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: 10553593
• 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/10553593
• 关键词: Acceleration; Address; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Pancreatitis; Alcohols; Anions; Antibiotics; 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; Enzymes; Epithelium; Exclusion; Exhibits; Frequencies; Functional disorder; General Population; Genetic; Histopathology; Hospitalization; Hydration status; Image; Immunity; Impairment; Infection; Infertility; Inflammatory; Inhalation; Inherited; 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; Phosphorylation; Physiological; Pneumonia; Predisposition; Property; Proteins; Pulmonary Cystic Fibrosis; Pulmonary Pathology; Rat Transgene; Rattus; Reporting; Research; Risk; Risk Factors; Role; Surface; Symptoms; Testing; Therapeutic; Time; United States; Viscosity; Vulnerable Populations; airway surface liquid; alcohol abstinence; alcohol effect; alcohol research; alcohol use disorder; antimicrobial; aspirate; burden of illness; chronic alcohol ingestion; cytokine; drinking; experience; improved; in vivo; inhibitor; lung health; lung injury; mortality; mucus clearance; non-genetic; novel; novel therapeutic intervention; overexpression; participant enrollment; pathogen; pharmacologic; phosphodiesterase IV; pneumonia treatment; prevent; pulmonary function; radiological imaging; rational design; 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.

酗酒是美国疾病和死亡的主要原因。饮酒会损害肺 防御并增加了细菌肺炎的风险。肺炎的酒精使用者对 抗生素，经历更严重的症状和更高的死亡率。粘膜纤毛清除率（MCC）是 原发性肺防御机制针对遗传/抽吸病原体，并因过量酒精而受到损害 使用。不幸的是，我们对酒精效应的有限理解阻止了干预措施的发展 逆转粘膜缩减功能障碍和增强宿主免疫免疫力，以防止感染。 最近，我们报道酒精降低了CFTR的离子传输功能，CFTR是有缺陷的渠道 引起囊性纤维化肺病，其特征在于MCC和经常感染。 支持这一发现，患有酒精诱发的胰腺炎的患者（另一种有时是连接的疾病 发现CFTR缺陷）即使在戒酒后也暴露了较低的CFTR活性。值得注意的是， 这些患者的CFTR遗传学正常，不包括遗传缺陷的作用，因此，确认 “获得CFTR功能障碍”的现象。 我们在慢性酒精给药大鼠模型中的初步研究大大降低了 CFTR离子运输，粘液粘度增加，MCC急剧降低。当与他们的 配对对照，酒精处理的大鼠无法清除肺炎克雷伯氏菌，并且表现出组织病理学 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）特异性降解营地的酶，导致PKA依赖性磷酸化降低和 CFTR离子通道的打开。此外，我们证明了一种临床使用的PDE4抑制剂Roflumilast是 成功恢复了经过酒精处理的细胞的营地水平，并逆转CFTR功能障碍和粘液 酒精处理的大鼠异常。 在这些强大的初步数据的指导下，我们建议追求三个特定的目标，以调查如何 酒精诱导的CFTR功能障碍可能会引起对细菌肺炎的敏感性：（1）确定特定 CFTR功能降低对酒精诱导的缺陷的贡献。 （2）确定 算法诱导的CFTR功能障碍的分子机制。 （3）确定 逆转酒精引起的CFTR功能障碍，可预防细菌肺炎。 总的来说，我们提出的研究将通过表征的基本作用来广泛影响该领域 CFTR功能障碍在酒精使用者中妥协肺防御。这些研究将有可能 发现细菌性肺炎的新型分子机制以及提前新治疗 减少疾病的方法。这些发现可能被外推到其他非肺泡酒精 使用胰腺炎，糖尿病和不孕症等疾病，那里有类似的治疗需求和 有关CFTR功能障碍的致病作用的知识差距。