CELLULAR ACIDIFICATION MECHANISMS: RESPIRATORY DISORDERS

细胞酸化机制：呼吸系统疾病

• 批准号: 3237398
• 负责人: NICOLAOS E MADIAS
• 金额: $ 17.06万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-15 至 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3237398
• 关键词: acid base balance; adenosinetriphosphatase; anions; apical membrane; basolateral membrane; bicarbonates; brush border membrane; carbon dioxide tension; cations; dogs; epithelium; glutamine; hypercapnia; hyperoxia; hyperpnea; hypocapnia; ion transport; laboratory rabbit; membrane permeability; phosphates; renal cortex; renal ischemia /hypoxia; renal tubule; respiratory disorder

It is the overall objective of the present proposal to investigate the cellular representation of the proximal-tubule acidification response to changes in PaCO2 in the rabbit and the dog utilizing membrane-vesicle methodologies. Our understanding of the cellular mechanisms of basal proximal acidification remains incomplete. Moreover, the mechanisms that mediate the adaptation of proximal acidification to respiratory disorders are largely unknown. Therefore, the specific aims of the present proposal are: 1) To further our knowledge on the multitude of the cellular systems of proximal acidification and to characterize their functional expression under normal acid-base conditions. 2) To explore the cellular mechanisms and the time-course of the adaptation of proximal acidification to acute and chronic changes in PaCO2. Changes in PaCO2 induce prompt, directional changes in proximal-tubule acidification. When the alterations in PaCO2 are sustained, additional, much larger, and slowly-evolving changes in the rate of bicarbonate reabsorption ensue that require several days for completion. Given the slowly-evolving nature of the changes in acidification, it is hypothesized that the renal response reflects graded adaptation and/or sequential recruitment of several cellular systems of acidification. It is further hypothesized that these adaptations occur in a coordinated fashion aiming at the maintenance of the intracellular milieu despite brisk changes in transcellular ionic fluxes. Cellular systems to be investigated include Na+-H+ and pH-dependent C1- transporters in brush-border vesicles (BBMV), H+ ATPase in cortical endosomes and BBMV, Na+-HCO3- cotransport in basolateral vesicles (BLMV), and Na+-dependent glutamine and phosphate uptake in BBMV and BLMV. Characterization of these systems in the basal state will be followed by studies during respiratory disorders. Hypercapnia and hypocapnia will be induced in unanesthetized animals within a large environment chamber. The adaptation of the above systems of proximal acidification will be examined at intervals of 1 hour, 1 day, and 5 days from induction of the respiratory disturbance. Preliminary results in support of widespread adaptive changes in the activity of the cellular systems of proximal acidification following 4 days of hypercapnia or 5 days of hypocapnia have been obtained; notably, BLMV Na+-HCO3- cotransport was not altered after only 1 hour of hypercapnia, nor had adaptation occurred in the BBMV Na+-H+ exchanger after 1 day of hypercapnia. These studies may provide important new insights into the mechanism and regulation of proximal acidification under basal conditions as well as during acute and chronic changes in PaCO2.

调查是本提案的总体目标 近端细胞酸化的细胞表示 对兔子和狗利用的paco2变化的响应 膜 - 帮助方法。 我们对 基础近端酸化的细胞机制仍然存在 不完整。 而且，介导的机制 适应呼吸系统疾病的近端酸化是 在很大程度上未知。 因此，当前的具体目的 建议是：1）进一步了解我们对众多的知识 近端酸化和表征的细胞系统 它们在正常酸碱条件下的功能表达。 2） 探索细胞机制和时间顺序 适应急性和慢性变化的近端酸化 在paco2中。 PACO2的变化会引起迅速，定向变化 在近端细胞酸化中。 当Paco2的更改 维持，额外，更大，缓慢发展 随之而来的碳酸氢盐重吸收速率发生了变化 几天完成。 考虑到缓慢发展的本质 酸化的变化，假设肾脏 响应反映了分级适应和/或顺序募集 几种酸化的细胞系统。 进一步 假设这些适应发生在协调中 旨在维护细胞内环境的时尚 尽管跨细胞离子通量变化很大。 细胞 要研究的系统包括Na+ -H+和pH依赖性C1- 刷子囊泡中的转运蛋白（BBMV），H+ ATPase 皮质内体和BBMV，Na+-HCO3-共晶型体 基底外侧囊泡（BLMV）和Na+依赖性谷氨酰胺和 BBMV和BLMV中的磷酸盐摄取。 这些系统以基础状态的表征将是 然后在呼吸系统疾病期间进行研究。 高碳酸盐和 在一个内部的非麻醉动物中将诱导低脑 大环境室。 上述系统的改编 将以1小时的间隔检查近端酸化 诱导呼吸道障碍后的1天和5天。 初步结果支持广泛的自适应变化 近端酸化细胞系统的活性 在4天的高碳酸血症或5天的低碳酸血症已有 获得;值得注意的是，blmv na+-hco3-旋转未改变 仅1小时的高碳酸盐，也没有发生适应 1天后1天后，BBMV NA+ -H+交换器。 这些 研究可能会为机制提供重要的新见解 和调节基础条件下近端酸化为 以及在PACO2的急性和慢性变化期间。