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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：
10452344
负责人：
BRIAN MARPLES
金额：
$ 26.95万
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/10452344
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 susceptibility Cancer Patient Cells Chronic Clinical Clinical Trials Complement Coronavirus Cytokine Signaling DNA Data Diffuse Dose Dyspnea Epithelial Event Exposure to Female Fibrosis Generations Goals Grant Heart Histopathology Human Immune Immune response Immunomodulators Impairment Inbred C3H Mice Infection 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 Activation Malignant neoplasm of lung Measures Mediating Mediator of activation protein 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 coronavirus SARS-CoV-2 infection Severities Signal Transduction Site Slice Targeted Radiotherapy Testing Time Tumor-infiltrating immune cells Viral Viral Load result Virus Virus Diseases Weight Whole-Body Irradiation age related aged base biobank cellular targeting chemokine clinically relevant comorbidity conditioning cytokine cytokine release syndrome epithelial injury experience fibrogenesis human old age (65+)immunoregulation infection risk influenza virus strain influenzavirus irradiation lung injury macrophage male mortality mouse model novel pathogenic virus pneumonitis and fibrosis prevent pulmonary function radiation effect radiation risk radiation-induced lung injury receptor recruit repaired respiratory response 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：肿瘤肺放疗（RT）后可发生肺炎和纤维化