Ethanol Effects on Recovery after Injury

乙醇对受伤后恢复的影响

• 批准号: 8101808
• 负责人: ELIZABETH J. KOVACS
• 金额: $ 41.16万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 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/8101808
• 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; Health; 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; Peroxidases; Platelet-Derived Growth Factor; Pneumonia; Production; Proteins; Pulmonary Edema; Pulmonary Pathology; Recovery; Regimen; Relative (related person); Reporting; Respiratory physiology; Risk Factors; Role; Source; TNFRSF1A gene; Testing; Time; Toll-like receptors; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; United States; Work; alcohol effect; alcohol exposure; base; chemokine; cost; cytokine; feeding; improved; in vivo; injured; macrophage; macrophage inflammatory protein 2; monocyte; mortality; problem drinker; response to injury; subcutaneous; vascular bed

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）：拟议的研究的总体目标是定义乙醇暴露加剧烧伤后肺后果的机制。每年有近100,000人因烧伤而被送进医院，据报道，大约一半的患者正在喝乙醇。乙醇暴露不仅是导致与火灾相关事故的事件的危险因素，而且还导致烧伤患者的发病率和死亡率增加。肺是一个关键器官，对远程损伤特别敏感。这部分是由于器官广泛的血管床和精致的肺泡建筑。急性肺损伤是由于促炎性细胞因子过量产生的原因，这些因子是由于损伤而在系统和局部（在肺中）产生的，例如烧伤，如果在损伤时存在酒精，则会放大。我们假设在暴露于乙醇的个体中出现的并发症是由过度肿瘤肺部炎症反应引起的。在本文中，我们建议使用体内和体外方法来确定在有或没有先前的乙醇消耗的燃烧患者中造成肺病理量增加和持续时间的机制，在我们良好成熟的急性乙醇暴露和烧伤的鼠模型中，它们与之并行。此外，我们计划定义燃烧后早期和后期在局部和系统上产生的关键促炎和纤维化细胞因子的作用。我们将检查这些因素的细胞来源，以确定肺泡巨噬细胞在多大程度上因其细胞因子的生产能力决定结果的程度。最后，我们计划利用我们较早的观察结果，即在乙醇和烧伤损伤后看到的全身和器官特异性炎症反应在使用抗炎方案（包括17-雌二醇）的全身治疗后可以改善。在拟议的研究中，我们将测试这种治疗方法是否会减少乙醇暴露的损伤，然后是烧伤损伤的小鼠中所看到的肺部炎症，仅相对于任何一种侮辱。预计这些研究将提供有价值的信息，这些信息可用于开发更有效的疗法，以治疗暴露于乙醇的烧伤患者。在美国的公共卫生相关性，在生命的头四十年中，受伤仍然是死亡的主要原因，人数超过了所有其他死亡原因，包括心脏病和癌症，并且占每年数百万损害伤害，年费用超过1300亿美元。乙醇作为损伤的复杂因素的重要性强调了，在入院时，多达50％的烧伤患者在循环中具有可检测到的乙醇水平。这些患者，大多数不是慢性酗酒者，而是急性或暴饮暴食，与非饮食受伤的受试者相比，发病率和死亡率增加。