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

针对明确的手术应激诱发的炎症途径来改善围手术期结果

• 批准号: 10565791
• 负责人: Elizabeth A Jacobsen
• 金额: $ 57.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565791
• 关键词: Acceleration; Adrenal Cortex Hormones; Age; Animal Model; Animals; Antibodies; Blood; Blood capillaries; Bone Marrow; Cell physiology; Cells; Chest; Clinical; Data; Development; Dysbarism; Environment; Eosinophilia; Epithelium; Evidence based practice; Excision; FDA approved; Fluid Balance; Genetic; Granulocyte-Macrophage Colony-Stimulating Factor; Homing; Human; Hypoxemia; Hypoxia; Immune response; Inflammation; Inflammatory; Interleukin-4; Interleukin-5; Interleukin-9; Intervention; Lead; Length of Stay; Liquid substance; Lung; Lung infections; Lymphoid Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metastatic Neoplasm to the Lung; Morbidity - disease rate; Mouse Strains; NOS2A gene; Nitric Oxide; Observational Study; Operative Surgical Procedures; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Initiation Factors; Perioperative; Pharmaceutical Preparations; Physiology; Play; Pneumonectomy; Population; Postoperative Period; Procedures; Process; Production; Protocols documentation; Pulmonary Edema; Pulmonary Emphysema; Pulmonary Pathology; Recovery; Respiratory Failure; Respiratory distress; Role; Signal Transduction; Steroids; Stress; Structure of parenchyma of lung; Testing; Therapeutic; Thoracic Surgical Procedures; Tidal Volume; Tissues; Toxic effect; United States Agency for Healthcare Research and Quality; Up-Regulation; Ventilator; Wound Infection; biological adaptation to stress; clinically relevant; cytokine; eosinophil; improved; improved outcome; insight; knockout gene; mortality; novel; novel therapeutic intervention; operation; partial recovery; patient response; patient safety; postoperative recovery; prevent; progenitor; pulmonary function; recruit; response; safe patient

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.

项目摘要/摘要 尽管有改善的术中管理，但一些胸外科手术患者遭受 肺切除后未知来源。基于人类观察性研究 周期性期与有害结果相关，我们决定研究一个周期性的炎症 肺手术的小动物模型。我们注意到肺切除会导致瞬态，但明显 血液和肺组织中嗜酸性粒细胞的升高。此外，我们确定全球嗜酸性粒细胞 肺切除之前的耗竭可改善周期性生存，氧合和改善 术后肺水肿。嗜酸性粒细胞的系统性增加是由于它们的加速而导致的 骨髓中祖细胞的成熟。违反直觉，加速了这种成熟过程 通过内源性皮质类固醇，与骨髓中特定细胞因子的上调有关 和肺组织。选择细胞因子的破坏，例如Alarmin IL-33或定义细胞的遗传缺失 种群，例如先天淋巴样细胞（ILC），消除了周期性的嗜酸性粒细胞并改善动物 大肺切除后的生存。这些发现导致了我们的中心假设，即周期性压力 介导内源性立体和细胞因子依赖性嗜酸性粒细胞成熟和动员 由于一氧化氮的产生而部分恢复有害。为了探讨这一假设，我们提出了三个 具体目标。在AIM 1中，我们建议定义“应力诱导的”内源性皮质类固醇的机理/s 肺切除后增加嗜酸性粒细胞的成熟。我们将专门针对细胞因子 环境以及嗜酸性粒细胞及其祖细胞的直接类固醇敏感性。在AIM 2中，我们将使用细胞 - 小鼠的特定条件基因敲除菌株，以确定嗜酸性粒细胞募集的机理/S 肺切除后的毒性。我们假设IL-33激活了第2组先天淋巴样细胞（ILC2），该细胞（ILC2） 然后促进嗜酸性粒细胞的归巢和/或成熟。我们还将定义嗜酸性粒细胞产生的一氮的作用 肺病理中的氧化物。在AIM 3中，我们将探索是否过量流体和大量通风 潮汐量会增加嗜酸性粒细胞的成熟和/或毒性。我们还计划评估嗜酸性粒细胞的破坏 开发，使用IL-5中和的临床相关方案有效地减少其数量， 可以在周期期改善有害影响。我们的数据将为细胞提供新颖的见解 导致肺部切除后呼吸衰竭的免疫反应。我们的数据可能允许探索 新型的热策略或重新利用FDA批准的药物目前尚未改善的药物 围手术期患者反应。