Malondialdehyde-acetaldehyde adducts and lung injury

丙二醛-乙醛加合物与肺损伤

基本信息

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
项目类别：
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

项目摘要

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.

客观与临床关系：我们的长期目标是确定酒精介导的组织损伤在患有酒精疾病的个体（AUD）中观察到的机制，以便更好的早期生物标志物的早期生物标志物可以发展受伤，从而增强方法，以最大程度地减少病原体的易感性并防止肺炎的高成本。研究设计与方法论：滥用酗酒，导致对肺炎的敏感性增加闻名超过200年。 NIAAA出版物指出，住院的酒精使用障碍患者（AUDS）肺炎死亡率有3倍。酒精可以调节先天和自适应肺的免疫系统导致敏感性增加和感染分辨率降低。 20 多年来，我们的研究小组一直是研究酒精对先天性的慢性影响的公认领导者粘毛转运设备提供的免疫力。因为多数（> 90％） auds烟烟，我们选择采用与公共卫生相关的方法来研究香烟和酒精的结合肺损伤作用。在以前的资金周期中，我们确定了肺代表了形成稳定丙二醛醛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肺部的先天病原体清除率。我们发表的初步数据表明，表面活性剂蛋白D（SPD）是一种主要的肺蛋白，当烟气和酒精暴露期间，肺醛浓度升高时，会加入。使用源自NIAAA支持的Colorado肺酒精研究联盟的人类样品，我们发现在肺灌洗巨噬细胞中检测到MAA加合物，并且仅在个体中检测到流体还有吸烟的听。我们观察到，吸烟者降低了肺粘膜Siga和气道上皮的MAA加合物治疗可阻止Siga粘膜分泌的跨神经毒性加工。由于这些重要和新颖的观察，我们现在建议扩展我们对 MAA加合物对肺巨噬细胞，粘膜Siga和SPD的发病机理。我们的总体假设是 MAA加合物在食用酒精和抽烟的个体的肺中独特形成，导致先天肺防御的改变。我们将通过3个目标进行调查：目标1：MAA 加入的肺SPD（MAA-SPD）通过清道夫受体与肺巨噬细胞结合，导致改变巨噬细胞功能； AIM 2：MAA-SPD通过改变上皮细胞来防止肺中的Siga粘膜分泌处理二聚IgA； AIM 3：SPD的MAA收益减少了其抗微生物作用。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

DOI：
10.1002/advs.202103676
发表时间：
2022-03
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
0
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。