Airway Injury Caused by MAA Adducts

MAA 加合物引起的气道损伤

• 批准号: 8299082
• 负责人: Todd A Wyatt
• 金额: $ 31.47万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299082
• 关键词: Acetaldehyde; Address; Agonist; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Aldehydes; Animals; Asthma; Bacterial Infections; Binding; Breathing; Cell Line; Cells; Chronic; Chronic Bronchitis; Chronic lung disease; Cigarette; Cilia; Clinical; Consumption; Cyclic Nucleotides; Disease; Epithelial Cells; Etiology; Exposure to; Functional disorder; Health; Hybrids; Immune; Impairment; In Vitro; Infection; Inflammatory; Injury; Liver Fibrosis; Lung; Lung Inflammation; Lung Lavage Fluid; Lung diseases; Malondialdehyde; Mediating; Membrane; Modality; Modeling; Motor; Mucociliary Clearance; Mus; Nitric Oxide; Pathologic; Phosphorylation; Phosphotransferases; Play; Production; Protein Binding; Proteins; Public Health; Pulmonary Emphysema; Receptor Activation; Reporting; Research; Role; Signal Transduction Pathway; Small Interfering RNA; Smoke; Smoker; Smoking; Stimulus; Testing; Time; Toxin; adduct; airway epithelium; alcohol effect; alcohol exposure; base; cell motility; cigarette smoking; cigarette smoking; disorder prevention; feeding; hepatic necrosis; in vivo; inhibitor/antagonist; injured; injured airway; innovation; interest; lung injury; mouse model; particle; pathogen; problem drinker; protein activation; protein kinase C epsilon; receptor binding; research study; response; restoration; scavenger receptor; therapeutic target

DESCRIPTION (provided by applicant): Our overall interest is chronic inflammatory lung disease mechanisms in the context of combined alcohol use and cigarette smoking. Some studies report that up to 30% of smokers are heavy alcohol users. The airways of smokers who drink alcohol are more susceptible to bacterial infection and colonization, suggesting a compromise in the protective mucociliary apparatus. We hypothesize that prolonged exposure to the unique combination of cigarette smoking and ethanol consumption results in the impairment of the mucociliary transport apparatus. Large concentrations of malondialdehyde and acetaldehyde are found in the lungs of smoking alcoholics. Accumulation of lung aldehydes results in formation of hybrid aldehyde adducted proteins that produce pro-inflammatory effects parallel to liver necrosis and fibrosis. One such airway protein adduct is the malondialdehyde-acetaldehyde (MAA) adduct. The major mechanism of protein adduct binding to cells is via membrane scavenger receptors. We will explore the relationship between MAA adducts, alcohol consumption, and cigarette smoking with the following specific aims: 1) Determine if co-exposure to the combination of cigarette smoke and alcohol results in unique alterations to the mucociliary transport apparatus. 2) Determine if co-exposure to smoke and alcohol results in the formation of MAA adducts. 3) Identify the scavenger receptor that binds MAA-adducted protein to airway epithelium. 4) Determine the mechanism of action for MAA adduct-mediated cilia slowing. With these aims, we will establish an association between alcohol consumption, cigarette smoking and cilia dysfunction as mediated by MAA adduct formation. While the etiology of chronic inflammatory lung diseases is largely unknown and likely multi-faceted, the study of MAA adduct formation is an innovative approach to the pathologic interaction between cigarette smoke and alcohol. PUBLIC HEALTH SIGNIFICANCE: This study greatly impacts public health. It has long been clinically known that chronic lung disease and lung infections are much more severe in alcoholics. Nearly all alcoholics smoke cigarettes. Our studies seek to define the mechanisms that injure proper lung clearance and health under conditions of combined smoke and alcohol consumption. Understanding the mechanisms of such injury will define the subsequent treatment modalities to restoring normative lung mucociliary clearance function and directly address disease prevention in the approximately 20 million US alcoholics.

