Mast Cell Mediated Regulation of Small Intestinal Chloride Malabsorption in SAMP1/YitFc Mouse Model of Spontaneous Chronic Ileitis.
Mast Cell Mediated Regulation of Small Intestinal Chloride Malabsorption in SAMP1/YitFc Mouse Model of Spontaneous Chronic Ileitis.
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DOI：
10.3390/cells10030697
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发表时间：
2021-03-21
期刊：
影响因子：
6
通讯作者：
Sundaram U
中科院分区：
文献类型：
--
作者：
Rahman MM;Afroz S;Arthur S;Sundaram U
在炎症性肠病（IBD）中，电解质（NaCl）吸收不良导致腹泻。在IBD中，已经报道了由Na：H和Cl：HCO 3交换剂在肠绒毛细胞刷状缘膜（BBM）上的双重操作介导的偶联NaCl吸收的抑制。在代表克罗恩病的自发性回肠炎的SAMP 1/YitFcs（SAMP 1）小鼠模型中，由于交换剂对Cl的亲和力降低，故显示出继发于Cl：HCO 3交换的抑制的HCO 3（在腺瘤中下调）介导的Cl：HCO 3交换。然而，NHE 3介导的Na：H交换不受影响。已知肥大细胞及其分泌的介质在IBD粘膜中增加，并且可以影响肠电解质吸收。然而，肥大细胞介质如何调节Cl：HCO 3交换SAMP 1小鼠是未知的。因此，本研究的目的是确定肥大细胞介质对SAMP 1小鼠中的RIP 1下调的影响。与对照AKR小鼠相比，SAMP 1小鼠的肥大细胞数量及其脱粒标志酶（β-氨基己糖苷酶）水平显著增加。然而，用肥大细胞稳定剂酮替芬处理SAMP 1小鼠，使肠道中的β-氨基己糖苷酶水平恢复至正常，表明酮替芬稳定肥大细胞。此外，下调Cl：HCO 3交换活性恢复酮替芬治疗SAMP 1小鼠。动力学研究表明，酮替芬恢复改变的亲和力的Cl：HCO 3交换在SAMP 1小鼠绒毛细胞，从而恢复其活动正常。此外，RT-qPCR、Western印迹和免疫荧光研究表明，在所有实验条件下，BBM mRNA和BBM蛋白的表达水平分别保持不变，支持动力学数据。因此，抑制Cl：HCO 3交换导致IBD中的氯吸收不良，从而导致腹泻，这可能是由肥大细胞介质介导的。
In Inflammatory Bowel Disease (IBD), malabsorption of electrolytes (NaCl) results in diarrhea. Inhibition of coupled NaCl absorption, mediated by the dual operation of Na:H and Cl:HCO3 exchangers on the brush border membrane (BBM) of the intestinal villus cells has been reported in IBD. In the SAMP1/YitFcs (SAMP1) mice model of spontaneous ileitis, representing Crohn’s disease, DRA (Downregulated in Adenoma) mediated Cl:HCO3 exchange was shown to be inhibited secondary to diminished affinity of the exchanger for Cl. However, NHE3 mediated Na:H exchange remained unaffected. Mast cells and their secreted mediators are known to be increased in the IBD mucosa and can affect intestinal electrolyte absorption. However, how mast cell mediators may regulate Cl:HCO3 exchange in SAMP1 mice is unknown. Therefore, the aim of this study was to determine the effect of mast cell mediators on the downregulation of DRA in SAMP1 mice. Mast cell numbers and their degranulation marker enzyme (β-hexosaminidase) levels were significantly increased in SAMP1 mice compared to control AKR mice. However, treatment of SAMP1 mice with a mast cell stabilizer, ketotifen, restored the β-hexosaminidase enzyme levels to normal in the intestine, demonstrating stabilization of mast cells by ketotifen. Moreover, downregulation of Cl:HCO3 exchange activity was restored in ketotifen treated SAMP1 mice. Kinetic studies showed that ketotifen restored the altered affinity of Cl:HCO3 exchange in SAMP1 mice villus cells thus reinstating its activity to normal. Further, RT-qPCR, Western blot and immunofluorescence studies showed that the expression levels of DRA mRNA and BBM protein, respectively remained unaltered in all experimental conditions, supporting the kinetic data. Thus, inhibition of Cl:HCO3 exchange resulting in chloride malabsorption leading to diarrhea in IBD is likely mediated by mast cell mediators.
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