Lung transplant injury drives chronic lung allograft dysfunction via recruitment ofmonocyte-derived alveolar macrophages

肺移植损伤通过单核细胞衍生的肺泡巨噬细胞的募集导致慢性肺同种异体移植功能障碍

• 批准号: 10034029
• 负责人: Alexander Misharin
• 金额: $ 72.83万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10034029
• 关键词: Acute; Allografting; Alveolar; Alveolar Macrophages; Automobile Driving; Biological Markers; Biopsy; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CSF1 gene; CSF1R gene; Caring; Cells; Chronic; Clinical; Colony-Stimulating Factor Receptors; Computer Analysis; Data; Data Set; Development; Disease; Endothelium; Event; Extravasation; Fibroblasts; Fibrosis; Functional disorder; Genetic; Heart-Lung Transplantation; Human; Immune; In Situ; Injury; Lead; Life; Link; Liquid substance; Lung; Lung Transplantation; Lung diseases; Macrophage Colony-Stimulating Factor; Maintenance; Methods; Molecular; Morbidity - disease rate; Mus; Neutrophil Infiltration; Operative Surgical Procedures; Organ Transplantation; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Perioperative; Play; Population; Procedures; Publishing; Pulmonary Fibrosis; RNA; Reperfusion Injury; Reporting; Residencies; Role; Sampling; Semaphorins; Signal Transduction; Solid; Spleen; Structure of parenchyma of lung; System; Testing; Therapeutic; Tissues; Transplant Recipients; Transplant Surgeon; Transplantation; Trauma; Work; autocrine; biomarker identification; cell type; clinical phenotype; effective therapy; epithelial injury; experimental study; lung allograft; lung injury; monocyte; mortality; mouse model; new therapeutic target; plexin; prevent; programs; recruit; response; single cell analysis; single-cell RNA sequencing; transcriptome sequencing; transcriptomics

Project Summary: For many patients with advanced lung disease, lung transplantation remains the only viable therapeutic option to extend life. Yet the 5-year survival for lung transplant patients is 54%, the worst among solid organ transplant recipients. Chronic lung allograft dysfunction (CLAD) is the leading cause of morbidity and late mortality after lung or heart-lung transplantation. Hence, identification of biomarkers and novel therapeutic targets is essential to prevent or treat CLAD and extend survival after lung transplantation. While multiple factors contribute to CLAD, early events after the lung transplant procedure play a crucial role in setting the stage for subsequent CLAD. These include surgical trauma and ischemia-reperfusion injury that activates circulating and resident immune cells followed by the endothelial injury and immune cell extravasation. We have reported that monocytes, recruited to the injured lung, can establish a long-term residency and differentiate into pathogenic monocyte-derived alveolar macrophages. We have causally linked monocyte-derived alveolar macrophages to tissue-remodeling and fibrosis (resembling CLAD) using a genetic deletion strategy. Moreover, using unbiased single-cell transcriptomic profiling (RNA-seq) of explanted lung tissue from the patients with pulmonary fibrosis and biopsies of the donor lung (both obtained during lung transplantation by lung transplant surgeon – Ankit Bharat, key contributor to this proposal), we identified a distinct population of pathogenic alveolar macrophages exclusively present in patients with pulmonary fibrosis. Our computational analyses of single-cell RNA-seq data suggest that monocyte-derived alveolar macrophages are guided to their new pathogenic niches via plexin D1/signaling and are uniquely maintained by M-CSF/M- CSFR signaling. Consistent with this hypothesis, targeting M-CSF/M-CSFR signaling specifically eliminated monocyte-derived alveolar macrophages and ameliorated pathology. We present preliminary data from mouse models and patients with chronic lung allograft dysfunction supporting relevance of this mechanism for CLAD. We will thus use mouse models and samples from lung transplant patients to test the hypothesis that pathogenic monocyte-derived alveolar macrophages, recruited during the initial peri-transplant injury, establish long term residency via plexin D1/semaphorin signaling and are maintained via M-CSF/M- CSFR signaling to drive CLAD in three interrelated aims: Aim 1: To determine whether monocyte-derived alveolar macrophages recruited to the transplanted lung within day of the transplant are maintained by M-CSF/M-CSFR signaling. Aim 2: To determine whether pathogenic monocyte-derived alveolar macrophages are localized to regions of lung fibrosis lung via plexin D1/semaphorin signaling. Aim 3: To determine whether the emergence of aberrant alveolar macrophages with increased expression of PLXND1 and autocrine M-CSF/M-CSFR signaling can be identified in BAL fluid from patients with early CLAD.

项目总结：对于许多晚期肺部疾病患者，肺移植仍然是唯一的治疗方法