Targeting macrophages to reduce the combined injury effects of radiation and virus exposure

靶向巨噬细胞以减少辐射和病毒暴露的综合损伤效应

基本信息

批准号：
10618330
负责人：
BRIAN MARPLES
金额：
$ 15.4万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-05 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618330
关键词：
2019-nCoV 3-Dimensional Acute Acute Respiratory Distress Syndrome Address Affect Age Alveolar Alveolar Macrophages Animals Anti-Inflammatory Agents Antioxidants Body Weight decreased Breathing CD 200 COVID-19 patient COVID-19 susceptibility Cancer Patient Cells Chronic Clinical Clinical Trials Complement Coronavirus Cytokine Signaling DNA Data Diffuse Dose Dyspnea Elderly Epithelium Event Exposure to Female Fibrosis Generations Goals Grant Heart Histopathology Human Immune Immune response Immunomodulators Impairment Inbred C3H Mice Infection Infiltration Inflammation Inflammatory Inflammatory Infiltrate Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza A virus Injury Lower respiratory tract structure Lung Macrophage Macrophage Activation Malignant neoplasm of lung Measures Mediating Mediator Modeling Molecular Molecular Target Morbidity - disease rate Murine hepatitis virus Mus Organ Oxidative Stress Pathogenicity Pathology Patients Peripheral Phase Phenotype Plasma Pleural effusion disorder Population Predisposition Process Production Proteins Puerto Rico Pulmonary Fibrosis Pulmonary Inflammation Pulmonary Pathology Radiation Radiation Pneumonitis Radiation Tolerance Radiation induced damage Radiation therapy Recombinants Recovery Regulation Reporting Resolution Risk SARS-CoV-2 infection Severities Signal Transduction Site Slice Targeted Radiotherapy Testing Time Viral Viral Load result Virulence Virus Virus Diseases Weight Whole-Body Irradiation age related aged biobank cellular targeting chemokine clinically relevant comorbidity conditioning cytokine cytokine release syndrome epithelial injury experience fibrogenesis human old age (65+)immune cell infiltrate immune modulating agents immunoregulation infection risk influenza virus strain irradiation lung injury male mortality mouse model novel pathogen pathogenic virus pneumonitis and fibrosis prevent pulmonary function radiation effect radiation risk radiation-induced lung injury receptor recruit repaired respiratory response risk mitigation severe COVID-19 sex time interval

项目摘要

PROJECT SUMMARY/ABSTRACT: Pneumonitis and fibrosis occur after oncologic lung radiotherapy (RT) or TBI conditioning for BMT. The sustained production of inflammatory cytokines, dysregulated macrophage activation and perpetual ROS generation are considered molecular mediators of these events. SARS-CoV-2- confirmed patients experience lower respiratory tract illness, dyspnea and peripheral fibrosis, along with production of proinflammatory cytokines from recruited immune cells; events that indicate the lungs are susceptible to SARS-CoV-2 infection, with old age and comorbidities also identified as predisposing conditions. Therefore, both high-dose RT and viral infection promote proinflammatory microenvironments in the lung, the recruitment of macrophage populations and cytokine signaling; suggesting a commonality to mechanisms of pulmonary fibrosis that involve a ‘cytokine storm’. In support of this, we reported preliminary data that lung- targeted RT, alone or combined with TBI, increased mortality and fibrosis from influenza virus A (HKx31 (H3N2)) and exacerbated infection risks in radiation-sensitive organs. Since both local microenvironmental alterations and innate immune cell recruitment were implicated, we now hypothesize that lung radiation produces long- term changes in the lung microenvironment that affect immune responses to respiratory viral pathogens. We will investigate the immediate (<24h) mechanistic interactions responsible for long-term lung injury (>26 wks) caused by combined exposures to focal lung RT followed by virus, and vice versa, using 3D precision cut lung slices and mouse models. The overall goal is to develop molecular-based protective/mitigating strategies. Aim 1.1: To investigate how prior lung irradiation of C57BL/6 and C3H mice, and dose-dependent radiation- induced lung injury, affects sensitivity and susceptibility to virus infection using Influenza and murine corona viral strains to model SARS-CoV-2 infection. Also, to investigate how persistent or latent lung injury from the first insult impacts the sensitivity to the second insult by varying the time interval between the two insults. Aim 1.2: To investigate how viral infection and the viral-induced ‘cytokine storm’ alters lung radiosensitivity, and the temporal progression through radiation-induced pneumonitis and fibrosis. Aged mice will also be used to determine how age- and weight-related co-morbidity factors exacerbate the risk for combined pulmonary injury. Aim 1.3: Use human 3D lung slice cultures to investigate how viral infection alters mechanisms of RT-induced DNA DSB repair, and the impact on cell lethality. Aim 2: To determine if mitigating inflammation and/or oxidative stress in the lungs with antioxidants AEOL-10150 and NaI, or preventing the aberrant recruitment and activation of infiltrating macrophages at sites of pulmonary injury by targeting the CD200 receptor, will mitigate risks for combined radiation and viral exposures. These studies will be significant because they model the relationship between radiation damage and viral infectivity in the lung, and offer the potential for molecular-targeted mitigation for RT and combined viral injury.

