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.

项目总结/摘要 尽管术中管理有所改善，但一些胸外科患者仍会发生呼吸窘迫， 肺切除术后不明原因。基于人类观察性研究， 围手术期与有害结果相关，我们决定研究围手术期炎症， 肺外科小动物模型。我们注意到肺切除术会导致短暂但明显的 血液和肺组织中嗜酸性粒细胞升高。此外，我们确定，全球嗜酸性粒细胞 肺切除术前的耗竭显著改善了围手术期生存率、氧合， 术后肺水肿嗜酸性粒细胞的全身性增加是由于它们的加速增殖导致的。 从骨髓中的祖细胞成熟。与直觉相反， 与骨髓中特异性细胞因子的上调有关 和肺组织。选定细胞因子（如Alarmin IL-33）的破坏或确定细胞的遗传缺失 群体，如先天性淋巴样细胞（ILC），消除围手术期嗜酸性粒细胞增多并改善动物免疫功能。 肺切除术后的生存率。这些发现导致了我们的中心假设，即围手术期压力 介导内源性类固醇和尼古丁依赖性嗜酸性粒细胞成熟和动员， 部分由于产生一氧化氮而对恢复有害。为了探索这一假设，我们提出了三个 具体目标。在目标1中，我们提出定义“应激诱导的”内源性皮质类固醇的机制 促进肺切除术后嗜酸性粒细胞成熟。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的直接类固醇敏感性。在目标2中，我们将使用细胞- 特异性条件基因敲除小鼠品系，以确定嗜酸性粒细胞募集的机制， 肺切除术后的毒性。我们假设IL-33激活第2组先天性淋巴样细胞（ILC 2）， 然后促进嗜酸性粒细胞归巢和/或成熟。我们还将确定嗜酸性粒细胞产生的一氧化氮的作用 氧化物在肺病理学中的作用。在目标3中，我们将探讨是否存在过量液体给药和大剂量 潮气量增加嗜酸性粒细胞成熟和/或毒性。我们还计划评估嗜酸性粒细胞是否受到干扰 通过使用临床相关的IL-5中和方案来有效地减少它们的数量， 可改善围手术期的不良反应。我们的数据将提供新的见解， 导致肺切除术后呼吸衰竭的免疫反应。我们的数据可以让我们探索 新的治疗策略或FDA批准的药物的再利用，目前还不知道改善 围手术期患者反应。