Anemia and the Chronic Hyperadrenergic State following Major Trauma

严重创伤后的贫血和慢性肾上腺素能亢进状态

• 批准号: 8740505
• 负责人: ALICIA M MOHR
• 金额: $ 25.65万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8740505
• 关键词: Acute; Adrenergic Agents; Adrenergic Receptor; Adrenergic beta-Antagonists; Anemia; Architecture; Atenolol; Blood Transfusion; Bone Marrow; Bone Marrow Aspiration; Bone Marrow Cells; Bone Marrow Suppression; C-KIT Gene; CD34 gene; CSF3 gene; CXCR4 gene; Cell Adhesion; Cell Culture Techniques; Cell Differentiation process; Cell surface; Cessation of life; Chronic; Chronic stress; Collagen; Contusions; Critical Illness; Defect; Development; Enzyme-Linked Immunosorbent Assay; Erythroid; Erythroid Cells; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Extracellular Matrix; Fibronectins; Flow Cytometry; Functional disorder; Gelatinase A; Gelatinase B; Genetic Transcription; Goals; Growth; HMGB1 gene; Hematopoietic; Hematopoietic stem cells; Hemoglobin; Hemoglobin concentration result; Hemorrhage; Hemorrhagic Shock; Hormones; Human; In Vitro; Incidence; Infection; Inflammatory; Injury; Integrins; Interleukin-10; Interleukin-3; Interleukin-6; LMO2 gene; Lead; Leukocyte Elastase; Link; Lung; Mediating; Mediator of activation protein; Modeling; Norepinephrine; Organ; Oxidopamine; Pathway interactions; Patients; Peripheral; Proteolysis; Rattus; Research; Reticulocytes; Risk Factors; Rodent Model; Role; STAT5A gene; Simulate; Site; Sorting - Cell Movement; Staining method; Stains; Stem Cell Factor; Stress; Stromal Cell-Derived Factor 1; Substance P; TFRC gene; Testing; Therapeutic; Thromboplastin; Transferrin Receptor; Trauma; Vascular Cell Adhesion Molecule-1; adrenergic; alternative treatment; base; cell growth; clinically relevant; cost; erythroid differentiation; hepcidin; human GATA1 protein; improved; leukemic stem cell; peripheral blood; prevent; progenitor; programs; protective effect; public health relevance; receptor; response; restraint; treatment strategy

DESCRIPTION (provided by applicant): Patients suffering major trauma and critical illness develop an injury-associated persistent anemia which is not related to acute blood loss. Understanding the pathophysiology of this persistent anemia would avoid the use of blood transfusions which is currently the only available treatment. Our overall goal is to develop treatment strategies for this persistent anemia. Injury and hemorrhagic shock worsen bone marrow (BM) dysfunction and inhibit the differentiation of hematopoietic progenitor cells (HPC) and lead to increased mobilization of HPC from the BM to the peripheral blood and sites of injury. Our recent studies suggest that this BM dysfunction is linked to a hyperadrenergic state and that with critical illness this hyperadrenergic state is prolonged. This proposal will test the central hypothesis that chronic adrenergic stimulation following injury and hemorrhagic shock worsens BM dysfunction further inhibiting the differentiation of HPCs and exaggerating the mobilization of HPCs from BM contributing to injury-associated persistent anemia. Our specific aims are to: Aim 1. Determine the effects of a persistent inflammatory milieu on BM erythroid differentiation and anemia. Aim 2. Determine if excessive and ongoing HPC mobilization contributes to persistent anemia. These aims will be examined in our established model of lung contusion and hemorrhagic shock followed by daily restraint to simulated chronic stress. To compliment both these aims we will also examine the use of beta adrenergic blockade and 6-hydroxydopamine to decrease the hyperadrenergic state and prevent BM dysfunction and thus alleviate persistent anemia.

描述（由申请人提供）：严重创伤和危重病患者发生与急性失血无关的损伤相关持续性贫血。了解这种持续性贫血的病理生理学将避免使用输血，这是目前唯一可用的治疗方法。我们的总体目标是为这种持续性贫血制定治疗策略。损伤和失血性休克使骨髓（BM）功能障碍恶化，抑制造血祖细胞（HPC）的分化，并导致HPC从BM向外周血和损伤部位的动员增加。我们最近的研究表明，这种BM功能障碍与肾上腺素能亢进状态有关，并且在危重疾病中，这种肾上腺素能亢进状态会延长。这项提案将考验 中心假说认为，损伤和失血性休克后慢性肾上腺素能刺激会导致BM功能障碍，进一步抑制HPC分化，并扩大HPC从BM的动员，导致损伤相关的持续性贫血。我们的具体目标是：目标1。确定持续炎症环境对BM红细胞分化和贫血的影响。目标二。确定过度和持续的HPC动员是否会导致持续性贫血。这些目标将在我们建立的肺挫伤和失血性休克模型中进行检查，然后每天限制模拟慢性应激。为了实现这两个目标，我们还将研究β肾上腺素能阻滞剂和6-羟基多巴胺的使用，以减少肾上腺素能亢进状态，防止BM功能障碍，从而缓解持续性贫血。