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

• 批准号: 9887977
• 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
• 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/9887977
• 关键词: Address; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Pancreatitis; Alcohols; Anions; Antibiotics; Aspirate substance; Bacteria; 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; Diagnostic radiologic examination; Diet; Disease; Dose; Enrollment; Enzymes; Epithelial; Epithelium; Exhibits; Frequencies; Functional disorder; General Population; Genetic; Health; 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; Respiratory physiology; 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; design; drinking; experience; improved; in vivo; inhibitor/antagonist; lung injury; mortality; mucus clearance; non-genetic; novel; overexpression; pathogen; phosphodiesterase IV; prevent; recurrent infection; restoration; therapy development; viscoelasticity

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。饮酒伤肺 防御和增加细菌性肺炎的风险。患有肺炎的酒精使用者 使用抗生素，症状更严重，死亡率更高。粘膜纤毛清除率（MCC）是一种 对吸入/吸入病原体的主要肺防御机制，并因过量酒精而受损 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和增强宿主对感染的免疫力。 最近，我们报道了酒精降低CFTR的离子转运功能，CFTR是一种有缺陷的通道， 导致囊性纤维化肺病，其特征还在于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缺陷的人）甚至在他们戒酒后也表现出较低的CFTR活性。值得注意的是， 这些患者具有正常的CFTR遗传学，排除了遗传缺陷的作用，因此，证实了 “获得性CFTR功能障碍”现象。 我们的初步研究，在大鼠模型的慢性酒精管理检测大大减少 CFTR离子转运，增加粘液粘度，并显着降低MCC。与他们的相比， 配对喂养的对照组，酒精处理的大鼠未能清除肺炎克雷伯氏菌，并表现出组织病理学 严重肺炎的证据。我们的数据表明，酒精增加磷酸二酯酶-4B的活性 （PDE 4 B）酶，其特异性降解cAMP，导致减少的PKA依赖性磷酸化， 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PDE 4抑制剂， 成功恢复酒精处理的细胞中的cAMP水平并逆转CFTR功能障碍和粘液 酒精处理大鼠的异常。 在这些强有力的初步数据的指导下，我们提出了三个具体目标，以调查如何 酒精诱导的CFTR功能障碍可能导致对细菌性肺炎的易感性：（1）确定特异性CFTR， CFTR功能降低对酒精诱导的粘膜纤毛清除缺陷的贡献。(2)确定 酒精诱导的CFTR功能障碍的分子机制。(3)确定临床受益 逆转酒精诱导的CFTR功能障碍以预防细菌性肺炎。 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功能障碍损害酒精使用者的肺防御。这些研究将有可能 揭示细菌性肺炎潜在的新分子机制以及先进的新治疗方法 减少疾病负担的方法。这些发现可以外推到其他非肺部酒精 使用疾病，如胰腺炎，糖尿病和不孕症，其中有类似的治疗需求， 关于CFTR功能障碍的致病作用的知识缺口。