Airway pH regulation in asthma

项目概要/摘要 项目2 气道上皮与肾小管上皮一样，表达调节管腔 pH 值的蛋白质。对于 例如，谷氨酰胺酶调节氨的产生；它被 Th1 细胞因子抑制，使气道酸化。 囊性纤维化跨膜调节蛋白调节 HCO3- 向外转运，其缺失会导致 管腔酸化。气道内壁液体 pH 值降低会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呈酸性，这都是因为高二氧化碳 水平和低 pH 层状体；随着气道内层液体向近端扫过，pH 值增加；并削弱了 气道管腔缓冲可能有助于哮喘的病理生理学。特别是，有证据表明 哮喘急性发作与气道腔 pH 值下降有关；糖皮质激素可逆转这种作用。 此外，一些哮喘患者的基线管腔pH值较低。在这里，我们将研究细胞决定因素 气道 pH 值调节。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）绘制哮喘气道体内低 pH 值的位置和影响。我们将学习 最近发现的雄激素（项目 3）对促进有益 pH 调节表达的作用 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。具体来说，我们将实现三个目标。 在目标 1 中，我们将描述气道 pH 值的细胞决定因素。在目标 2 中，我们将绘制上皮 pH 值图 正常气道和哮喘气道。在目标 3 中，我们将测量吸入缓冲液对炎症和炎症的影响 哮喘对 β2 激动剂的反应。在项目结束时，我们预计已经绘制了细胞图 气道上皮 pH 值的调节以及健康和哮喘中气道 pH 值的解剖学变化；我们会 开发了一种新的个性化方法来针对哮喘急性发作患者的 pH 异常。

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.