Gastroenterology:Ca 2+通道抑制剂SARAF可保护小鼠免于急性胰腺炎损伤

2019-09-09 MedSci MedSci原创

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背景与目的

胰腺炎的病理特征是Ca 2+流入腺泡细胞,导致细胞生理功能受损,而引起一系列的损伤。因此,Ca 2+流入通道的抑制剂可有效治疗急性胰腺炎,但是有导致死亡的副作用。本项研究旨在探究腺泡细胞Ca 2+通道的表达模式和功能以及在急性胰腺炎发展过程中调节它们的因子,以及钙进入相关调节因子(SARAF)在控制胰腺炎损伤中的作用。


方法

研究人员使用CRISPR / Cas9基因编辑和分离的腺泡细胞产生血凝素标记的SARAF的小鼠。并使用荧光共振能量转移显微镜和免疫沉淀分析了用卡巴胆碱刺激的HEK细胞中基质相互作用分子1(STIM1)和SARAF之间的相互作用。研究人员给小鼠注射蓝藻素或L-精氨酸以诱导胰腺炎的产生,最后收集胰腺组织和血液样品,测量血清淀粉酶,胰蛋白酶,组织损伤,炎症介质和炎性细胞的水平。同时,研究人员对6名无胰腺疾病的患者(对照组)和9名酒精相关性胰腺炎患者的胰腺组织进行了定量PCR分析。


结果

本项研究结果显示,胰腺水平的Ca 2+流入通道或STIM1在没有胰腺炎的小鼠的腺泡细胞之间没有显着差异。相比之下,Saraf mRNA和SARAF蛋白的胰腺水平最初显着增加,但随后在细胞刺激或注射蓝藻素的小鼠中减少,导致过量的Ca 2+流入。研究人员观察到,对健康照组相比,在给予蓝藻素或L-精氨酸后胰腺炎患者的胰腺组织中的SARAF mRNA水平明显降低。SARAF敲除小鼠比对照小鼠产生更严重的胰腺炎,并且来自这些小鼠的胰腺腺泡细胞具有显着增加的Ca 2+流入。相反,过度表达SARAF可减少Ca 2+流入,并可消除炎症并降低急性胰腺炎的严重程度。


结论

在患有胰腺炎的小鼠中,SARAF最初增加但随后降解,这个过程导致腺泡细胞过量的Ca 2+流入细胞。因此,SARAF似乎可预防急性胰腺炎发展过程中的胰腺损伤。


原始出处:

Aran Son. Et al. Ca2+ Influx Channel Inhibitor SARAF Protects Mice From Acute Pancreatitis.Gastroenterology.2019.


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    2020-03-27 许安
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    2020-05-28 jklm09
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