Netosis in Trauma mediated Acute Lung Injury

项目总结 高达40%的严重创伤患者在住院期间会出现严重的感染并发症。 住院和呼吸道感染是导致受伤患者败血症的最常见原因。虽然大家都知道 创伤性损伤触发无菌炎症反应，可导致急性肺损伤(ALI)，其机制是 这一点及其对肺炎等继发性感染发展的贡献还没有得到很好的了解。这个 本研究的主要目标是了解先天免疫系统在创伤所致肺损伤中的作用。 以便为治疗和预防提供新的靶点。我们最近建立了一个多发性创伤的小鼠模型。 这概括了在严重受伤的患者中对革兰氏阴性肺炎的易感性增加。在……里面 初步研究表明，创伤本身既会导致急性肺损伤，又会增加对 肺炎假单胞菌。我们进一步发现，在第二次侮辱后，中性粒细胞网织增多 假单胞菌。中性粒细胞网状沉着症是一种强烈的抗菌性中性粒细胞反应，通过激活中性粒细胞 挤出一张布满细胞毒性颗粒的DNA网络，这些颗粒具有固定和杀死入侵病原体的功能。而当 蚊虫中毒是一种关键的抗感染途径，过量的蚊虫中毒已被证明会导致对 宿主组织。我们还表明，创伤小鼠的血清可以使未激活的中性粒细胞为网织红细胞病做准备。 基于这些数据，我们假设创伤导致中性粒细胞增多，导致ALI和过度兴奋 创伤后革兰氏阴性细菌性肺炎的反应。为了检验这一假设，我们提出了两个具体目标。 目的1：确定多发伤后急性肺损伤(ALI)所致的中性粒细胞网织红细胞增多是否加重肺炎。 目的2：明确GCSF在促进多发伤后内毒素血症中的作用 目的：明确中性粒细胞网织红细胞增多症在继发性免疫应答失调中的作用。 创伤后的感染。 成功实现这些目标所获得的知识将为预防和治疗急性肺损伤提供一条新的途径 创伤和临床上可翻译的，因为目前FDA批准的几种疗法已知对 蚊虫肺炎所需的关键酶和多种特定疗法目前正在开发中。这一知识是 至关重要的是，伦纳德博士的实验室可以将这些转化为可能改善的机械疗法的开发 病人的结果。

PROJECT SUMMARY Up to 40% of critically injured trauma patients will develop a serious infectious complication during their inpatient hospitalization and respiratory infections are the most common cause of sepsis in injured patients. While it is known that traumatic injury triggers a sterile inflammatory response that can result in acute lung injury (ALI), the mechanism of this and its contribution to the development of secondary infections such as pneumonia is not well understood. The overarching goal of this research is to understand the role of the innate immune system in trauma induced lung injury in order to provide new targets for treatment and prevention. We have recently established a mouse model of polytrauma that recapitulates the increased susceptibility to gram negative pneumonia seen in critically injured patients. In preliminary studies, we demonstrate that trauma alone induces both an acute lung injury and increased susceptibility to Pseduomonas pneumonia. We further find an increase in neutrophil NETosis following a second insult with pseudomonas bacteria. Neutrophil NETosis is a strong antimicrobial neutrophil response whereby activated neutrophils extrude a web of DNA studded with cytotoxic granules which function to immobilize and kill invading pathogens. While NETosis is a critical anti-infective pathway, excessive NETosis has been demonstrated to result in collateral damage to host tissues. We also show that serum from traumatically injured mice can prime unactivated neutrophils for NETosis. Based on these data we hypothesize that trauma primes neutrophils for NETosis causing ALI and an overexuberant response to gram negative bacterial pneumonia after trauma. To test this hypothesis we propose two specific aims. Aim 1: Determine if neutrophil NETosis triggered by polytrauma-induced ALI exacerbates pneumonia. Aim 2: Define the the role of GCSF in promoting NETosis after polytrauma AIM3: Define the contribution of neutrophil NETosis to the dysregulated immune response induced by a secondary infection after trauma. The knowledge gained from successfully achieving these aims will provide a novel pathway to prevent and treat ALI after trauma and are clinically translatable as several current FDA approved therapeutics are known to have activity against key enzymes required for NETosis and multiple specific therapeutics are currently being developed. This knowledge is crucial so that Dr. Leonard’s laboratory can translate these to development of mechanistic therapies that may improve patient outcomes.