Yamaguchi Makoto, Steward Martin C, Smallbone Kieran, Sohma Yoshiro, Yamamoto Akiko, Ko Shigeru B H, Kondo Takaharu, Ishiguro Hiroshi
Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan.
School of Medical Sciences.
J Physiol. 2017 Mar 15;595(6):1947-1972. doi: 10.1113/JP273306. Epub 2017 Feb 8.
The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO concentrations as high as 140 mm during hormonal stimulation. A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea-pig pancreatic ducts. The model was readily able to secrete 140 mm HCO . Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers. We conclude that the main requirement for secreting high HCO concentrations is to minimize the secretion of Cl ions. These findings help to clarify the mechanism responsible for pancreatic HCO secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease.
A computational model of guinea-pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least-squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP-stimulated secretion were well replicated by increasing the activities of the basolateral Na -HCO cotransporter (NBC1) and apical Cl /HCO exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K permeability and apical Cl and HCO permeabilities (CFTR), and reducing the activity of the basolateral Cl /HCO exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO at a rate of ∼3 nl min mm , which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl /HCO exchange via SLC26A6 at the apical membrane were able to support a HCO -rich secretion. Raising the HCO /Cl permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by ∼80% was essential in minimizing the intracellular Cl concentration following cAMP stimulation and thereby maximizing the secreted HCO concentration. The addition of a basolateral Na -K -2Cl cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl and resulted in a lower secreted HCO concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl secretion is the main requirement for secreting 140 mm HCO .
在激素刺激下，胰腺的导管系统分泌大量碱性液体，其中碳酸氢根（HCO）浓度高达140 mmol/L。构建了一个计算模型来探究潜在的离子转运机制。通过将模型与豚鼠胰腺导管的实验数据拟合来估计参数。该模型能够轻松分泌140 mmol/L的HCO。其分泌能力并不依赖于囊性纤维化跨膜电导调节因子（CFTR）阴离子通道和溶质载体家族26成员A6（SLC26A6）阴离子交换器的特殊性质。我们得出结论，分泌高浓度HCO的主要要求是尽量减少氯离子（Cl）的分泌。这些发现有助于阐明胰腺HCO分泌的机制，这是一个至关重要的过程，可防止导管中形成蛋白质栓子和粘性黏液，否则可能导致胰腺疾病。
开发了豚鼠胰腺导管上皮的计算模型，以确定分泌浓度超过140 mmol/L的HCO的转运机制。通过将模型预测值与在一系列实验条件下从分离的导管和完整胰腺获得的实验数据进行最小二乘拟合，估计了定义各个离子通道和转运体贡献的参数。通过增加基底外侧钠-碳酸氢根协同转运体（NBC1）和顶端氯/碳酸氢根交换器（溶质载体家族26成员A6；SLC26A6）的活性、增加基底外侧钾通透性以及顶端氯和碳酸氢根通透性（CFTR），并降低基底外侧氯/碳酸氢根交换器（阴离子交换器2；AE2）的活性，很好地重现了环磷酸腺苷（cAMP）刺激分泌的效果。在这些条件下，模型以约3 nl·min⁻¹·mm⁻²的速率分泌约140 mmol/L的HCO，这与实验观察结果一致。顶端膜通过SLC26A6进行氯/碳酸氢根交换的1:2和1:1化学计量比能够支持富含HCO的分泌。将CFTR的HCO/Cl通透性比值从0.4提高到1.0对分泌的HCO浓度或体积流量几乎没有影响。然而，模型显示，在cAMP刺激后，将基底外侧AE2活性降低约80%对于最小化细胞内Cl浓度并从而最大化分泌HCO浓度至关重要。添加假定存在于大鼠和小鼠导管中的基底外侧钠-钾-2氯协同转运体（NKCC1）会提高细胞内Cl浓度，并导致分泌的HCO浓度降低，这是这些物种的特征。因此，我们得出结论，尽量减少Cl分泌的驱动力是分泌140 mmol/L HCO的主要要求。
