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Role of Spleen educated monocytes in mediating ischemia-reperfusion injury following lung transplant

脾脏单核细胞在介导肺移植后缺血再灌注损伤中的作用

基本信息

批准号：
10132385
负责人：
Ankit Bharat
金额：
$ 59.15万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132385
关键词：
Affect Allografting Alveolar Alveolar Macrophages Atlases Biopsy Blood Vessels Bone Marrow CCL2 gene CX3CL1 gene Caring Cells Chronic Clinical Data Development Disease Donor person Endothelium Experimental Designs Extravasation Fractalkine Functional disorder Genes Genetic Genetic study Herpes zoster disease Hour Human Hypoxemia Image Immune Inflammasome Injury Interleukin-1 beta Intervention Life Lung Lung Transplantation Lung diseases Mediating Membrane Molecular Mus Mutate Neutrophil Infiltration Organ Outcome Paper Pathologic Patient-Focused Outcomes Patients Pharmacology Production Proteins Publishing Pulmonary Inflammation Receptor Activation Reperfusion Injury Reperfusion Therapy Reporting Respiratory Failure Risk Factors Role Savings Signal Pathway Signal Transduction Spleen Splenic Red Pulp Structure of parenchyma of lung Syndrome System TLR2 gene Testing Tight Junctions Time Toll-like receptors Transforming Growth Factor beta Transgenic Organisms Translations Transplantation Variant allograft rejection clinical application clinical practice clinically relevant experimental study genetic approach improved interstitial lung injury macrophage monocyte mortality mouse model neutrophil novel therapeutics pathogen post-transplant reconstitution recruit response severe injury spleen transplantation two-photon

项目摘要

PROJECT SUMMARY Primary graft dysfunction (PGD) after lung transplantation, resulting from ischemia reperfusion injury (IRI), is the predominant cause of poor lung transplant outcomes. Pathologically, PGD is characterized by neutrophil extravasation into the alveolar space. In murine models of lung transplantation, NETosis of extravasated neutrophils induces irreversible allograft injury. Non-selective depletion of neutrophils can ameliorate PGD, but is not clinically feasible given their importance in pathogen clearance. Accordingly, we have focused on understanding the specific mechanisms that drive neutrophil extravasation into the allograft leading to PGD after lung transplantation. We discovered that after lung transplantation, Ly6ClowCCR2- non-classical monocytes (NCM), retained in the donor lung, and Ly6ChighCCR2+ classical monocytes (CM), recruited to the allograft, are both necessary for the extravasation of neutrophils into the interstitial space and the resulting lung injury. Both NCM and CM produce IL-1β in response to IRI, with differing consequences. We present preliminary data suggesting that IL-1β produced by NCM activates donor alveolar macrophages (AM), inducing their secretion of monocyte chemoattractant protein 1 (MCP-1) which results in recruitment of CM. Our data also demonstrates that CM recruited to the allograft further produce IL-1β in response to signaling through toll-like receptors, which permeabilizes the endothelium by downregulating the tight junction protein, Zona Occludens 2 (ZO-2), to promote neutrophil extravasation. Using a genetic lineage tracing system and heterochronic spleen transplants we reported that CMs originating in the bone marrow receive signals from the spleen necessary for their function in mediating neutrophil extravasation after transplantation revealing the spleen as an active immune organ in this response. We present preliminary data to support our hypothesis that after lung transplantation, IL-1β released by donor NCM induces the secretion of MCP-1 from donor alveolar macrophages, which is necessary for the recruitment of recipient CM primed by splenic red pulp macrophages. This results in sustained IL-β signaling in the allograft that promotes neutrophil extravasation and graft injury. We will test this hypothesis in two aims. Aim 1. To determine whether donor NCM and alveolar macrophage-dependent MCP-1 secretion recruits host splenic CM to mediate neutrophil extravasation after lung transplantation. Aim 2. To determine whether splenic endothelial fractalkine retains CM recruited by TGF-β released from red pulp macrophages to prime the NLRP3 inflammasome. We use causal genetic strategies in mouse models identify disease mechanisms and tie these experiments to applicable therapies that can be tested in humans. In addition, we have taken care to pair our results with unbiased analyses of human lung tissue obtained from biopsies of the donor lung before and at several times after reperfusion during lung transplantation to create a molecular atlas of human ischemia reperfusion injury. These studies will facilitate the rapid translation of our findings to clinical practice.

肺移植术后原发性移植物功能障碍（PGD），由缺血引起