Inflammatory Mechanisms in Post Burn Anemia of Critical Illness

危重病烧伤后贫血的炎症机制

基本信息

批准号：
10365617
负责人：
Jason Gardner
金额：
$ 45.87万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365617
关键词：
Anemia Attenuated Autocrine Communication Blood Blood Vessels Body Surface Area Bone Marrow Burn Units Burn injury CSF3 gene Caring Cells Characteristics Clinical Complication Critical Illness Cytokine Signaling Data Debridement Elective Surgical Procedures Erythrocytes Erythroid Cells Erythropoiesis Erythropoietin Event Fibroblasts Genes Genetic Models Goals Hemolysis Hormones Human Impairment Individual Infection Inflammation Inflammatory Institution Insulin-Like Growth Factor I Interleukin-1 alpha Interleukin-1 beta Interleukin-6 Interruption Intervention Iron Island Knock-out Lead Ligands Longevity MYD88 deficiency Maintenance Mediating Mediator of activation protein Medical Modeling Molecular Mus Myelogenous Outcome Pathogenesis Pathologic Pathway interactions Patients Play Production Protocols documentation Red Cell Mass result Reporter Resistance Risk Factors Role Signal Pathway Signal Transduction Skin Source Sterility TLR2 gene TLR4 gene Testing Therapeutic Transfusion Trauma autocrine base burn model burn wound cell type hepcidin improved iron supplement iron supplementation macrophage mortality neutralizing antibody novel pre-clinical receptor response severe burns single-cell RNA sequencing skin burn therapeutic development tissue injury transcriptomics translational therapeutics wound

项目摘要

Abstract The anemia of critical illness is (ACI) is a frequent complication in the ICU and in burn patients a primary determinant of transfusion requirements. Poor medical outcomes have been associated with excessive transfusion in burn patients and have compelled the move to more conservative transfusion protocols. Even with the institution of a more conservative approach to transfusion, burn patients still require large quantities of blood. There are no alternatives to reduce transfusion in victims of severe burn or trauma because erythropoietin (EPO) and iron supplementation do not effectively promote erythropoiesis in these patients. This is characteristic of an inflammatory anemia such as ACI that involves iron restriction, reduced erythrocyte lifespan and impairment of erythropoietic activity. The rationale for this proposal is that development of therapeutic approaches to treat ACI can only be realized with a more complete understanding of inflammatory mechanisms that drive ACI. The objective of this proposal is to identify the targetable inflammatory mechanisms that can be exploited to reduce transfusion requirements in the burn unit and ICU. The central hypothesis of this proposal is that post burn ACI develops as a result of impaired EPO signaling and iron restriction that are mediated by G-CSF and IL-6 secretion that is controlled by inflammatory signaling in the burn wound. We propose test this hypothesis in three aims that if successful will reveal 1) the inflammatory networks that initiate post burn ACI, 2) the role of the EBI niche in the pathogenesis of post burn ACI, and 3) the role of iron restriction in the pathogenesis of post burn ACI. Successful completion of the proposed aims will identify an axis of cytokines, signaling pathways, and cellular responses that can be targeted with approved or emerging therapeutics to alleviate post burn ACI.

抽象的危重症贫血（ACI）是 ICU 中常见的并发症，也是烧伤患者的主要并发症。输血需求的决定因素。不良的医疗结果与过度治疗有关烧伤患者的输血并迫使采取更保守的输血方案。甚至随着更保守的输血方法的建立，烧伤患者仍然需要大量的输血血。没有其他方法可以减少严重烧伤或创伤患者的输血，因为促红细胞生成素（EPO）和补铁不能有效促进这些患者的红细胞生成。这是炎症性贫血（例如 ACI）的特征，涉及铁限制、红细胞减少寿命和红细胞生成活性受损。该提案的理由是，发展只有对炎症有更全面的了解，才能实现治疗 ACI 的治疗方法驱动 ACI 的机制。该提案的目的是确定可靶向的炎症可用于减少烧伤病房和 ICU 输血需求的机制。中央该提议的假设是，烧伤后 ACI 的发生是由于 EPO 信号传导和铁受损由 G-CSF 和 IL-6 分泌介导的限制，而 IL-6 分泌受炎症信号控制烧伤伤口。我们建议通过三个目标来测试这一假设，如果成功，将揭示 1) 炎症启动烧伤后 ACI 的网络，2) EBI 生态位在烧伤后 ACI 发病机制中的作用，以及 3) 铁限制在烧伤后 ACI 发病机制中的作用。成功完成拟议目标将确定细胞因子、信号传导途径和细胞反应的轴，这些轴可以针对已批准的或减轻烧伤后 ACI 的新兴疗法。