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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要尽管术中管理有所改善，但一些胸外科患者仍遭受呼吸窘迫根据人体观察研究，肺切除术后出现嗜酸性粒细胞增多。围手术期与有害结果相关，我们决定研究围手术期炎症我们注意到肺切除术会导致短暂但明显的结果。血液和肺组织中嗜酸性粒细胞升高此外，我们确定了总体嗜酸性粒细胞。肺切除术前的耗竭可显着提高围手术期生存率、氧合和改善术后肺水肿是由于嗜酸性粒细胞加速增加所致。与直觉相反，这种成熟过程是由骨髓中的祖细胞成熟的。由内源性皮质类固醇引起，并与骨髓中特定细胞因子的上调有关特定细胞因子的破坏，例如警报素 IL-33，或特定细胞的基因删除。群体，如先天淋巴细胞（ILC），消除围手术期嗜酸性粒细胞增多并改善动物这些发现得出了我们的中心假设：围手术期压力。介导内源性类固醇和细胞因子依赖性嗜酸性粒细胞的成熟和动员部分由于一氧化氮的产生而对恢复有害为了探索这一假设，我们提出了三个假设。具体目标在目标 1 中，我们建议定义“应激诱导”内源性皮质类固醇的机制。我们将特别关注细胞因子。在目标 2 中，我们将使用细胞-环境以及嗜酸性粒细胞及其祖细胞的直接类固醇敏感性。特定条件基因敲除小鼠品系，以确定嗜酸性粒细胞募集的机制和我们勇敢地面对肺切除术后的毒性 IL-33 激活第 2 组先天淋巴细胞 (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的作用。在目标 3 中，我们将探讨是否过度输液和大量通气。潮气量会增加嗜酸性粒细胞的成熟和/或毒性。我们还计划评估是否会破坏嗜酸性粒细胞。通过使用临床相关的 IL-5 中和方案来有效减少其数量，可以改善围手术期的有害影响，我们的数据将为细胞提供新的见解。我们的数据可能有助于探索肺切除后呼吸衰竭的免疫反应。新的治疗策略或 FDA 批准的药物的重新利用目前尚不清楚是否可以改善围手术期患者的反应。