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Disordered Proteostasis as a Driver of Disease in the Aging Lung

蛋白质稳态紊乱是衰老肺疾病的驱动因素

基本信息

批准号：
10208506
负责人：
GR Scott Budinger
金额：
$ 31.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10208506
关键词：
2019-nCoV Acute Address Adult Respiratory Distress Syndrome Affect Aging Agonist Alveolar Alveolar Macrophages Autopsy Biological Markers Biopsy Blood Blood Coagulation Factor Bronchoalveolar Lavage Fluid C-reactive protein COVID-19 Cardiovascular system Cause of Death Cell Death Cells Clinical Clinical Trials Coagulation Process Data Diffuse Disease Disease model Distant Elderly Endothelial Cells Endothelium Epithelial Cells Evaluation Functional disorder Genetic Transcription Heart Human Hypotension Hypoxemia IL6 gene Immune Individual Infection Inflammasome Inflammation Inflammatory Influenza A virus Interleukin-1 Interleukin-6 Intubation Irrigation Kidney Link Liquid substance Liver Lung Lymphocyte Macrophage Activation Mechanical ventilation Mediating Modeling Morbidity - disease rate Muscle Organ Patients Pneumonia Primates Publishing Reporting Research Personnel Respiratory Failure Rodent Role Sampling Serum Slice Source Spleen Testing Therapeutic Thromboplastin Thrombosis Time Tissue Harvesting Tissues Viral Viral Pneumonia Virus Virus Replication age related aged base cytokine cytokine release syndrome experimental study inhibitor/antagonist lymph nodes macrophage monocyte mortality neutrophil organ injury prevent proteostasis respiratory virus response single-cell RNA sequencing sound uptake

项目摘要

Pneumonia is the leading cause of death in patients with COVID-19 infection and disproportionately affects older individuals. In addition to the diffuse patchy alveolar infiltrates and acute hypoxemic respiratory failure typical of viral pneumonia, patients with COVID-19 often develop hypotension requiring alpha-adrengergic agonists, very high serum levels of IL-6 and its transcriptional target C-Reactive Protein (CRP) and display evidence of intravascular coagulation. This is accompanied by the death of cells in multiple tissues including the kidney, muscle, liver and occasionally the heart. This end-organ injury is an important driver of morbidity and perhaps mortality in COVID-19 patients. These unusual clinical features suggest a virus-induced cytokine storm, but the underlying mechanisms are unknown and these clinical features are not recapitulated in rodent or primate models of the disease.Our early analysis of bronchoalveolar lavage fluid collected from the alveolar space of patients with severe COVID-19 pneumonia requiring mechanical ventilation challenge the existing paradigm that IL-6 originates in immune cells within the alveolar space. Specifically, we found that at the time of intubation, the alveolar space in the majority of patients with severe COVID-19-induced ARDS harbors mature alveolar macrophages and lymphocytes none of which produce IL-6. Instead, a subset of resident alveolar macrophages produce IL-1? and appear to support replication of SARS-CoV-2.We hypothesize that disordered proteostasis in alveolar macrophages from aged individuals prevents viral killing after uptake of SARS- CoV-2. Replicating virus activates the inflammasome to induce IL-1? release in the lung, which in turn induces the release of IL-6 from endothelial cells in the lung and distant organs. We will test this hypothesis in two related experiments. Experiment 1. To determine whether activation of the inflammasome in response to COVID- 19 infection is necessary for the release of IL-6 from the lung endothelium. We will infect lung slices from normal human donors with SARS-CoV-2 in the presence or absence of an IL-1? inhibitor that is under evaluation as a therapy for patients with COVID-19 associate pneumonia (canakinumab). We will examine the lung slices after infection using single cell RNA-Seq and RNAscope. Experiment 2. To determine whether endothelial cells in tissues outside the lung express IL6 in patients with severe COVID-19. We will perform RNAscope on fixed tissues harvested from 9 patients who have undergone autopsy after COVID-19 at Northwestern and RNAscope plus single cell RNA-Seq on lung, kidney, spleen and lymph nodes from 5 patients who undergo post- mortem biopsy in our ICU.

肺炎是COVID-19感染患者死亡的主要原因，对老年人的影响尤为严重