Malondialdehyde-acetaldehyde adducts and lung injury

丙二醛-乙醛加合物与肺损伤

• 批准号: 9898239
• 负责人: Todd A Wyatt
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898239
• 关键词: Acetaldehyde; Adaptive Immune System; Address; Alcohol abuse; Alcohol consumption; Alcohols; Aldehydes; Alveolar; Binding; Binding Proteins; Biological; Biological Markers; Bronchoalveolar Lavage; CYP2E1 gene; Chronic; Cigarette; Cigarette Smoker; Cilia; Clinical; Collectins; Colorado; Consumption; Data; Disease; Environment; Epithelial; Epithelial Cells; Epithelium; Funding; Goals; Human; Immunity; Immunoglobulin A; Immunoglobulins; Impairment; Incubators; Individual; Infection; Inflammatory Response Pathway; Inhalation; Injury; Irrigation; Lipid Peroxidation; Liquid substance; Lung; Lung Lavage Fluid; Lung diseases; Lung infections; Malondialdehyde; Mediating; Mucociliary Clearance; Mucous Membrane; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Oral Ingestion; Pathogenesis; Phagocytosis; Pneumonia; Predisposition; Production; Proteins; Public Health; Publications; Publishing; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactant-Associated Proteins; Research; Research Design; Research Methodology; Resolution; Sampling; Secretory Immunoglobulin A; Severities; Smoke; Smoker; Smoking; Tobacco; Transforming Growth Factor beta; Translating; Veterans; Virus; adduct; airway epithelium; alcohol abuser; alcohol effect; alcohol exposure; alcohol research; alcohol use disorder; antimicrobial; cigarette smoke; cigarette smoking; cost; cytokine; dimer; disorder risk; drinking; early detection biomarkers; hybrid protein; improved; in vivo; inflammatory lung disease; lung injury; macrophage; mortality risk; mouse model; novel; pathogen; prevent; problem drinker; scavenger receptor; tissue injury; transcytosis

Objective & Clinical Relationship: Our long-term goal is to identify the alcohol-mediated tissue injury mechanisms observed in individuals with alcohol-use disorders (AUDs) so that better early biomarkers of injury can be developed leading to enhanced approaches to minimize pathogen susceptibility and prevent the high costs of pneumonia. Research Design & Methodology: Alcohol abuse causing increased susceptibility to pneumonia has been known for over 200 years. NIAAA publications state that hospitalized individuals with alcohol use disorders (AUDs) have a 3-fold risk of mortality from pneumonia. Alcohol modulates both the innate and adaptive immune systems of the lung resulting in increased susceptibility and decreased resolution of infection. For 20 years, our research group has been a recognized leader in studying the chronic effects of alcohol on the innate immunity provided by the mucociliary transport apparatus. Because the majority (>90%) individuals with AUDs smoke cigarettes, we have chosen to take the public health relevant approach of studying the combination lung injury effects of both cigarettes and alcohol. In our previous funding cycle, we identified that the lungs represent a unique environment for the formation of stable malondialdehyde-acetaldehyde protein adducts (MAA adducts), but only under conditions of combined cigarette smoke and alcohol exposure. These MAA adducts cause airway epithelial cell cilia slowing and impair the innate pathogen clearance from the lung. Our published and preliminary data demonstrate that surfactant protein D (SPD) is a major lung protein that gets adducted when lung aldehyde concentrations are elevated during combined smoke and alcohol exposure. Using human samples derived from the NIAAA-supported Colorado Pulmonary Alcohol Research Consortium, we have found that MAA adducts are detected in the lung lavage macrophages and fluid only in individuals with AUDs who also smoke. We have observed that the AUD smokers have decreased lung mucosal sIgA and that MAA adduct treatment of airway epithelium blocks transcytotic processing of sIgA mucosal secretion. Because of these important and novel observations, we now propose to extend our research on the pathogenesis of the MAA adduct to lung macrophages, mucosal sIgA, and SPD. Our overall hypothesis is that MAA adducts uniquely form in the lungs of individuals who consume both alcohol and smoke cigarettes, leading to alterations in innate lung defense. We will investigate this hypothesis through 3 aims: Aim 1: MAA adducted lung SPD (MAA-SPD) binds to lung macrophages via scavenger receptor A leading to alterations in macrophage function; Aim 2: MAA-SPD prevents sIgA mucosal secretion in lung by altering epithelial cell processing of dimerized IgA; and Aim 3: MAA adduction of SPD decreases its anti-microbial action.

