Controlling the Source of Inflammatory Signaling in a Burn Model

描述（由申请人提供）：重度热损伤诱导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，因此大多数研究都集中在这种过度旺盛的免疫应答的全身调节上。然而，几种抗炎或免疫调节剂的全身给药未能证明在各种条件下存活或器官衰竭的改善。此外，由于这些药剂不是组织特异性的并且作用于多个器官，因此全身给药可能在细胞特异性途径的复杂相互作用系统中具有不可预测的有害结果。因此，我们集中在一个新的方法，要求“炎症源控制”。我们已经证明，局部皮肤和全身炎症反应之间存在强烈的相互作用;因此，控制烧伤创面的局部炎症信号传导将减轻随后的并发症，如急性肺损伤。该应用的过度假设是，局部免疫调节的烧伤伤口炎症应激屏蔽减弱了全身炎症激活和终末器官功能障碍，而全身给予相同的免疫调节剂将产生不可预测的结果。在烧伤后模型中，我们将通过向烧伤伤口局部施用细胞内应激信号传导抑制剂来研究真皮和全身炎症反应之间的相互作用。所用的药物是p38和c-Jun N-末端激酶（JNK）的抑制剂，它们被认为是响应生理应激而活化的促分裂原活化蛋白激酶。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传导不影响先天免疫系统抵抗随后细菌感染的能力，而全身给药将干扰正常的免疫应答。因此，该提案旨在阐明大面积热损伤后激活全身炎症反应的机制以及烧伤后局部应用免疫调节剂的潜在治疗方法。了解局部和随后的全身炎症反应之间的相互作用，在这个模型中可能适用于其他病理生理系统，这是由一个更本地化的炎症刺激。此外，作为抑制终末器官损伤的实验策略的炎症信号传导的局部烧伤-创伤抑制是一种有前景的疗法，其是实用的并且适合当前局部抗微生物剂的日常应用的临床实践。这种局部治疗很容易应用，可以在受伤后早期开始，甚至在现场。公共卫生相关性：相关性每年约有50万美国人遭受烧伤，估计有4,000人死亡。我们正在研究一种局部免疫调节疗法，它有可能降低器官衰竭和死亡率，并且可以在现场启动。世界范围内针对平民的暴力行为不断增加，预计烧伤的人数和严重程度都会增加。这种有前途的治疗可能会有显着的影响，在降低这些受害者的发病率和死亡率。

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.