A physics-based model for maintenance of the pH gradient in the gastric mucus layer
A physics-based model for maintenance of the pH gradient in the gastric mucus layer
复制标题
DOI：
10.1152/ajpgi.00221.2017
复制
发表时间：
2017-12-01
影响因子：
4.5
通讯作者：
Fogelson, Aaron L.
中科院分区：
文献类型：
--
作者：
Lewis, Owen L.;Keener, James P.;Fogelson, Aaron L.
人们普遍认为，胃粘液层在管腔和粘膜之间提供了保护屏障，保护粘膜免受酸和消化酶的侵害，并防止胃上皮的自身消化。然而，有助于这种保护功能的确切机制仍有争议。特别是，目前尚不清楚是什么物理过程负责将胃凹内分泌的氢质子穿过粘液层运输到管腔，而不酸化上皮附近的环境。一种假设是，当粘蛋白聚合物对流离开粘膜表面并最终在胃腔中降解时，氢可能与粘蛋白聚合物本身结合。目前还不清楚是什么机制阻止氢气扩散回粘膜表面，从而降低局部 pH 值。在这项工作中，我们基于类能斯特-普朗克方程研究了粘膜层内离子传输的物理模型。对该模型的分析表明，传输与粘液凝胶结合的质子的机制能够再现文献中报道的跨粘液 pH 梯度。此外，当与上皮表面的离子交换相结合时，我们的分析表明，即使面对巨大的氢扩散梯度，仅碳酸氢盐分泌就能够中和上皮 pH 值。研究发现，pH 梯度的维持对于生理学和现象学模型参数的各种扰动都具有鲁棒性，这表明了一种强大的生理控制机制。新的和值得注意的这项工作结合了基于物理原理的建模技术以及新颖的数值模拟，以测试一种假设的质子穿过胃粘液层运输机制的合理性。结果表明，这种机制能够维持体内实验中看到的极端 pH 梯度，并提出了一种高度稳健的调节机制，可以在面对动态管腔组成时维持这种梯度。
It is generally accepted that the gastric mucus layer provides a protective barrier between the lumen and the mucosa, shielding the mucosa from acid and digestive enzymes and preventing autodigestion of the stomach epithelium. However, the precise mechanisms that contribute to this protective function are still up for debate. In particular, it is not clear what physical processes are responsible for transporting hydrogen protons, secreted within the gastric pits, across the mucus layer to the lumen without acidifying the environment adjacent to the epithelium. One hypothesis is that hydrogen may be bound to the mucin polymers themselves as they are convected away from the mucosal surface and eventually degraded in the stomach lumen. It is also not clear what mechanisms prevent hydrogen from diffusing back toward the mucosal surface, thereby lowering the local pH. In this work we investigate a physics-based model of ion transport within the mucosal layer based on a Nernst-Planck-like equation. Analysis of this model shows that the mechanism of transporting protons bound to the mucus gel is capable of reproducing the trans-mucus pH gradients reported in the literature. Furthermore, when coupled with ion exchange at the epithelial surface, our analysis shows that bicarbonate secretion alone is capable of neutralizing the epithelial pH, even in the face of enormous diffusive gradients of hydrogen. Maintenance of the pH gradient is found to be robust to a wide array of perturbations in both physiological and phenomenological model parameters, suggesting a robust physiological control mechanism.NEW & NOTEWORTHY This work combines modeling techniques based on physical principles, as well as novel numerical simulations to test the plausibility of one hypothesized mechanism for proton transport across the gastric mucus layer. Results show that this mechanism is able to maintain the extreme pH gradient seen in in vivo experiments and suggests a highly robust regulation mechanism to maintain this gradient in the face of dynamic lumen composition.