Dialysis Unit, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain.
PLoS One. 2009 Aug 13;4(8):e6634. doi: 10.1371/journal.pone.0006634.
Inflammation may lead to tissue injury. We have studied the modulation of inflammatory milieu-induced tissue injury, as exemplified by the mesothelium. Peritoneal dialysis is complicated by peritonitis episodes that cause loss of mesothelium. Proinflammatory cytokines are increased in the peritoneal cavity during peritonitis episodes. However there is scarce information on the modulation of cell death by combinations of cytokines and on the therapeutic targets to prevent desmesothelization.
Human mesothelial cells were cultured from effluents of stable peritoneal dialysis patients and from omentum of non-dialysis patients. Mesothelial cell death was studied in mice with S. aureus peritonitis and in mice injected with tumor necrosis factor alpha and interferon gamma. Tumor necrosis factor alpha and interferon gamma alone do not induce apoptosis in cultured mesothelial cells. By contrast, the cytokine combination increased the rate of apoptosis 2 to 3-fold over control. Cell death was associated with the activation of caspases and a pancaspase inhibitor prevented apoptosis. Specific caspase-8 and caspase-3 inhibitors were similarly effective. Co-incubation with both cytokines also impaired mesothelial wound healing in an in vitro model. However, inhibition of caspases did not improve wound healing and even impaired the long-term recovery from injury. By contrast, a polymeric nanoconjugate Apaf-1 inhibitor protected from apoptosis and allowed wound healing and long-term recovery. The Apaf-1 inhibitor also protected mesothelial cells from inflammation-induced injury in vivo in mice.
Cooperation between tumor necrosis factor alpha and interferon gamma contributes to mesothelial injury and impairs the regenerative capacity of the monolayer. Caspase inhibition attenuates mesothelial cell apoptosis but does not facilitate regeneration. A drug targeting Apaf-1 allows protection from apoptosis as well as regeneration in the course of inflammation-induced tissue injury.
炎症可能导致组织损伤。我们研究了炎症环境引起的组织损伤的调节，以间皮为例。腹膜透析会引发腹膜炎，导致间皮细胞丢失。腹膜炎期间，腹腔内的促炎细胞因子会增加。然而，关于细胞因子组合对细胞死亡的调节以及预防去间皮化的治疗靶点的信息很少。
我们从稳定腹膜透析患者的流出液和非透析患者的大网膜中培养人间皮细胞。我们在金黄色葡萄球菌腹膜炎小鼠和注射肿瘤坏死因子-α和干扰素-γ的小鼠中研究间皮细胞死亡。肿瘤坏死因子-α和干扰素-γ单独不能诱导培养的间皮细胞凋亡。相比之下，细胞因子组合使细胞凋亡率比对照组增加了 2 至 3 倍。细胞死亡与半胱天冬酶的激活有关，泛半胱天冬酶抑制剂可预防凋亡。特异性半胱天冬酶-8 和半胱天冬酶-3 抑制剂同样有效。两种细胞因子的共孵育也会损害体外模型中的间皮细胞伤口愈合。然而，抑制半胱天冬酶并不能改善伤口愈合，甚至会损害损伤后的长期恢复。相比之下，一种聚合纳米缀合物 Apaf-1 抑制剂可防止凋亡，并允许伤口愈合和长期恢复。Apaf-1 抑制剂还可防止体内小鼠炎症诱导的间皮细胞损伤。
肿瘤坏死因子-α和干扰素-γ的合作导致间皮损伤，并损害单层的再生能力。半胱天冬酶抑制可减轻间皮细胞凋亡，但不能促进再生。一种靶向 Apaf-1 的药物可在炎症诱导的组织损伤过程中提供凋亡和再生的保护。
