Controlling the Source of Inflammatory Signaling in a Burn Model

摘要 严重的热损伤会导致体内平衡和调节机制的严重紊乱。自.以来 异常的全身炎症激活似乎是最终器官的潜在机制。 失败后，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节上。然而， 几种抗炎或免疫调节剂的全身应用未能证明 在各种情况下存活率或器官衰竭的改善。此外，由于这些药剂不是组织 特定的和作用于多个器官的，全身给药可能在 复杂的细胞特异性通路相互作用系统。因此，我们将重点放在一种新的方法上，即 呼吁对“炎症源进行控制”。我们已经证明，在 局部皮肤和全身炎症反应；因此，控制局部炎症信号在 烧伤创面可以减轻随后的并发症，如急性肺损伤。拱顶 这种应用的假说是烧伤创面的炎性应力屏蔽外用 免疫调节可减轻全身炎症激活和终末器官功能障碍，而全身性 使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 将通过局部给药来研究皮肤和全身炎症反应之间的相互作用 细胞内应激信号传递给烧伤创面的抑制剂。使用的药物是p38和c-jun-N的抑制剂- 末端激酶(JNK)，被认为是丝裂原激活的蛋白激酶，在 对生理压力的反应。我们会将这些免疫调节剂的局部应用与烧伤后进行比较。 系统性管理。我们进一步假设局部抑制炎症信号并不 影响先天免疫系统抵抗后续细菌感染的能力，而系统性 用药会干扰正常的免疫反应。因此，这项提议旨在阐明 大面积热损伤后全身炎症反应激活的机制 烧伤后局部应用免疫调节剂的潜在治疗方法。了解 在这个模型中，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，这是由更局部的炎症刺激启动的。此外， 局部烧伤创面抑制炎症信号作为抑制终末器官的实验策略 损伤是一种很有前途的治疗方法，它是一种实用的治疗方法，适合目前临床上日常使用的外用药物。 抗菌剂。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 场景。

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.