项目摘要/摘要：肿瘤学肺放疗（RT）或 BMT的TBI条件。炎症细胞因子的持续产生，巨噬细胞失调激活和永久性ROS产生被认为是这些事件的分子介质。 SARS-CoV-2- 确认患者患有下呼吸道疾病，呼吸困难和外周纤维化，以及从募集的免疫细胞中产生促炎性细胞因子；表明肺的事件是易感SARS-COV-2感染，年龄和合并症也被确定为易感性条件。因此，高剂量RT和病毒感染都促进了肺中的促炎微环境，巨噬细胞种群和细胞因子信号传导的募集；提出与机制的共同点涉及“细胞因子风暴”的肺纤维化。为此，我们报道了肺部的初步数据靶向RT单独或与TBI结合，增加了影响力A（HKX31（H3N2））的死亡率和纤维化。并加剧了对辐射敏感器官的风险。由于两个本地微环境改变并暗示了先天免疫菌株的募集，我们现在假设肺辐射产生很长的肺微环境中的项变化，影响免疫复杂对呼吸道病毒病原体。我们将研究负责长期肺损伤的直接（<24h）机械相互作用（> 26周）由对局灶性肺RT的组合暴露，然后是病毒，反之亦然，使用3D精度切割肺切片和鼠标模型。总体目标是制定基于分子的保护/缓解策略。 AIM 1.1：研究C57BL/6和C3H小鼠的先前肺照射以及剂量依赖性辐射诱发肺损伤，使用流感和鼠电晕病毒影响对病毒感染的敏感性和敏感性菌株以建模SARS-COV-2感染。此外，要研究第一次持续或潜在的肺损伤侮辱通过改变两种侮辱之间的时间间隔来影响对第二次侮辱的敏感性。目标1.2：研究病毒感染和病毒诱导的“细胞因子风暴”如何改变肺部放射敏感性，并通过辐射诱导的肺炎和纤维化的暂时进展。老年小鼠也将习惯确定年龄和体重相关的合并症因素如何加剧肺部损伤的风险。目标1.3：使用人类3D肺切片培养物研究病毒感染如何改变RT诱导的机制 DNA DSB修复以及对细胞致死性的影响。目标2：确定用抗氧化剂AEOL-10150减轻肺中的注射和/或氧化应激和NAI，或防止肺部部位的异常募集和激活渗透巨噬细胞通过靶向CD200受体的损伤将减轻辐射和病毒式暴露的风险。这些研究将很重要，因为它们建模了辐射损伤与病毒之间的关系肺中的感染性，并为RT和组合病毒损伤提供了分子靶向缓解的潜力。