Physiological insights into electrodiffusive maintenance of gastric mucus through sensitivity analysis and simulations.
Physiological insights into electrodiffusive maintenance of gastric mucus through sensitivity analysis and simulations.
复制标题
DOI：
10.1007/s00285-021-01643-w
复制
发表时间：
2021-08-26
影响因子：
1.9
通讯作者：
Lewis OL
中科院分区：
文献类型：
--
作者：
Aggarwal M;Cogan NG;Lewis OL
人们普遍认为，胃粘膜和邻近的粘液层在维持胃腔到胃壁的pH梯度、保护粘膜免受管腔酸性环境的影响以及防止上皮层的自动消化方面起着至关重要的作用。目前还没有确凿的研究表明，哪些物理、化学和调控机制负责维持这种梯度。然而，实验工作和建模工作表明，上皮壁的浓度依赖的离子交换，加上氢离子/粘液网络结合，可能会产生体内看到的巨大的pH梯度。到目前为止，还没有关于这些建模结果对模型参数的变化有多敏感的详尽研究，也没有关于这种调节机制对物理/生物参数的变化有多敏感的详尽研究。在这项工作中，我们对先前报道的胃pH梯度维持模型进行了敏感性分析(使用Sobol指数)。我们量化了粘膜壁pH值(作为上皮健康的替代指标)对生物学相关参数变化的敏感性，并说明了这些参数的变化如何影响测量的pH值的分布。在所有参数区域中，我们看到上皮壁的阳离子/氢交换速率是影响粘膜pH变化的主要参数/效应。通过仔细的敏感性分析，我们还研究了代表高和低氢分泌的两种不同的模式，并对其进行了不同的生理解释。通过用参数敏感性分析补充机制建模和生物假设检验，我们能够得出哪些生物过程必须严格调控才能有力地维持胃的健康功能所必需的pH值。
It is generally accepted that the gastric mucosa and adjacent mucus layer are critical in the maintenance of a pH gradient from stomach lumen to stomach wall, protecting the mucosa from the acidic environment of the lumen and preventing auto-digestion of the epithelial layer. No conclusive study has shown precisely which physical, chemical, and regulatory mechanisms are responsible for maintaining this gradient. However, experimental work and modeling efforts have suggested that concentration dependent ion-exchange at the epithelial wall, together with hydrogen ion/mucus network binding, may produce the enormous pH gradients seen in vivo. As of yet, there has been no exhaustive study of how sensitive these modeling results are with respect to variation in model parameters, nor how sensitive such a regulatory mechanism may be to variation in physical/biological parameters. In this work, we perform sensitivity analysis (using Sobol’ Indices) on a previously reported model of gastric pH gradient maintenance. We quantify the sensitivity of mucosal wall pH (as a proxy for epithelial health) to variations in biologically relevant parameters and illustrate how variations in these parameters affects the distribution of the measured pH values. In all parameter regimes, we see that the rate of cation/hydrogen exchange at the epithelial wall is the dominant parameter/effect with regards to variation in mucosal pH. By careful sensitivity analysis, we also investigate two different regimes representing high and low hydrogen secretion with different physiological interpretations. By complementing mechanistic modeling and biological hypotheses testing with parametric sensitivity analysis we are able to conclude which biological processes must be tightly regulated in order to robustly maintain the pH values necessary for healthy function of the stomach.
登录
查看更多内容
影响因子：
1.8
作者：
Harenberg, Daniel;Marelli, Stefano;Winschel, Viktor
通讯作者：
Winschel, Viktor
影响因子：
24.5
作者：
BAHARI, HMM;ROSS, IN;TURNBERG, LA
通讯作者：
TURNBERG, LA
影响因子：
8.1
作者：
Kucherenko, S.;Song, S.
通讯作者：
Song, S.
DOI：
10.1152/ajpgi.00221.2017
发表时间：
2017-12-01
影响因子：
4.5
作者：
Lewis, Owen L.;Keener, James P.;Fogelson, Aaron L.
通讯作者：
Fogelson, Aaron L.
影响因子：
6.1
作者：
Li, Leon;Lieleg, Oliver;Han, Jongyoon
通讯作者：
Han, Jongyoon