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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.

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

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.

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)
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。