Acquired CFTR Dysfunction in Alcohol-related Lung Pathology

酗酒是美国疾病和死亡的主要原因。饮酒损害肺 防御并增加细菌性肺炎的风险。患有肺炎的酗酒者对药物反应不佳 抗生素，会出现更严重的症状和更高的死亡率。粘膜纤毛清除率（MCC）是 肺部针对吸入/吸入病原体的主要防御机制，会因过量酒精而受损 使用。不幸的是，我们对酒精影响的有限了解阻碍了干预措施的发展 逆转粘膜纤毛功能障碍并增强宿主对感染的免疫力。 最近，我们报道了酒精会降低 CFTR 的离子转运功能，CFTR 是一个有缺陷的通道， 引起囊性纤维化肺病，其特征还包括 MCC 减少和频繁感染。 支持这一发现的是，患有酒精诱发的胰腺炎（另一种与胰腺炎有因果关系的疾病）的患者 具有 CFTR 缺陷的）被发现即使在戒酒后也表现出较低的 CFTR 活性。值得注意的是， 这些患者的 CFTR 遗传学正常，排除了遗传缺陷的影响，因此证实了 “获得性 CFTR 功能障碍”现象。 我们对长期饮酒的大鼠模型的初步研究发现， CFTR 离子传输，增加粘液粘度，并显着降低 MCC。与他们相比时 配对喂养对照组，酒精处理的大鼠未能清除肺炎克雷伯氏菌，并且表现出组织病理学特征 严重肺炎的证据。我们的数据表明酒精会增加磷酸二酯酶 4B 的活性 (PDE4B) 酶，特异性降解 cAMP，导致 PKA 依赖性磷酸化减少， CFTR 离子通道的开放。此外，我们证明罗氟司特（一种临床使用的 PDE4 抑制剂） 成功恢复酒精处理细胞中的 cAMP 水平并逆转 CFTR 功能障碍和粘液 酒精治疗大鼠的异常。 在这些强有力的初步数据的指导下，我们建议追求三个具体目标来研究如何 酒精引起的CFTR功能障碍可能导致细菌性肺炎的易感性：（1）确定具体的 CFTR 功能降低对酒精引起的粘膜纤毛清除缺陷的贡献。 (2) 确定 酒精诱导 CFTR 功能障碍的分子机制。 (3) 确定临床获益 逆转酒精引起的 CFTR 功能障碍，预防细菌性肺炎。 总的来说，我们提出的研究将通过描述以下方面的重要作用来广泛影响该领域： CFTR 功能障碍会损害酒精使用者的肺防御能力。这些研究将有可能 揭示细菌性肺炎的新分子机制并推进新的治疗方法 减轻疾病负担的方法。这些发现可以推断到其他非肺部酒精 使用胰腺炎、糖尿病和不孕症等具有类似治疗需求的疾病，并且 关于 CFTR 功能障碍致病作用的知识差距。

Alcohol abuse is a leading cause of disease and death in the United States. Alcohol consumption impairs lung defense and increases the risk of bacterial pneumonia. Alcohol users with pneumonia respond poorly to antibiotics, experience more severe symptoms and higher rates of mortality. Mucociliary clearance (MCC) is a primary lung defense mechanism against inhaled/aspirated pathogens and is impaired by excessive alcohol use. Unfortunately, our limited understanding of alcohol effects has prevented the development of interventions to reverse mucociliary dysfunction and augment host immunity against infections. Recently, we reported that alcohol reduces ion transport function of CFTR, the defective channel that causes cystic fibrosis lung disease, which is also characterized by diminished MCC and frequent infections. Supporting this discovery, patients with alcohol-induced pancreatitis (another disorder that is causally linked with CFTR defects) were found to exhibit lower CFTR activity even after they abstained from drinking. Of note, these patients had normal CFTR genetics excluding the role of inherited defects and thus, confirming the phenomenon of ‘acquired CFTR dysfunction’. Our preliminary studies in rat model of chronic alcohol administration detected substantially reduced CFTR ion transport, increased mucus viscosity and, dramatically decreased MCC. When compared to their pair-fed controls, alcohol-treated rats failed to clear Klebsiella pneumoniae and, exhibited histopathologic evidence of severe pneumonia. Our data indicate alcohol increases the activity of phosphodiesterase-4B (PDE4B) enzyme that specifically degrades cAMP causing reduced PKA-dependent phosphorylation and opening of CFTR ion channels. Moreover, we demonstrate that roflumilast, a clinically used PDE4 inhibitor, is successful in restoring cAMP levels in alcohol-treated cells and reversing CFTR dysfunction and mucus abnormalities in alcohol-treated rats. Guided by these strong preliminary data, we propose to pursue three Specific Aims to investigate how alcohol-induced CFTR dysfunction may cause susceptibility to bacteria pneumonia: (1) Determine the specific contribution of reduced CFTR function to alcohol-induced defects in mucociliary clearance. (2) Determine the molecular mechanisms underlying alcohol-induced CFTR dysfunction. (3) Determine the clinical benefits of reversing alcohol-induced CFTR dysfunction towards preventing bacterial pneumonia. Collectively, our proposed research will broadly impact the field by characterizing the essential role of CFTR dysfunction in compromising lung defense in alcohol users. These studies will have the potential to uncover novel molecular mechanisms underlying bacterial pneumonia as well as advance new treatment approaches to reduce disease burden. These findings may be extrapolated to other non-pulmonary alcohol use disorders such as pancreatitis, diabetes and infertility, where there are similar therapeutic needs and knowledge gaps regarding the pathogenic role of CFTR dysfunction.