Acquired CFTR Dysfunction in Alcohol-related Lung Pathology

酒精相关肺部病理学中的获得性 CFTR 功能障碍

基本信息

批准号：
10316995
负责人：
S.Vamsee Raju
金额：
$ 38.61万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316995
关键词：
Address Affect Alcohol abuse Alcohol consumption Alcoholic Pancreatitis Alcohols Anions Antibiotics Aspirate substance Bacterial Counts Bacterial Infections Bacterial Pneumonia Biological Assay Cause of Death Cells Cessation of life Chronic Clinical Colorado Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cystic Fibrosis Transmembrane Conductance Regulator Data Defect Defense Mechanisms Diabetes Mellitus Diagnosis Diet Disease Dose Enrollment Enzymes Epithelial Exhibits Frequencies Functional disorder General Population Genetic Histopathology Hospitalization Hydration status Image Immunity Impairment Infection Infertility Inflammatory Inhalation Intervention Ion Channel Ion Transport Klebsiella pneumoniae Knock-out Knowledge Link Lung Lung infections Measures Mediating Messenger RNA Metabolic Clearance Rate Modeling Molecular Monitor Morbidity - disease rate Mucociliary Clearance Mucous body substance Optical Coherence Tomography Outcome PDE4B Pancreatitis Pathogenicity Patients Pharmaceutical Preparations Pharmacology Phosphorylation Physiological Pneumonia Predisposition Property Proteins Pulmonary Cystic Fibrosis Pulmonary Pathology Rattus Reporting Research Risk Risk Factors Role Surface Symptoms Testing Therapeutic Time Transgenic Organisms United States Viscosity Vulnerable Populations airway surface liquid alcohol abstinence alcohol effect alcohol research alcohol use disorder antimicrobial burden of illness chronic alcohol ingestion cytokine drinking experience improved in vivo inhibitor lung health lung injury mortality mucus clearance non-genetic novel overexpression pathogen phosphodiesterase IV pneumonia treatment prevent pulmonary function radiological imaging rational design recurrent infection restoration therapy development viscoelasticity

项目摘要

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.

在美国，酗酒是导致疾病和死亡的主要原因。饮酒会损害肺部。防御并增加细菌性肺炎的风险。患有肺炎的饮酒者对此反应不佳。抗生素，会出现更严重的症状和更高的死亡率。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，导致囊性纤维化肺病，其特点还包括 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）的患者值得注意的是，患有 CFTR 缺陷的人即使在戒酒后也表现出较低的 CFTR 活性。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，与它们相比，CFTR 离子传输、粘液粘度增加并且 MCC 显着降低。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，并且显示组织病理学我们的数据表明，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，此外，我们证明临床上使用的 PDE4 抑制剂罗氟司特是一种开放 CFTR 离子通道的药物。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易感性：（1）确定具体原因 (2) 确定酒精引起的 CFTR 功能障碍的分子机制 (3) 确定临床益处。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。揭示细菌性肺炎的新分子机制并推进新的治疗方法这些发现可以推广到其他非肺部酒精。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。