Ethanol Effects on Recovery after Injury

乙醇对受伤后恢复的影响

基本信息

批准号：
7674857
负责人：
ELIZABETH J. KOVACS
金额：
$ 2.67万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7674857
关键词：
Abbreviations Accidents Accounting Acute Acute Lung Injury Admission activity Adult Respiratory Distress Syndrome Alcohol consumption Alcohols Alveolar Alveolar Macrophages Alveolar wall Animals Anti-Inflammatory Agents Anti-inflammatory Architecture Blood Circulation Blood Vessels Blood alcohol level measurement Body Surface Area Bronchoalveolar Lavage Burn injury Capillary Endothelial Cell Cause of Death Cell Adhesion Molecules Cells Chronic Collagen Colony-forming units Control Groups Data Deposition Estradiol Estrogen Receptors Estrogens Ethanol Event Extravasation Fibroblasts Fire - disasters Goals Heart Diseases Hematoxylin and Eosin Staining Method Hospitals IL8 gene Immunoglobulin G In Vitro Individual Infection Control Infiltration Inflammation Inflammatory Inflammatory Response Injury Intercellular adhesion molecule 1 Interleukin-1 Interleukin-10 Interleukin-6 Interleukin-8 Knock-out Lead Leukocytes Life Ligands Lipopolysaccharides Liquid substance Lung Macrophage Inflammatory Protein-1 Malignant Neoplasms Mitogen Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mitogens Modeling Monocyte Chemoattractant Protein-1 Morbidity - disease rate Multiple Organ Failure Mus Myosin Light Chain Kinase Neutrophil Infiltration Organ Outcome Patients Peroxidase Platelet-Derived Growth Factor Pneumonia Production Proteins Public Health Pulmonary Edema Pulmonary Pathology Recovery Relative (related person)Reporting Respiratory physiology Risk Factors Role Source TNFRSF1A gene Testing Time Toll-like receptors Transforming Growth Factor beta Transforming Growth Factors Treatment Protocols Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States Work alcohol effect alcohol exposure base chemokine cost cytokine feeding fluorouracil/semustine/vincristine protocol human TNF protein improved in vivo injured macrophage macrophage inflammatory protein 2 monocyte mortality problem drinker response to injury subcutaneous vascular bed

项目摘要

DESCRIPTION (provided by applicant): The overall objective of the proposed studies is to define the mechanism by which the pulmonary consequences following burn injury are exacerbated by ethanol exposure. Nearly 100,000 people each year are admitted to hospitals due to burn injury and about half of those patients are reported to have been drinking ethanol. Ethanol exposure is not only a risk factor for the events that lead up to the fire-related accidents, but also leads to increased morbidity and mortality among burned patients. The lung is a critical organ, which is particularly sensitive to remote injury. This is, in part, because of the organ's extensive vascular bed and delicate alveolar architecture. Acute lung injury results from the overproduction of pro-inflammatory cytokines, which are generated both systemically and locally (in the lung) in response to injury, such as burn, and is amplified if alcohol is present at the time of injury. We hypothesize that the complications which arise in ethanol-exposed individuals who sustain burn injury are triggered by an overexuberant pulmonary inflammatory response. Herein, we propose to employ both in vivo and in vitro approaches to determine the mechanism(s) responsible for the increased magnitude and duration of pulmonary pathology in burn patients with or without prior ethanol consumption, which are paralleled in our well established murine model of acute ethanol exposure and burn injury. Additionally, we plan to define the roles of key pro-inflammatory and fibrogenic cytokines produced locally and systemically during the early and later post-burn period. We will examine the cellular sources of these factors to determine the extent to which the alveolar macrophage dictates the outcome by virtue of its cytokine production capacity. Finally, we plan to exploit our earlier observation that both systemic and organ-specific inflammatory responses seen after ethanol and burn injury can be ameliorated following systemic treatment with anti-inflammatory regimens, including 17?-estradiol. In the proposed studies, we will test whether this treatment will reduce the pulmonary inflammation seen in mice given the combined insult of ethanol exposure followed by burn injury, relative to either insult alone. It is anticipated that these studies will provide valuable information, which can be used to develop more efficacious therapies for the treatment of ethanol-exposed, burn patients. PUBLIC HEALTH RELEVANCE In the United States, injury remains the primary cause of death during the first four decades of life, outnumbering all other causes of death, including heart disease and cancer, and accounts for millions of disabling injuries per year and an annual cost of over $130 billion. The importance of ethanol as a complicating factor regarding injury is underscored by the finding that up to 50% of burn patients have detectable levels of ethanol in their circulation at the time of admission to the hospital. These patients, the majority of whom are not chronic alcoholics, but rather consumed alcohol on an acute or binge basis, suffer from increased morbidity and mortality compared with that of non-alcohol-consuming subjects with similar injuries.

描述（由申请人提供）：拟议研究的总体目标是确定乙醇暴露加剧烧伤后肺部后果的机制。每年有近 10 万人因烧伤而入院治疗，据报道其中约一半患者曾饮用乙醇。乙醇暴露不仅是导致火灾相关事故的危险因素，而且还会导致烧伤患者的发病率和死亡率增加。肺是一个重要的器官，对远程损伤特别敏感。部分原因是该器官拥有广泛的血管床和精致的肺泡结构。急性肺损伤是由于促炎性细胞因子过度产生所致，促炎性细胞因子是因损伤（例如烧伤）而在全身和局部（肺部）产生的，如果损伤时存在酒精，则促炎性细胞因子会被放大。我们假设，接触乙醇的烧伤患者出现的并发症是由过度旺盛的肺部炎症反应引发的。在此，我们建议采用体内和体外方法来确定烧伤患者肺部病理学程度和持续时间增加的机制，无论其是否先前消耗过乙醇，这在我们完善的小鼠模型中是平行的。急性乙醇暴露和烧伤。此外，我们计划确定烧伤后早期和后期局部和全身产生的关键促炎和纤维形成细胞因子的作用。我们将检查这些因素的细胞来源，以确定肺泡巨噬细胞凭借其细胞因子生产能力在多大程度上决定结果。最后，我们计划利用我们早期的观察结果，即在使用包括17β-雌二醇在内的抗炎方案进行全身治疗后，乙醇和烧伤后出现的全身和器官特异性炎症反应都可以得到改善。在拟议的研究中，我们将测试这种治疗是否会减少小鼠在乙醇暴露和烧伤联合损伤（相对于单独的损伤）中观察到的肺部炎症。预计这些研究将提供有价值的信息，可用于开发更有效的疗法来治疗暴露于乙醇的烧伤患者。公共卫生相关性在美国，伤害仍然是生命前四十年死亡的主要原因，其数量超过了包括心脏病和癌症在内的所有其他死亡原因，每年造成数以百万计的致残伤害和每年的医疗费用。超过1300亿美元。多达 50% 的烧伤患者在入院时循环中可检测到乙醇含量，这一发现强调了乙醇作为导致损伤的复杂因素的重要性。这些患者大多数不是慢性酗酒者，而是急性或暴饮暴食的人，与具有类似损伤的不饮酒受试者相比，其发病率和死亡率有所增加。