Airway pH regulation in asthma

哮喘气道 pH 值调节

• 批准号: 10269973
• 负责人: Benjamin Gaston
• 金额: $ 30.26万
• 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/10269973
• 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; Epithelial Cells; 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; 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.

项目摘要/摘要 项目2 与肾小管上皮一样，呼吸道上皮也表达调节管腔pH值的蛋白质。为 例如，谷氨酰胺酶调节氨的产生；它被Th1细胞因子抑制，使呼吸道酸化。 囊性纤维化跨膜调节蛋白调节向外的HCO3转运，其缺失导致 管腔酸化。降低呼吸道衬里液体的pH值可促进呼吸道炎症以及病毒性肺炎和 细菌复制。我们假设呼吸道远端上皮表面是酸性的，这两者都是因为高二氧化碳。 水平和低pH板层小体；pH值随着呼吸道衬里液体被近端扫过而增加；以及受损 气道腔缓冲在哮喘的病理生理学中起重要作用。特别是，有证据表明， 急性哮喘加重与呼吸道管腔pH值下降有关；糖皮质激素可逆转这种影响。 此外，一些哮喘患者基线时的管腔pH值较低。在这里，我们将研究细胞决定因素 呼吸道pH调节的影响。我们将利用呼吸道pH值的影响来改变气道NO代谢，并 生物活性(项目1)绘制低pH值在体内哮喘呼吸道的位置和影响。我们会研究 新近发现的雄激素促进有益pH调节表达的作用(项目3) 哮喘中的酶。最后，我们将研究吸入缓冲液对哮喘患者的潜在益处。 病情加重。具体地说，我们将实现三个目标。 在目标1中，我们将描述呼吸道pH的细胞决定因素。在目标2中，我们将绘制出上皮细胞的pH值 正常和哮喘的呼吸道。在目标3中，我们将测量吸入缓冲液对炎症和 哮喘患者对β-2激动剂的反应。在项目结束时，我们预计已经绘制了两个细胞 在健康和哮喘中调节呼吸道上皮pH和呼吸道pH的解剖变化；我们将 已经开发出一种新的、个性化的方法来针对哮喘恶化患者的pH异常。