Controlling the Source of Inflammatory Signaling in a Burn Model

摘要 严重的热损伤诱导了体内平衡和调节机制的重大紊乱。以来 异常的全身炎症激活似乎是最终器官损伤的潜在机制。 失败后，大多数研究都集中在这种过度旺盛的免疫反应的系统调节上。然而，在这方面， 几种抗炎或免疫调节剂的全身给药未能证明 在各种情况下生存或器官衰竭的改善。此外，由于这些药剂不是组织 特异性且作用于多个器官，全身给药可能具有不可预测的有害结果， 细胞特异性通路的复杂相互作用系统。因此，我们专注于一种新颖的方法， 呼吁"控制炎症源"。我们已经证明了， 局部-真皮和全身炎症反应;因此，控制局部炎症信号， 烧伤可减轻并发症如急性肺损伤。The over 这种应用的假设是，烧伤伤口炎症应激屏蔽与局部 免疫调节减弱全身性炎症活化和终末器官功能障碍，而全身性炎症活化和终末器官功能障碍则不明显。 施用相同的免疫调节剂将具有不可预测的结果。在烧伤后模型中，我们 将通过局部给药研究皮肤和全身炎症反应之间的相互作用， 烧伤创面的细胞内应激信号的抑制剂。所用的药物是p38和c-Jun N的抑制剂。 末端激酶（JNK），其被认为是促分裂原活化的蛋白激酶， 对生理压力的反应我们将比较局部应用这些免疫调节剂， 系统管理。我们进一步假设，局部抑制炎症信号传导并不 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，本提案旨在阐明 在大量热损伤后激活全身炎症反应的机制， 烧伤后局部应用免疫调节剂的潜在治疗方法。了解 在该模型中局部和随后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，这是由一个更本地化的炎症刺激启动。此外，委员会认为， 局部烧伤抑制炎症信号传导作为终末器官抑制的实验策略 损伤是一种有前途的治疗方法， 抗菌剂。这种局部治疗很容易应用，可以在受伤后早期开始，即使在受伤后， 现场

Abstract 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.