Airway pH regulation in asthma

哮喘气道 pH 值调节

• 批准号: 10662247
• 负责人: Benjamin Gaston
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662247
• 关键词: Acute; Affect; Agonist; Ammonia; Anatomy; Androgens; Asthma; Attenuated; Bicarbonates; Buffers; Carbon Dioxide; Cell Culture Techniques; Cell surface; Cystic Fibrosis; Distal; Enzymes; Epithelial Cells; Epithelium; Exhalation; Functional disorder; Glucocorticoids; Glutaminase; Health; Human; IL17 gene; IL6 gene; In Vitro; Inflammation; Inflammatory; Inhalation; Interleukin-13; Interleukin-4; Kidney; Lactate Dehydrogenase; Liquid substance; Location; Maps; Measures; Membrane; Metabolism; Oxidases; Oxidoreductase; Patients; Production; Proteins; Protons; Regulation; Respiratory Tract Infections; S-Nitrosoglutathione; Surface; Testing; Tubular formation; Variant; Viral; airway epithelium; airway inflammation; alveolar lamellar body; asthma exacerbation; asthmatic airway; asthmatic patient; beta-2 Adrenergic Receptors; carbonate dehydratase; cell growth regulation; cytokine; dehydroepiandrosterone; experience; falls; genetic regulatory protein; improved; in vivo; injured airway; innovation; novel strategies; personalized approach; protein expression; response; vacuolar H+-ATPase; voltage

PROJECT SUMMARY/ABSTRACT Project 2 The airway epithelium, like the renal tubular epithelium, expresses proteins that regulate luminal pH. For example, glutaminase regulates ammonia production; it is inhibited by Th1 cytokines, acidifying the airway. Cystic fibrosis transmembrane regulatory protein regulates outward HCO3- transit, and its absence results in luminal acidification. Decreased airway lining fluid pH can promote airway inflammation as well as viral and bacterial replication. We hypothesize that the distal airway epithelial surface is acidic, both because of high CO2 levels and low- pH lamellar bodies; that pH increases as airway lining fluid is swept proximally; and that impaired airway luminal buffering can contribute to the pathophysiology of asthma. In particular, there is evidence that acute asthma exacerbations are associated with a fall in airway luminal pH; an effect reversed by glucocorticoids. Further, some asthma patients have a low luminal pH at baseline. Here, we will study the cellular determinants of airway pH regulation. We will make use of the effect of airway pH to alter airway NO metabolism and bioactivities (Project 1) to map the location and effects of low pH in the asthmatic airway in vivo. We will study the recently discovered effects of androgens (Project 3) to promote the expression of beneficial pH regulatory enzymes in asthma. Finally, we will study the potential benefit of inhaled buffer in asthma patients with exacerbations. Specifically, we will carry out three aims. In Aim 1, we will characterize the cellular determinants of airway pH. In Aim 2, we will map the epithelial pH of the normal and asthmatic airway. In Aim 3, we will measure the effect of inhaled buffer on inflammation and response to β2 agonists in asthma. At the end of the project, we anticipate having mapped both the cellular regulation of airway epithelial pH and the anatomic variations in airway pH in health and in asthma; and we will have developed a new, personalized approach to target pH abnormalities in patients with asthma exacerbations.

项目总结/摘要 计划2 气道上皮，如肾小管上皮，表达调节管腔pH的蛋白质。 例如，谷氨酰胺酶调节氨的产生;它被Th 1细胞因子抑制，使气道酸化。 囊性纤维化跨膜调节蛋白调节向外的HCO 3转运，其缺失导致 管腔酸化降低的气道衬里液pH可促进气道炎症以及病毒和 细菌复制我们假设远端气道上皮表面是酸性的，这是因为高CO2 水平和低pH值板层体;当气道衬里液被近端扫过时pH值升高; 气道腔缓冲可导致哮喘的病理生理学。特别是，有证据表明， 急性哮喘恶化与气道腔pH值下降有关;糖皮质激素可逆转该效应。 此外，一些哮喘患者在基线时具有低管腔pH。在这里，我们将研究细胞决定因素 气道pH调节。我们将利用气道pH值的影响来改变气道NO代谢， 生物活性（项目1），以绘制哮喘气道中低pH的体内位置和影响。我们将研究 最近发现的雄激素的作用（项目3），以促进表达有益的pH调节 哮喘中的酶最后，我们将研究吸入缓冲剂对哮喘患者的潜在益处， 加重具体而言，我们将实现三个目标。 在目标1中，我们将描述气道pH的细胞决定因素。在目标2中，我们将绘制 正常和哮喘气道。在目标3中，我们将测量吸入缓冲液对炎症的影响， 哮喘对β2受体激动剂的反应。在项目结束时，我们预计已经绘制了细胞 调节气道上皮pH值和在健康和哮喘气道pH值的解剖变异;我们将 他们开发了一种新的个性化方法来治疗哮喘急性发作患者的pH值异常。