Acquired CFTR Dysfunction in Alcohol-related Lung Pathology

在美国，酗酒是导致疾病和死亡的主要原因。饮酒损害肺 并增加细菌性肺炎的风险。患有肺炎的酗酒者对 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(MCC)是一种 肺对吸入/吸入性病原体的初级防御机制和过量酒精的损害 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 逆转粘液纤毛功能障碍，增强宿主对感染的免疫力。 最近，我们报道了酒精降低了cftr的离子转运功能，这是一种有缺陷的通道，可以 导致囊性纤维性肺部疾病，其特征也是MCC减少和频繁感染。 支持这一发现的是，酒精性胰腺炎(另一种因果联系的疾病)患者 有CFTR缺陷的人)即使在戒酒后也表现出较低的CFTR活性。值得注意的是， 这些患者都有正常的CFTR遗传学，排除了遗传缺陷的作用，从而证实了 “获得性CFTR功能障碍”现象。 我们在慢性酒精灌胃大鼠模型上的初步研究发现， CFTR离子转运，增加粘液粘度，并显著降低MCC。与他们的 配对饲养的对照组，酒精处理的大鼠未能清除肺炎克雷伯菌，并表现出组织病理学 严重肺炎的证据。我们的数据表明酒精增加了磷酸二酯酶-4B的活性 (PDE4B)专门降解cAMP的酶，导致PKA依赖的磷酸化减少，并 开放CFTR型离子通道。此外，我们还证明了临床使用的PDE4抑制剂罗氟司特是 成功恢复酒精处理细胞的cAMP水平并逆转CFTR功能障碍和粘液 酒精处理的大鼠的异常。 在这些强劲的初步数据的指导下，我们建议追求三个具体目标，以调查 酒精性CFTR功能障碍可能导致细菌性肺炎易感性：(1)确定特异性 CFTR功能降低在酒精引起的粘膜纤毛清除缺陷中的作用。(2)确定 酒精引起CFTR功能障碍的分子机制。(3)确定其临床效益。 逆转酒精诱导的CFTR功能障碍，预防细菌性肺炎。 总而言之，我们提议的研究将通过表征 酒精使用者肺防御功能受损的CFTR功能障碍。这些研究将有可能 发现细菌性肺炎的新分子机制并推进新的治疗方法 减少疾病负担的方法。这些发现可能外推到其他非肺性酒精。 使用胰腺炎、糖尿病和不孕不育等有类似治疗需求和 关于cftr功能障碍致病作用的知识空白。

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.