A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide.
A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide.
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DOI：
10.1242/dmm.013284
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发表时间：
2013-11
影响因子：
4.3
通讯作者：
Pritchard DM
中科院分区：
文献类型：
--
作者：
Williams JM;Duckworth CA;Watson AJ;Frey MR;Miguel JC;Burkitt MD;Sutton R;Hughes KR;Hall LJ;Caamaño JH;Campbell BJ;Pritchard DM
肠道屏障由一层由紧密连接在一起的肠道上皮细胞(IECs)组成，阻止有害微生物、抗原和毒素从肠道进入血液。正常情况下，小肠的动态平衡是由绒毛顶端衰老的肠细胞的脱落速率与隐窝中新细胞的生成速率完全匹配来维持的。然而，在各种局部和全身性炎症条件下，肠内皮细胞脱落增加可能会扰乱肠道内环境的稳定。这种病理性的IEC脱落可导致上皮屏障形成一过性间隙，并导致肠道通透性增加。尽管病理性IEC脱落与炎症性肠病等疾病的发病机制有关，但我们对其潜在机制的了解仍然有限。因此，我们开发了一个小鼠模型来研究这一现象，因为该物种的IEC脱落在形态上与人类相似。用脂多糖诱导野生型C57BL/6小鼠和肿瘤坏死因子受体1(TnFR1−/−)、TnFR2(TnFR2−/−)、核因子kappab1(NFκb1−/−)或核因子ĸb2(NFĸb2−/−)缺陷小鼠的肠上皮细胞脱落。用免疫组织化学方法检测caspase-3活性，通过测定荧光素-异硫氰酸盐-葡聚糖灌胃后的血浆荧光来评估肠到循环的通透性。剂量为0.125 mg/kg体重的≥可诱导绒毛内皮细胞迅速凋亡，细胞脱落高峰出现在处理后1.5h。这与显著的绒毛缩短、液体渗入肠腔和腹泻不谋而合。肠到循环通透性在5小时后显著增加。κ-1是脂多糖诱导内皮细胞凋亡和脱落所必需的，其命运也依赖于NF-κ-B，通过NF-κ-B1有利于细胞存活，通过NF-TNFR-B2有利于细胞凋亡。这一模型将有助于研究病理性IEC凋亡和细胞脱落在各种疾病中的重要性和调控。
The gut barrier, composed of a single layer of intestinal epithelial cells (IECs) held together by tight junctions, prevents the entrance of harmful microorganisms, antigens and toxins from the gut lumen into the blood. Small intestinal homeostasis is normally maintained by the rate of shedding of senescent enterocytes from the villus tip exactly matching the rate of generation of new cells in the crypt. However, in various localized and systemic inflammatory conditions, intestinal homeostasis can be disturbed as a result of increased IEC shedding. Such pathological IEC shedding can cause transient gaps to develop in the epithelial barrier and result in increased intestinal permeability. Although pathological IEC shedding has been implicated in the pathogenesis of conditions such as inflammatory bowel disease, our understanding of the underlying mechanisms remains limited. We have therefore developed a murine model to study this phenomenon, because IEC shedding in this species is morphologically analogous to humans. IEC shedding was induced by systemic lipopolysaccharide (LPS) administration in wild-type C57BL/6 mice, and in mice deficient in TNF-receptor 1 (Tnfr1−/−), Tnfr2 (Tnfr2−/−), nuclear factor kappa B1 (Nfκb1−/−) or Nfĸb2 (Nfĸb2−/−). Apoptosis and cell shedding was quantified using immunohistochemistry for active caspase-3, and gut-to-circulation permeability was assessed by measuring plasma fluorescence following fluorescein-isothiocyanate–dextran gavage. LPS, at doses ≥0.125 mg/kg body weight, induced rapid villus IEC apoptosis, with peak cell shedding occurring at 1.5 hours after treatment. This coincided with significant villus shortening, fluid exudation into the gut lumen and diarrhea. A significant increase in gut-to-circulation permeability was observed at 5 hours. TNFR1 was essential for LPS-induced IEC apoptosis and shedding, and the fate of the IECs was also dependent on NFκB, with signaling via NFκB1 favoring cell survival and via NFκB2 favoring apoptosis. This model will enable investigation of the importance and regulation of pathological IEC apoptosis and cell shedding in various diseases.
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DOI：
10.1177/09680519010070040901
发表时间：
2001-01-01
期刊：
JOURNAL OF ENDOTOXIN RESEARCH
影响因子：
--
作者：
Beutler, B;Du, X;Poltorak, A
通讯作者：
Poltorak, A
影响因子：
24.5
作者：
Arrieta, M. C.;Madsen, K.;Doyle, J.;Meddings, J.
通讯作者：
Meddings, J.
Toll样受体4位于高尔基体中，并与肠上皮细胞中的内部脂多糖共定位。
DOI：
10.1084/jem.20011788
发表时间：
2002-03-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hornef MW;Frisan T;Vandewalle A;Normark S;Richter-Dahlfors A
通讯作者：
Richter-Dahlfors A
影响因子：
8.8
作者：
Fukushima H;Matsumoto A;Inuzuka H;Zhai B;Lau AW;Wan L;Gao D;Shaik S;Yuan M;Gygi SP;Jimi E;Asara JM;Nakayama K;Nakayama KI;Wei W
通讯作者：
Wei W
影响因子：
7.3
作者：
Lau KS;Juchheim AM;Cavaliere KR;Philips SR;Lauffenburger DA;Haigis KM
通讯作者：
Haigis KM