Controlling the Source of Inflammatory Signaling in a Burn Model

控制烧伤模型中炎症信号的来源

• 批准号: 8024542
• 负责人: SAMAN ARBABI
• 金额: $ 31.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8024542
• 关键词: Acute Lung Injury; Affect; American; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bacterial Infections; Burn injury; Cells; Cessation of life; Complex; Dermal; Fatal Outcome; Functional disorder; Goals; Growth; Health; Host Defense; Immune response; Immune system; Immunomodulators; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Literature; Lung; MAP Kinase Gene; MAPK14 gene; Measures; Medical; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Natural Immunity; Nature; Organ; Organ failure; Outcome; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Pneumonia; Population; Predisposition; Process; Regulation; Research Personnel; Risk; Role; Sepsis Syndrome; Severities; Signal Transduction; Source; Specificity; Stimulus; Stress; Study models; System; Therapeutic; Tissues; Topical Antibiotic; Topical application; Violence; Wound Healing; Wound Infection; antimicrobial drug; cell type; clinical practice; heat injury; immune activation; immunoregulation; improved; in vivo; inhibitor/antagonist; injured; intraperitoneal; intravenous administration; mortality; neutrophil; novel strategies; p38 MAPK Signaling Pathway; research study; response; stress-activated protein kinase 1; wound

DESCRIPTION (provided by applicant): Severe thermal insult induces a major disturbance in homeostatic and regulatory mechanisms. Since an aberrant systemic inflammatory activation appears to be the underlying mechanism for ultimate organ failure, most studies have focused on systemic modulation of this over-exuberant immune response. However, systemic administration of several anti-inflammatory or immunomodulatory agents has failed to demonstrate improvement in survival or organ failure in various conditions. In addition, since these agents are not tissue specific and act on multiple organs, systemic administration may have unpredictable deleterious results in a complex interacting system of cell-specific pathways. We therefore have focused on a novel approach which calls for "inflammatory source control". We have demonstrated that there is a strong interaction between the local-dermal and systemic inflammatory response; hence, controlling the local inflammatory signaling at the burn wound would attenuate the subsequent complications such as acute lung injury. The over arching hypothesis for this application is that the burn-wound inflammatory stress shielding with topical immunomodulation attenuates systemic inflammatory activation and end-organ dysfunction, whereas systemic administration of the same immunomodulators will have unpredictable results. In a post burn injury model, we will investigate the interaction between dermal and systemic inflammatory response by topical administration of inhibitors of intracellular stress signaling to the burn wound. The agents used are inhibitors of p38 and c-Jun N- terminal kinase (JNK), which are recognized as mitogen-activated protein kinases that are activated in response to physiological stress. We will compare topical application of these immunomodulators to post-burn systemic administration. We further hypothesize that topical inhibition of the inflammatory signaling does not affect the innate immune system's ability to resist subsequent bacterial infections, while systemic administration will interfere with the normal immune response. Thus this proposal sets out to elucidate the mechanisms responsible for the activation of systemic inflammatory response after a large thermal insult and the potential therapeutic approach by topical application of immunomodulators post-burn. Understanding the interaction between local and subsequent systemic inflammatory response in this model may be applicable to other pathophysiological systems, which are initiated by a more localized inflammatory stimulus. Furthermore, topical burn-wound inhibition of inflammatory signaling as an experimental strategy for inhibition of end-organ injury is a promising therapy that is practical and fits the current clinical practice of daily application of topical antimicrobial agents. This topical treatment is easy to apply and can be initiated early post injury, even at the scene. PUBLIC HEALTH RELEVANCE: Relevance Approximately 500,000 Americans suffer burn injuries with an estimated 4,000 deaths annually. We are investigating a topical immunomodulatory therapy that has the potential to decrease organ failure and mortality and can be initiated at the scene. Increasing world-wide violence directed towards the civilian population would predict a rise in the number and the severity of burn injuries. This promising therapy may have a significant impact in decreasing the morbidity and mortality of these victims.

描述(由申请人提供)：严重的热损伤会导致体内平衡和调节机制的重大紊乱。由于异常的全身炎症激活似乎是最终器官衰竭的潜在机制，大多数研究都集中在对这种过度活跃的免疫反应的系统调控上。然而，在各种情况下，全身应用几种抗炎或免疫调节剂并不能改善存活率或器官衰竭。此外，由于这些药物不是组织特异性的，作用于多个器官，全身给药可能会在细胞特异性途径的复杂相互作用系统中产生不可预测的有害结果。因此，我们把重点放在了一种新的方法上，它要求“炎症源控制”。我们已经证明，局部真皮和全身炎症反应之间存在着强烈的相互作用；因此，控制烧伤创面的局部炎症信号将减轻随后的并发症，如急性肺损伤。这一应用的总体假设是，烧伤创面局部免疫调节的炎性应力屏蔽可以减轻全身炎症激活和终末器官功能障碍，而全身应用相同的免疫调节剂将产生不可预测的结果。在烧伤后损伤模型中，我们将通过局部给予烧伤创面细胞内应激信号的抑制剂来研究真皮和全身炎症反应之间的相互作用。使用的药物是p38和c-jun氨基末端激酶(JNK)的抑制剂，这两种蛋白被认为是丝裂原激活的蛋白激酶，在生理压力下被激活。我们将比较这些免疫调节剂的局部应用与烧伤后全身给药。我们进一步假设，局部抑制炎症信号不会影响先天性免疫系统抵抗后续细菌感染的能力，而全身给药将干扰正常的免疫反应。因此，本研究旨在阐明大面积热损伤后全身炎症反应激活的机制，以及烧伤后局部应用免疫调节剂的潜在治疗方法。在这个模型中理解局部和随后的全身炎症反应之间的相互作用可能适用于其他病理生理系统，这些系统是由更局部的炎症刺激启动的。此外，烧伤创面局部抑制炎症信号作为一种抑制终末器官损伤的实验策略是一种很有前途的治疗方法，它是一种实用的治疗方法，适合目前日常应用局部抗菌药物的临床实践。这种局部治疗很容易应用，而且可以在受伤后早期启动，即使在现场也是如此。公共卫生相关性：每年约有50万美国人遭受烧伤，估计有4000人死亡。我们正在研究一种局部免疫调节疗法，这种疗法有可能减少器官衰竭和死亡率，并可以在现场启动。世界范围内针对平民人口的暴力不断增加将预示着烧伤人数和严重程度的上升。这种有希望的治疗方法可能会对降低这些受害者的发病率和死亡率产生重大影响。