描述（由申请人提供）：我们的总体兴趣是饮酒和吸烟联合作用下的慢性炎症性肺病机制。一些研究报告称，高达 30% 的吸烟者是重度饮酒者。饮酒的吸烟者的气道更容易受到细菌感染和定植，这表明保护性粘液纤毛装置受到损害。我们假设，长期接触吸烟和乙醇消耗的独特组合会导致粘膜纤毛运输装置受损。在吸烟酗酒者的肺部发现了高​​浓度的丙二醛和乙醛。肺醛的积累导致杂合醛加合蛋白的形成，其产生与肝坏死和纤维化平行的促炎作用。一种这样的气道蛋白加合物是丙二醛-乙醛（MAA）加合物。蛋白质加合物与细胞结合的主要机制是通过膜清道夫受体。我们将探讨 MAA 加合物、饮酒和吸烟之间的关系，具体目标如下：1) 确定同时暴露于香烟烟雾和酒精的组合是否会导致粘膜纤毛运输装置发生独特的改变。 2) 确定同时接触烟雾和酒精是否会导致 MAA 加合物的形成。 3) 鉴定将 MAA 加合蛋白与气道上皮结合的清道夫受体。 4) 确定 MAA 加合物介导的纤毛减慢的作用机制。出于这些目标，我们将建立饮酒、吸烟和 MAA 加合物形成介导的纤毛功能障碍之间的关联。虽然慢性炎症性肺病的病因很大程度上未知，并且可能是多方面的，但 MAA 加合物形成的研究是研究香烟烟雾和酒精之间病理相互作用的一种创新方法。公共卫生意义：这项研究极大地影响了公共卫生。临床上早已知道，酗酒者的慢性肺病和肺部感染要严重得多。几乎所有酗酒者都吸烟。我们的研究旨在确定在吸烟和饮酒相结合的情况下损害正常肺部清除和健康的机制。了解这种损伤的机制将确定恢复正常肺粘膜纤毛清除功能的后续治疗方式，并直接解决美国约 2000 万酗酒者的疾病预防问题。

项目成果

Convergence of 3',5'-cyclic adenosine 5'-monophosphate/protein kinase A and glycogen synthase kinase-3beta/beta-catenin signaling in corpus luteum progesterone synthesis.

• DOI: 10.1210/en.2009-0771
• 发表时间: 2009-11
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Lynn Roy;C. A. McDonald;Chao Jiang;D. Maroni;A. Zeleznik;T. Wyatt;X. Hou;John S. Davis

Alcohol, Aldehydes, Adducts and Airways.

• DOI: 10.3390/biom5042987
• 发表时间: 2015-11-05
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Sapkota M;Wyatt TA
• 通讯作者: Wyatt TA

Dietary diallyl disulfide supplementation attenuates ethanol-mediated pulmonary vitamin D speciate depletion in C57Bl/6 mice.

膳食二烯丙基二硫化物补充剂可减轻 C57Bl/6 小鼠中乙醇介导的肺维生素 D 物种消耗。

• DOI: 10.1186/s40795-015-0012-z
• 发表时间: 2015
• 期刊: BMC nutrition
• 影响因子: 2
• 作者: McCaskill,MichaelL;Hottor,HenryT;Sapkota,Muna;Wyatt,ToddA
• 通讯作者: Wyatt,ToddA

Malondialdehyde-Acetaldehyde-Adducted Surfactant Protein Alters Macrophage Functions Through Scavenger Receptor A.

• DOI: 10.1111/acer.13248
• 发表时间: 2016-12
• 期刊: Alcoholism, clinical and experimental research
• 作者: Sapkota M;Kharbanda KK;Wyatt TA
• 通讯作者: Wyatt TA

RACK1, a PKC targeting protein, is exclusively localized to basal airway epithelial cells.

RACK1 是一种 PKC 靶向蛋白，专门定位于基底气道上皮细胞。

• DOI: 10.1369/jhc.7a7249.2007
• 发表时间: 2008
• 期刊: The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
• 作者: Slager,RebeccaE;Devasure,JaneM;Pavlik,JaquelineA;Sisson,JosephH;Wyatt,ToddA
• 通讯作者: Wyatt,ToddA