors, including highly concentrated glucose in the dialysis solution, are believed to be potent agents for peritoneal fibrosis, the underlying mechanism remains unclear. During PD, the dialysis solution continuously generates fluid flow stress to the peritoneum under peristalsis and body motion. Fluid flow stress has been implicated as playing a critical role in the physiologic responses of many cell types. We therefore hypothesized that fluid flow stress may be involved in the pathogenesis of peritoneal fibrosis leading to EPS.
To generate fluid flow stress, culture containers were placed on a rotatory shaker in a thermostatic chamber. In this system, the shaker rotated at a speed of 25 rpm with a radius of 1.5 cm. Mesothelial cells were cultured in low-glucose (1000 mg/L) or high-glucose (4500 mg/L) complete medium with and without flow stress.
Fluid flow stress promoted hyperplasia and epithelial-mesenchymal transition (EMT) of mesothelial cells independent of glucose concentration. Fluid flow stress inhibited expression of ERK (extracellular signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) in mesothelial cells. Administration of ERK and p38 MAPK inhibitors replicated the stress-induced morphology of mesothelial cells.
The present data indicate that fluid flow stress promotes hyperplasia and EMT of mesothelial cells via the MAPK axis, suggesting that fluid flow stress may be involved in the pathogenesis of peritoneal fibrosis.
腹膜纤维化是形成包裹性腹膜硬化症（EPS）的重要前期病变。这种严重的并发症会导致腹膜透析（PD）患者的死亡率很高。尽管人们认为高浓度葡萄糖等多种因素是导致腹膜纤维化的有力因素，但潜在机制尚不清楚。在 PD 过程中，透析液在蠕动和身体运动下不断对腹膜产生流体流动应力。流体流动应力被认为在许多细胞类型的生理反应中起着关键作用。因此，我们假设流体流动应力可能与导致 EPS 的腹膜纤维化的发病机制有关。
为了产生流体流动应力，将培养容器放置在恒温箱中的旋转摇床上。在这个系统中，摇床以 25rpm 的速度旋转，半径为 1.5 厘米。在有和没有流动应力的情况下，将间皮细胞培养在低糖（1000mg/L）或高糖（4500mg/L）完全培养基中。
流体流动应力促进了间皮细胞的增生和上皮-间充质转化（EMT），而与葡萄糖浓度无关。流体流动应力抑制了间皮细胞中 ERK（细胞外信号调节激酶）和 p38MAPK（丝裂原激活蛋白激酶）的表达。ERK 和 p38MAPK 抑制剂的给药复制了间皮细胞应激诱导的形态。
本研究数据表明，流体流动应力通过 MAPK 轴促进间皮细胞的增生和 EMT，提示流体流动应力可能与腹膜纤维化的发病机制有关。
