Inflammatory response after combined insult of radiation and burn injury

辐射和烧伤联合损伤后的炎症反应

• 批准号: 7559294
• 负责人: ELIZABETH J. KOVACS
• 金额: $ 18.56万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559294
• 关键词: Abbreviations; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Alveolar wall; Animals; Anti-Inflammatory Agents; Architecture; Blood Vessels; Blood alcohol level measurement; Body Surface Area; Bronchoalveolar Lavage; Burn injury; Capillary Endothelial Cell; Cell Adhesion Molecules; Cells; Clinical; Collagen; Colony-forming units; Data; Deposition; Dorsal; Elevation; Event; Extravasation; Fc Receptor; Fibroblasts; Goals; Hematoxylin and Eosin Staining Method; IL8 gene; Immunoglobulin G; Impairment; Individual; Infection; Infiltration; Inflammatory; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Interleukin-1; Interleukin-10; Interleukin-6; Interleukin-8; Intestines; Knock-out; Laboratories; Leukocytes; Ligands; Lipopolysaccharides; Liquid substance; Literature; Lung; MAP Kinase Gene; Macrophage Inflammatory Protein-1; Mediator of activation protein; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Monocyte Chemoattractant Protein-1; Multiple Organ Failure; Mus; Myosin Light Chain Kinase; Neutrophil Infiltration; Organ; Outcome; Pathology; Patients; Permeability; Peroxidase; Phase; Phosphotransferases; Platelet-Derived Growth Factor; Pneumonia; Production; Proteins; Pulmonary Edema; Pulmonary Pathology; Radiation; Radiation Injuries; Relative (related person); Respiratory physiology; Role; Signal Transduction; Source; TNFRSF1A gene; Therapeutic Intervention; Time; Tissues; Toll-like receptors; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; alcohol exposure; chemokine; chemokine receptor; cytokine; feeding; fluorouracil/semustine/vincristine protocol; human TNF protein; improved; injured; intraperitoneal; lung injury; macrophage inflammatory protein 2; monocyte; mortality; research study; response; response to injury; size; therapy design; vascular bed

DESCRIPTION (provided by applicant): The overall objective of the proposed studies is to determine the mechanism by which the combined insult of radiation exposure and burn injury cause greater acute lung injury (ALI) than either insult alone. 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 radiation injury, and is likely to be amplified after a combined insult. We hypothesize that the complications which arise in radiation-exposed individuals who sustain burn injury are triggered by an overexuberant pulmonary inflammatory response which is triggered by systemic inflammatory mediators. Herein, during the R21 component of this application, we will determine whether there is an increase in the magnitude and duration of pulmonary pathology and greater impairment in function in burn-injured mice who are also subjected to radiation injury relative to animals given either insult alone. This will be accomplished using an established murine model of dorsal scald (burn) injury in combination with sublethal radiation exposure. If we see differences in response to the combined insult, then we will go on to define the roles of key pro-inflammatory and fibrogenic cytokines which are produced locally and systemically during the early and later post-injury period. During the R33 phase, we will explore both the mechanisms responsible for the aberrant pulmonary response, including the cellular sources of these factors and the signaling cascades which turn on their expression in order to determine the extent to which the alveolar macrophage dictates the outcome by virtue of its cytokine production capacity. Additionally, we will determine if therapeutic interventions designed to decrease pulmonary inflammation improve lung pathology using anti-chemokine receptor and anti-adhesion molecule receptor antibodies, as well as if decreasing permeability of critical barriers in the lung and the intestine is beneficial. Taken together, it is anticipated that the proposed experiments will provide valuable information about the mechanisms responsible for the elevated level of tissue damage after the combined injury of radiation and burn. In addition, subsequent experiments will explore therapeutic interventions designed to diminish pulmonary inflammatory responses after injury.

描述（由申请人提供）：所提议研究的总体目标是确定辐射暴露和烧伤的联合损伤比单独的损伤引起更严重的急性肺损伤（ALI）的机制。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的过度产生造成的，促炎性细胞因子是为了响应损伤（例如烧伤和放射损伤）而在全身和局部（在肺中）产生的，并且在联合损伤后可能会被放大。我们假设，受辐射暴露的烧伤个体出现的并发症是由全身炎症介质引发的过度旺盛的肺部炎症反应引发的。在此，在本申请的 R21 部分中，我们将确定相对于单独接受任一损伤的动物，也遭受辐射损伤的烧伤小鼠的肺部病理学的程度和持续时间是否增加以及功能损伤是否更大。这将通过使用已建立的背部烫伤（烧伤）损伤小鼠模型并结合亚致死辐射暴露来完成。如果我们看到对联合损伤的反应存在差异，那么我们将继续定义关键促炎细胞因子和纤维形成细胞因子的作用，这些细胞因子是在损伤后早期和后期局部和全身产生的。在 R33 阶段，我们将探索导致异常肺部反应的机制，包括这些因子的细胞来源以及开启其表达的信号级联，以确定肺泡巨噬细胞在多大程度上决定结果其细胞因子产生能力。此外，我们将确定旨在减少肺部炎症的治疗干预措施是否可以使用抗趋化因子受体和抗粘附分子受体抗体改善肺部病理学，以及降低肺部和肠道关键屏障的通透性是否有益。总而言之，预计所提出的实验将提供有关辐射和烧伤联合损伤后组织损伤水平升高的机制的有价值的信息。此外，后续实验将探索旨在减少损伤后肺部炎症反应的治疗干预措施。