Multi-organ Inflammatory Responses after Burn Trauma

烧伤是一种创伤性损伤，不仅影响皮肤，还可能对多个器官造成损害。 系统。在美国每年遭受烧伤的100万人中，有4万人入院 去医院。值得注意的是，这些患者中约有一半在受伤时喝醉了。烧伤患者 与烧伤相比，醉酒造成的伤害增加了发病率和死亡率 没有饮酒的病人。肺是远程损伤后最常见的衰竭器官，如 皮肤烧伤，45%的烧伤患者即使在没有烧伤的情况下也表现出某种形式的肺损伤 吸入性损伤。肺炎和急性呼吸窘迫综合征(ARDS)是主要的 醉酒烧伤患者出现的并发症。然而，人们对其致病机制知之甚少。 酒精中毒调节全身炎症反应，导致肺过度 烧伤患者的炎症和对肺部感染和损害的易感性增加。有证据表明 继发于烧伤的肠道上皮屏障的完整性降低在这一过程中起着关键作用。 烧伤和酒精中毒通过改变肠道屏障的完整性独立地降低肠道屏障的完整性 上皮紧密连接蛋白的定位。在经历了酒精中毒和烧伤的双重侮辱之后， 这些反应是复合的(如果不是协同作用，也是相加的)。结果是一个更戏剧性的释放 细菌产物和内毒素进入门静脉和体循环，触发所谓的“细胞因子” “风暴”是由损伤引起的全身性炎症。从这些观察中，我们假设 烧伤后，1)肠道功能障碍，包括肠上皮完整性受损 屏障，调节观察到的多器官并发症，2)这些变化可以通过 测量血液中肠道损伤和炎症的生物标记物，并以肠道为导向 治疗将恢复肠道和全身的稳态，改善远端器官的功能 比如肺。为了验证这一假设，首先，在目标1中，我们将检查肠道屏障 酒精中毒和烧伤的环境失调先于肺部炎症，如果 使用一组血液生物标志物，可以随着时间的推移跟踪肠道屏障的变化。在目标2中，我们将 研究肠屏障完整性的恢复是否降低了全身和肺指数 炎症在小鼠酒精中毒和烧伤模型中的应用及肠道修复 屏障可改善肺部对感染的反应。最后，在目标3中，我们将研究烧伤患者，以及 在没有近期酒精中毒的情况下，纵向确定烧伤与烧伤的叠加影响 酗酒改变肠道屏障失调的程度比烧伤或单纯饮酒更大。此外， 我们将看看肠道调节失调是否与全身和肺脏有关 发炎。在这个目标中，我们还将评估炎症和肠道屏障的循环生物标记物。 损害并确定它们是否可用于预测急性缺氧性呼吸衰竭和不良反应 在肺部感染之后。综上所述，这些研究将在有限的知识基础上扩展 在烧伤创伤的背景下，酒精中毒改变了肠道屏障。针对我们的肠道的研究 动物模型可以作为开发新的治疗干预措施的第一步 现役军人和退伍军人中的烧伤患者。此外，这项工作还意味着 超越烧伤，因为肠屏障功能障碍可能在非烧伤相关疾病中发挥作用 从创伤性脑损伤到创伤后应激障碍。

Burn is a form of traumatic injury that affects more than just the skin and can cause damage to multiple organ systems. Of the one million people per year who suffer burn injuries in the United States, 40,000 are admitted to hospitals. Remarkably, about half of those patients are intoxicated at the time of injury. Burn patients who were intoxicated when they sustained their injuries have increased morbidity and mortality compared to burn patients who had not been drinking. The lung is the most frequent organ to fail after a remote injury such as cutaneous burn, with 45% of burn patients showing some form of lung damage even in the absence of inhalation injury. Pneumonia and acute respiratory distress syndrome (ARDS) are among the major complications seen in intoxicated burn patients. However, little is known about the mechanism by which alcohol intoxication modulates systemic inflammatory responses that lead to excessive pulmonary inflammation and increased susceptibility to lung infection and damage in burn victims. Evidence suggests that reduced integrity of the epithelial barrier of the gut secondary to burn injury plays a critical role in this process. Burn trauma and alcohol intoxication independently reduce the intestinal barrier integrity by altering the localization of epithelial tight junction proteins. Following the dual insult of alcohol intoxication and burn injury, the responses are compounded (additively, if not synergistically). The result is a more dramatic release of bacterial products and endotoxins into the portal and systemic circulation, triggering the so-called “cytokine storm” characteristic of injury-induced systemic inflammation. From these observations, we hypothesize that after burn injury, 1) intestinal dysfunction, including a breach in the integrity of the intestinal epithelial barrier, mediates the observed multi-organ complications, 2) that these changes can be monitored by measuring biomarkers of intestinal damage and inflammation in the blood, and that 3) gut-directed therapies will restore intestinal and systemic homeostasis improving the function of distal organs such as the lung. To test this hypothesis, first, in Aim 1, we will examine whether intestinal barrier dysregulation in the setting of alcohol intoxication and burn injury precedes pulmonary inflammation and if the intestinal barrier changes can be followed over time using a panel of blood-borne biomarkers. In Aim 2, we will investigate whether restoration of intestinal barrier integrity attenuates systemic and pulmonary indices of inflammation in our mouse model of alcohol intoxication and burn injury and whether repairing the intestinal barrier improves the pulmonary response to an infection. Lastly, in Aim 3, we will study burn patients, with and without recent alcohol intoxication, longitudinally to determine if the superimposed impact of burn injury with alcohol abuse alters intestinal barrier dysregulation to a greater extent than burn or alcohol alone. Moreover, we will see if there is a relationship between intestinal dysregulation and systemic and pulmonary inflammation. In this aim, we will also assess circulating biomarkers of inflammation and intestinal barrier damage and determine if they can be used to predict acute hypoxic respiratory failure and poor responses following pulmonary infections. Taken together, these studies will expand on the limited knowledge of how alcohol intoxication alters the gut intestinal barrier in the context of burn trauma. Studies targeting the gut in our animal model can serve as the first step in developing novel therapeutic interventions for the treatment of patients with burn injuries in active military and veteran populations. Moreover, this work has implications that extend beyond burn injury as intestinal barrier dysfunction may play a role in non-burn injury related disorders ranging from traumatic brain injury to post-traumatic stress disorder.