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：
10536629
负责人：
Jason Gardner
金额：
$ 43.54万
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/10536629
关键词：
Anemia Attenuated Autocrine Communication Blood Blood Transfusion Blood Vessels Body Surface Area Bone Marrow Burn Units Burn injury CSF3 gene Caring Cells Characteristics Clinical Complication Critical Illness Data Debridement Disparate Elective Surgical Procedures Erythrocytes Erythroid Cells Erythropoiesis Erythropoietin Event Fibroblasts Genes Genetic Models Goals Hemolysis Hormones Human IL1R1 gene 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 Ligands Longevity MYD88 deficiency Macrophage Maintenance Mediating Mediator Medical Modeling Molecular Mus Myelogenous Outcome Pathogenesis Pathologic Pathway interactions Patients 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 access restrictions autocrine burn model burn wound cell type cytokine hepcidin improved iron supplement iron supplementation 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.

抽象的危害疾病的贫血是（ACI）是ICU的常见并发症，在烧伤患者中输血要求的决定因素。不良的医疗结果与过度有关烧伤患者的输血，并迫使转移到更保守的输血方案。甚至通过采用更保守的输血方法，烧伤患者仍然需要大量血。没有其他选择可以减少严重烧伤或创伤的受害者的输血，因为促红细胞生成素（EPO）和补充铁不能有效地促进这些患者的红细胞生成。这是涉及铁限制的ACI等炎症性贫血的特征，降低了红细胞寿命和促红细胞生成活动的损害。该提议的理由是发展治疗ACI的治疗方法只能通过对炎症的更全面了解才能实现驱动ACI的机制。该提案的目的是确定可靶向的炎症可以利用以减少燃烧单元和ICU中输血要求的机制。中央该提议的假设是，烧伤后ACI由于EPO信号和铁受损而发展由G-CSF和IL-6分泌介导的限制，该分泌由炎症信号控制烧伤。我们提出了这一假设的三个目标，即如果成功揭示1）炎症启动烧伤后ACI的网络，2）EBI小众在烧伤后的发病机理中的作用，3）铁限制在烧伤后ACI发病机理中的作用。成功完成拟议的目标将识别一个可用于批准的细胞因子，信号通路和细胞反应的轴或新兴的治疗剂减轻烧伤后的ACI。