Chronic Stress and Anemia Recovery following Major Trauma

重大创伤后的慢性压力和贫血恢复

• 批准号: 10217153
• 负责人: ALICIA M MOHR
• 金额: $ 52.43万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217153
• 关键词: Acute; Adrenergic Agents; Affect; Anemia; Award; Binding; Blood Transfusion; Bone Marrow; Cell Differentiation process; Cessation of life; Chronic; Chronic stress; Clinical; Clonidine; Complication; Contusions; Critical Illness; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Event; Foundations; Functional disorder; Funding; Future; GATA1 gene; Genomics; Growth; Hematopoietic stem cells; Hemoglobin; Hemorrhage; Hemorrhagic Shock; Human; Impairment; Infection; Injury; Intensive Care Units; Intervention; Iron; Knock-out; LMO2 gene; Link; Lung; Manuscripts; MicroRNAs; Modeling; Morbidity - disease rate; Neurosecretory Systems; Norepinephrine; Patients; Period Analysis; Play; Prevention; Propranolol; Publishing; Recovery; Resolution; Risk Factors; Rodent; Rodent Model; Sampling; Site; Stat5 protein; Stress; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Transfusion; Translations; Trauma; Trauma patient; Traumatic injury; Validation; base; erythroid differentiation; hepcidin; improved; inflammatory milieu; injury recovery; iron deficiency; mortality; novel; peripheral blood; progenitor; receptor expression; response; restraint stress; severe injury; therapy development; transcription factor; treatment strategy

Abstract Injury-associated anemia develops in patients suffering major trauma and remains persistent when followed by critical illness. Currently, the only available treatment is blood transfusions. In the initial period of this award, we demonstrated that bone marrow erythropoietic dysfunction was linked to a hyperadrenergic state and that with critical illness and chronic stress this hyperadrenergic state is prolonged. We also described a novel critical illness rodent model that combined lung contusion, hemorrhagic shock and chronic stress that led to persistent anemia on day seven following initial injury. The prolonged adrenergic stimulation that occurred with chronic stress following injury and hemorrhagic shock worsened erythropoietic dysfunction, reduced the growth of erythroid progenitors, and exaggerated the mobilization of hematopoietic progenitors from the bone marrow. In addition, chronic stress led to the combined deficit of reduced iron availability due to hepcidin activation and reduced bone marrow erythropoietin receptor expression associated with an ineffective erythropoietin response that accompanied injury-associated anemia. These findings were confirmed in bone marrow obtained from severely injured trauma patients. In addition, we also demonstrated that we could improve erythropoietic function in our rodent model with either propranolol or clonidine, both agents act to reduce the effects of norepinephrine through two different mechanisms. The mechanistic studies proposed in this application are the natural extension of our recent findings and will test if chronic stress and prolonged adrenergic stimulation following injury and hemorrhagic shock are directly responsible for the persistence of injury-associated anemia with impaired differentiation and maturation of erythroid cells, and if reduction of chronic stress can improve anemia and alter recovery. To accomplish this, there are three specific aims: 1) To delineate if long term chronic stress results in a persistent inflammatory milieu that further impairs recovery of injury-associated anemia; 2) To determine if alterations in the erythropoietin receptor or hepcidin or stress-related genomic changes in erythroid differentiation is the primary event following injury and chronic stress contributing to persistent injury-associated anemia; 3) To determine the optimal therapeutic agent to reduce chronic stress and investigate if it leads to faster resolution of injury-associated anemia and improved recovery. The first aim will further characterize injury-associated anemia long-term and during recovery. The second aim will determine the how chronic stress mechanistically alters hepcidin function and stress-related genomic changes in erythropoiesis leading to impaired differentiation and maturation of erythroid cells. The third aim will determine the optimal therapeutic agent to reduce the hyperadrenergic state following trauma and possibly decrease the duration of persistent injury-associated anemia. Combining rodent and human studies gives us the opportunity to mechanistically study injury-associated persistent anemia and its recovery, as well as identify potential therapeutic interventions to reduce morbidity and mortality associated with anemia and transfusion.

摘要 损伤相关性贫血发生在遭受严重创伤的患者中， 病危目前唯一的治疗方法是输血。在这个奖项的最初阶段，我们 表明骨髓红细胞生成功能障碍与肾上腺素能亢进有关， 严重的疾病和慢性压力会延长这种肾上腺素能亢进的状态。我们还描述了一种新的危重病 啮齿动物模型，结合肺挫伤，失血性休克和慢性应激，导致持续性贫血， 第七天受伤后。长期的肾上腺素能刺激发生在慢性应激后， 损伤和失血性休克使红细胞生成功能障碍恶化，减少红系祖细胞的生长， 夸大了骨髓造血祖细胞的动员。此外，慢性压力导致 铁调素活化导致的铁可用性降低和骨髓促红细胞生成素降低的联合缺陷 受体表达与无效的促红细胞生成素反应相关， 贫血这些发现在从严重受伤的创伤患者获得的骨髓中得到证实。此外，本发明还提供了一种方法， 我们还证明，我们可以改善红细胞生成功能，在我们的啮齿动物模型与心得安或 可乐定，这两种药物通过两种不同的机制来降低去甲肾上腺素的作用。的 本申请中提出的机制研究是我们最近发现的自然延伸，并将测试 损伤和失血性休克后的慢性应激和长时间肾上腺素能刺激是直接原因 对于持续存在的损伤相关性贫血伴红系细胞分化和成熟受损，如果 减少慢性压力可以改善贫血并改变恢复。为了实现这一点，有三个具体的 目的：1）描述长期慢性应激是否会导致持续的炎症环境， 损伤相关性贫血的恢复; 2）确定促红细胞生成素受体或铁调素或铁调素的改变是否与损伤相关性贫血的恢复有关。 红细胞分化中与应激相关的基因组变化是损伤和慢性应激后的主要事件 导致持续性损伤相关性贫血; 3）确定最佳治疗药物，以减少慢性 并研究它是否能更快地解决与损伤相关的贫血和改善恢复。第一 aim将进一步描述长期和恢复期损伤相关性贫血的特征。第二个目标将决定 慢性应激如何机械地改变hepcidin的功能和应激相关的基因组变化， 红细胞生成，导致红系细胞分化和成熟受损。第三个目标将决定 降低创伤后肾上腺素能亢进状态并可能缩短持续时间的最佳治疗剂 持续性损伤相关性贫血结合啮齿动物和人类的研究，我们有机会 从机制上研究损伤相关的持续性贫血及其恢复，并确定潜在的治疗方法， 采取干预措施，降低与贫血和输血相关的发病率和死亡率。