Targeting a Defined Surgical Stress-Induced Inflammatory Pathway to Improve Peri-Operative Outcomes

项目摘要/摘要 尽管改进了术中处理，但一些胸部手术患者仍存在呼吸窘迫。 肺切除后来源不明。基于人类的观察研究，嗜酸性粒细胞增多 围手术期与不良结局相关，我们决定研究围手术期炎症。 肺手术的小动物模型。我们注意到，肺切除会导致一过性但明显的 血液和肺组织中的嗜酸性粒细胞增多。此外，我们确定全球嗜酸性粒细胞 肺切除前的耗竭显著改善了围手术期的存活率、氧合和改善情况。 术后肺水肿。嗜酸性粒细胞的系统性增加是由于它们加速了 来自骨髓中的祖细胞的成熟。与直觉相反，这一成熟过程正在加速。 通过内源性皮质类固醇，并与骨髓中特定细胞因子的上调有关 和肺组织。破坏选定的细胞因子，如警报蛋白IL-33，或确定的细胞的基因缺失 群体，如先天淋巴样细胞(ILCs)，消除了围手术期的嗜酸性粒细胞增多，并改善了动物 肺大切除术后的存活率。这些发现导致了我们的中心假设，即围手术期应激 介导内源性类固醇和细胞因子依赖的嗜酸性粒细胞成熟和动员，即 有害于康复，部分原因是一氧化氮的产生。为了探索这一假设，我们提出了三个假设 明确的目标。在目标1中，我们建议定义“应激诱导”内源性皮质类固醇的机制/S 促进肺切除后嗜酸性粒细胞的成熟。我们将特别关注细胞因子 环境以及嗜酸性粒细胞及其祖细胞对类固醇的直接敏感性。在目标2中，我们将使用细胞- 特异性条件性基因敲除小鼠确定嗜酸性粒细胞募集和聚集的机制/S 肺切除术后的毒性反应。我们假设IL-33激活了第二组固有淋巴样细胞(ILC2)， 然后促进嗜酸性粒细胞归巢和/或成熟。我们还将定义嗜酸性粒细胞产生的硝酸盐的作用 肺病理中的氧化物。在目标3中，我们将探索是否过度输液和大通气量 潮气量增加嗜酸性粒细胞成熟和/或毒性。我们还计划评估是否破坏嗜酸性粒细胞 发展，通过使用临床相关的IL-5中和方案来有效减少它们的数量， 可减轻围手术期的不良反应。我们的数据将提供对蜂窝网络的新见解 免疫反应导致肺切除术后呼吸衰竭。我们的数据可能会让我们探索 FDA批准的药物的新治疗策略或改变用途目前尚不清楚是否有改善 围手术期病人的反应。

PROJECT SUMMARY/ ABSTRACT Despite improved intraoperative management some thoracic surgery patients suffer respiratory distress of unknown origin after lung resection. Based on human observational studies that eosinophilia in the perioperative period correlates with deleterious outcomes, we decided to study perioperative inflammation in a small animal model of lung surgery. We noted that pulmonary resection results in a transient but pronounced elevation of eosinophils in the blood and pulmonary tissue. Furthermore, we determined that global eosinophil depletion prior to lung resection substantially improves perioperative survival, oxygenation, and ameliorates post-operative pulmonary edema. The systemic increase in eosinophils results from their accelerated maturation from progenitors in the bone marrow. This process of maturation is, counterintuitively, accelerated by endogenous corticosteroids and is associated with the upregulation of specific cytokines in the bone marrow and lung tissue. Disruption of select cytokines, such as the alarmin IL-33, or genetic deletion of defined cell populations, such as innate lymphoid cells (ILCs), abrogates perioperative eosinophilia and improves animal survival after major pulmonary resection. These findings led to our central hypothesis that perioperative stress mediates endogenous steroid and cytokine-dependent eosinophil maturation and mobilization that is deleterious to recovery partially due to production of nitric oxide. To explore this hypothesis, we propose three Specific Aims. In Aim 1 we propose to define the mechanism/s of “stress-induced” endogenous corticosteroids that increase maturation of eosinophils after pulmonary resection. We will specifically focus on the cytokine environment as well as direct steroid sensitivity by eosinophils and their progenitors. In Aim 2 we will use cell- specific conditional gene knockout strains of mice to determine the mechanism/s of eosinophil recruitment and toxicity after pulmonary resection. We hypothesize IL-33 activates group 2 innate lymphoid cells (ILC2) which then promote eosinophil homing and/or maturation. We will also define the role of eosinophil produced nitric oxide in pulmonary pathology. In Aim 3 we will explore if excessive fluid administration and large ventilatory tidal volumes increase eosinophil maturation and/or toxicity. We also plan to evaluate if disruption of eosinophil development, by using clinically relevant protocols of IL-5 neutralization to effectively reduce their numbers, can ameliorate deleterious effects in the perioperative period. Our data will provide novel insight into cellular immune responses contributing to post-lung resection respiratory failure. Our data may allow for exploration of novel therapeutic strategies or repurposing of FDA-approved drugs not currently known to improve perioperative patient responses.