目的与临床关系：我们的长期目标是确定酒精介导的组织损伤 在酒精使用障碍（AUDs）患者中观察到的机制， 损伤可以导致增强的方法，以最大限度地减少病原体的易感性和预防 肺炎的高成本。 研究设计和方法：酒精滥用导致肺炎易感性增加， 已经有200多年的历史了NIAAA出版物指出，患有酒精使用障碍的住院患者 （AUD）有3倍的肺炎死亡风险。酒精调节先天和适应性 肺的免疫系统，导致易感性增加和感染消退降低。了20 多年来，我们的研究小组一直是研究酒精对先天性心脏病慢性影响的公认领导者。 由粘液纤毛运输装置提供的免疫力。因为大多数人（>90%） 鉴于澳大利亚青少年吸烟，我们选择了与公共卫生相关的方法， 香烟和酒精的联合肺损伤效应。在上一个融资周期中，我们发现， 肺代表了形成稳定的丙二醛-乙醛蛋白的独特环境 加合物（MAA加合物），但仅在香烟烟雾和酒精暴露相结合的条件下。这些 MAA加合物导致气道上皮细胞纤毛减慢并损害先天性病原体从肺中的清除。 我们发表的和初步的数据表明，表面活性蛋白D（SPD）是一种主要的肺蛋白， 当肺醛浓度在吸烟和酒精联合暴露期间升高时会内收。 使用来自NIAAA支持的科罗拉多肺酒精研究联盟的人类样本， 我们发现MAA加合物仅在个体的肺灌洗液巨噬细胞和液体中检测到 也抽烟的人我们观察到AUD吸烟者肺粘膜sIgA降低， MAA加合物处理气道上皮阻断了sIgA粘膜分泌的胞吞作用。 由于这些重要而新颖的观察结果，我们现在建议将我们的研究扩展到 肺巨噬细胞、粘膜sIgA和SPD的MAA加合物的发病机制。我们的总体假设是 MAA加合物在饮酒和吸烟的人的肺中独特地形成， 导致先天肺防御的改变。我们将通过3个目标来研究这一假设：目标1：MAA 内收肺SPD（MAA-SPD）通过清道夫受体A与肺巨噬细胞结合，导致肺巨噬细胞内分泌的改变。 目的2：MAA-SPD通过改变肺上皮细胞， 目的3：SPD的MAA加合降低了其抗微生物作用。

项目成果

Perfluorocarbon Nanoemulsions Enhance Therapeutic siRNA Delivery in the Treatment of Pulmonary Fibrosis.

全氟化合物纳米乳剂在治疗肺纤维化时增强了治疗性siRNA递送。

• DOI: 10.1002/advs.202103676
• 发表时间: 2022-03
• 期刊: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
• 作者: Ding L;Tang S;Tang W;Mosley DD;Yu A;Sil D;Romanova S;Bailey KL;Knoell DL;Wyatt TA;Oupický D
• 通讯作者: Oupický D

An association between MMP-9 and impaired T cell migration in ethanol-fed BALB/c mice infected with respiratory syncytial virus-2A.

MMP-9 与感染呼吸道合胞病毒 2A 的乙醇喂养 BALB/c 小鼠中 T 细胞迁移受损之间的关联。

• DOI: 10.1016/j.alcohol.2018.09.009
• 发表时间: 2019
• 期刊: Alcohol (Fayetteville, N.Y.)
• 作者: Warren,KristiJ;Poole,JillA;Sweeter,JeneaM;DeVasure,JaneM;Wyatt,ToddA
• 通讯作者: Wyatt,ToddA

Dual Substance Use of Electronic Cigarettes and Alcohol.

• DOI: 10.3389/fphys.2020.593803
• 发表时间: 2020
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Wetzel TJ;Wyatt TA
• 通讯作者: Wyatt TA

Organic barn dust inhibits surfactant protein D production through protein kinase-c alpha dependent increase of GPR116.

有机谷仓灰尘通过 GPR116 的蛋白激酶 C α 依赖性增加抑制表面活性剂蛋白 D 的产生。

• DOI: 10.1371/journal.pone.0208597
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Schneberger,David;DeVasure,JaneM;Kirychuk,ShelleyA;Wyatt,ToddA
• 通讯作者: Wyatt,ToddA

Alcohol and lung derangements: An overview.

酒精和肺部紊乱：概述。

• DOI: 10.1016/j.alcohol.2019.01.002
• 发表时间: 2019
• 期刊: Alcohol (Fayetteville, N.Y.)
• 作者: Yeligar,SamanthaM;Wyatt,ToddA
• 通讯作者: Wyatt,ToddA