Pancreatic acinar cell dysfunction in CFTR-/- mice is associated with impairments in luminal pH and endocytosis
Pancreatic acinar cell dysfunction in CFTR-/- mice is associated with impairments in luminal pH and endocytosis
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DOI：
10.1053/gast.2001.27992
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发表时间：
2001-10-01
期刊：
影响因子：
29.4
通讯作者：
Scheele, GA
中科院分区：
文献类型：
--
作者：
Freedman, SD;Kern, HF;Scheele, GA
背景&施舍：我们以前已经表明，胰腺腺泡细胞顶端质膜的内吞作用与导管碳酸氢盐分泌到管腔中相耦合。我们假设囊性纤维化（CF）中碳酸氢盐分泌减少抑制顶端内吞作用。本研究的目的是确定cftr（-/-）小鼠（1）与野生型（WT）对照相比，胰液的pH值是否为酸性，（2）是否存在内吞作用的选择性阻断，以及（3）腔液的碱化是否逆转了这一缺陷。方法：测定胰液分泌量和pH值。比较cftr（-/-）和WT小鼠胰腺小叶的胞吐、胞吞和形态。结果：WT小鼠的胰液pH值为8.12 +/- 0.06，而cftr（-/-）小鼠为6.60 +/- 0.04。虽然胆囊收缩素刺激的淀粉酶分泌没有显著差异，但与WT小鼠相比，cftr（-/-）中的内吞作用明显受到抑制。GP 2（一种与内吞作用激活密切相关的GPI锚定蛋白）的裂解也减少。在pH 8.3下孵育cftr-/-小鼠的小叶逆转了管腔扩张。结论：这些数据表明，在cftr（-/-）小鼠中，顶端内吞作用选择性受损，这部分解释了在顶端质膜处观察到的管腔扩张。在体外碱化腔液导致逆转膜动力学的缺陷，恢复耦合胞吐和胞吞作用，并取消在这个动物模型的CF管腔扩张。腔分泌物中的酸性pH变化可能在CF中观察到的胰腺膜功能障碍中发挥作用。
Background & Alms: We have previously shown that endocytosis at the apical plasma membrane in pancreatic acinar cells is coupled to ductal bicarbonate secretion into the lumen. We hypothesized that decreased bicarbonate secretion in cystic fibrosis (CF) inhibits apical endocytosis. The aim of this study was to determine in cftr(-/-) mice (1) if the pH of the pancreatic juice is acidic compared with wild-type (WT) controls, (2) if there is a selective block in endocytosis, and (3) if alkalinization of the luminal fluid reverses this defect. Methods; Fluid secretion and pH of pancreatic juice were measured. Exocytosis, endocytosis, and morphology were compared in pancreatic lobules from cftr(-/-) and WT mice. Results: Pancreatic juice pH was 8.12 +/- 0.06 in WT mice compared with 6.60 +/- 0.04 in cftr(-/-) mice. Although cholecystokinin-stimulated amylase secretion was not significantly different, endocytosis was markedly inhibited in cftr(-/-) compared with WT mice. Cleavage of GP2, a GPI-anchored protein tightly associated with activation of endocytosis, was also decreased. Incubation of lobules from cftr-/- mice at pH 8.3 reversed the luminal dilatation. Conclusions: These data indicate that apical endocytosis is selectively impaired in cftr(-/-) mice, which explains, in part, the luminal dilatation observed at the apical plasma membrane. In vitro alkalinization of luminal fluid led to reversal of defects in membrane dynamics, restored coupled exocytosis and endocytosis, and abolished the luminal dilatation in this animal model of CF. Acidic pH changes in luminal secretions may play a role in the pancreatic membrane dysfunction observed in CF.