Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis.
Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis.
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DOI：
10.1053/j.sempedsurg.2004.10.025
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发表时间：
2005-02-01
影响因子：
1.7
通讯作者：
Ford, Henri R
中科院分区：
文献类型：
--
作者：
Hackam, David J;Upperman, Jeffrey S;Ford, Henri R
坏死性小肠结肠炎（NEC）是新生儿胃肠道疾病死亡的主要原因，其特征是在应激的早产儿中发生弥漫性肠坏死。全身性应激导致肠粘膜屏障的破坏，这导致细菌和内毒素的移位以及肠上皮细胞内信号应答的启动。本文综述了肠上皮细胞信号转导缺陷通过以下机制在NEC发病中的作用：1）肠绒毛细胞局部产生一氧化氮，导致肠上皮细胞凋亡增加，增殖受损; 2）内毒素的移位导致RhoA的PI 3 K依赖性活化。3）内毒素引起的肠上皮细胞内钠-质子交换失调使肠上皮细胞单层在面对全身性脓毒症的酸性微环境特征时更容易受到损伤;和4）内毒素引起肠上皮细胞对促炎分子考克斯-2的p38依赖性释放，这增强了全身炎症反应。了解紊乱的肠上皮细胞信号传导有助于屏障衰竭和NEC的发病机制-通过这些和其他机制-可能会导致确定这种毁灭性疾病的新治疗方法。
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in neonates, and is characterized by the development of diffuse intestinal necrosis in the stressed, pre-term infant. Systemic stress causes a breakdown in the intestinal mucosal barrier, which leads to translocation of bacteria and endotoxin and the initiation of a signaling response within the enterocyte. This review summarizes recent evidence defining a clear role that defective enterocyte signaling plays in the pathogenesis of NEC through the following mechanisms: 1) The localized production of nitric oxide by villus enterocytes results in an increase in enterocyte apoptosis and impaired proliferation; 2) The translocation of endotoxin results in a PI3K-dependent activation of RhoA-GTPase within the enterocyte leading to decreased enterocyte migration and impaired restitution; 3) Dysregulated sodium-proton exchange within the enterocyte by endotoxin renders the enterocyte monolayer more susceptible to damage in the face of the acidic microenvironment characteristic of systemic sepsis; and 4) Endotoxin causes a p38-dependent release of the pro-inflammatory molecule COX-2 by the enterocyte, which potentiates the systemic inflammatory response. An understanding of the mechanisms by which disordered enterocyte signaling contributes to the pathogenesis of barrier failure and NEC--through these and other mechanisms--may lead to the identification of novel therapeutic approaches for this devastating disease.