Red blood cell ATP export and transfusion in sepsis
脓毒症中红细胞 ATP 输出和输血
基本信息
- 批准号:10584768
- 负责人:
- 金额:$ 73.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-05 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Lung InjuryAcute Respiratory Distress SyndromeAdenineAdhesionsAdhesivesAdultAnemiaAttenuatedBloodBlood TransfusionBlood VesselsBlood flowBlood specimenCaliberCardiac OutputCellsChildClinicalConsumptionCouplingCritical IllnessCryopreserved CellDepressed moodEndothelial CellsEndotheliumEnsureErythrocyte TransfusionErythrocytesExposure toFunctional disorderGeneticHemoglobinHomeostasisHumanHypoxemiaHypoxiaImmune responseImpairmentIn VitroIncubatedInfectionInflammationInfluenzaInosineInterventionInvestigationLeukocytesLungMediatingMediatorMetabolicMethodsModelingMorbidity - disease rateMusOralOrganOutcomeOxygenPatientsPeripheralPersonsPhasePhenotypePyruvatePyruvate KinaseRespiration DisordersRespiratory physiologyRiskRisk FactorsRoleSamplingSchemeSepsisSignal TransductionSiteSpecimenTestingTherapeuticTissuesTransfusionTranslationsbiobankcandidate identificationcecal ligation puncturecell injurycell typeclinical investigationclinical translationclinically relevantdesignempowermentexperimental studygenetic approachimprovedin vivoinorganic phosphateinsightlead candidatemortalitymouse modelnovelpharmacologicpreservationprospectiverespiratoryresponseseptictissue oxygenationuptake
项目摘要
ABSTRACT
O2 uptake in the lung and O2 delivery peripherally depend on the efficient matching of blood flow to regional O2
availability in the lung and O2 consumption in tissues. To achieve this matching, red blood cell (RBC) hemoglobin
allostery regulates not only trans-erythrocytic O2 flux but also RBC export of vasoactive mediators that respond
to O2 demand. RBCs export vasoregulatory ATP basally and in response to O2 deficit. This RBC-based vascular
control of the uptake and delivery of O2 may be disrupted by endogenous (e.g., in sepsis) and exogenous (via
storage for transfusion) RBC injuries. Septic persons with moderate anemia are frequently transfused, but
infrequently benefit. Yet conversely any anemia is a negative risk factor. Lung morbidity is frequent after RBC
transfusion, possibly due to impaired RBC ability to export ATP, disrupting O2 uptake via pulmonary RBC-
endothelial adhesion. We show in septic mice (cecal ligation/puncture, CLP) that the RBC’s ability to produce
and export ATP is impaired. We will test the hypothesis that the O2-transport dysfunction in sepsis is
mediated in part by impaired export by RBCs of vasoregulatory ATP, a dysfunction compounded by
transfused RBCs, exacerbating acute lung injury (ALI) and hypoxemia, by achieving these Aims: Aim 1.
Determine the role of RBC ATP export in mortality and ALI in a mouse model of sepsis and transfusion.
Exchange transfusion of CLP RBCs into healthy mice exposed to hypoxia drives mortality. RBC ATP export
takes place via pannexin 1 (Px1). We will determine the role and mechanism of depressed RBC ATP export via
Px1 in the mortality, ALI, and O2 transport responses to sepsis (CLP or severe influenza) and transfusion in mice
using genetic and pharmacological approaches. Aim 2. Determine the influence of augmenting transfusate
RBC ATP content and/or export on organ function and O2 transport in septic mice. RBC ATP export can
be augmented via clinically available approaches: hypoxic RBC storage; transfusate incubation with PIPA
(phosphate, inosine, pyruvate, adenine) solution that preserves stored-RBC ATP and DPG; or using an activator
of RBC pyruvate kinase (PKR), which augments RBC ATP with little effect on DPG or P50. We will test these
approaches to augment or preserve RBC ATP content on ATP export in mice transfused during sepsis. Aim 3.
Determine the influence of human sepsis on RBC vasoregulatory function ex vivo, and the functional
influence of candidate modulators of ATP content and export in septic RBCs. We validated a novel RBC
cryopreservation scheme with superior phenotype fidelity. We built a unique biobank of RBC specimens from
septic children and adults. We prospectively sampled over 150 patients with severe sepsis; most subjects have
ALI. We will determine the influence of translation-ready lead candidates identified in Aim 2 to augment RBC
ATP export on key RBC respiratory functions: vasoactivity, anti-adhesivity, and O2 transport. We will model the
effects of transfusate intervention in admixed septic and stored RBCs. Our novel focus on disrupted signaling by
RBCs will produce novel, practical, and relevant insight into respiratory dysfunction in sepsis and transfusion.
摘要
肺中的O2摄取和外周O2输送取决于血流与局部O2的有效匹配
肺中的可用性和组织中的O2消耗。为了实现这种匹配,红细胞(RBC)血红蛋白
变构不仅调节跨红细胞O2通量,而且调节红细胞输出血管活性介质,
到O2需求。红细胞输出血管调节ATP的基础和响应O2赤字。这种基于红细胞的血管
O2的摄取和输送的控制可能被内源性(例如,败血症)和外源性(通过
输血储存)RBC损伤。中度贫血的败血症患者经常输血,但
很少受益。然而,相反,任何贫血都是一个负面的风险因素。RBC治疗后肺部发病率较高
输血,可能是由于RBC输出ATP的能力受损,破坏了通过肺RBC的O2摄取-
内皮粘附我们在脓毒症小鼠(盲肠结扎/穿孔,CLP)中发现,
输出ATP受损。我们将检验脓毒症中氧转运功能障碍的假设,
部分由RBC的血管调节ATP输出受损介导,这是一种功能障碍,
输注红细胞,加重急性肺损伤(ALI)和低氧血症,通过实现这些目的:目的1。
在败血症和输血的小鼠模型中确定RBC ATP输出在死亡率和ALI中的作用。
CLP RBC向暴露于缺氧的健康小鼠的交换输血导致死亡。RBC ATP输出
通过泛连接蛋白1(Px 1)发生。我们将通过以下方法确定抑制RBC ATP输出的作用和机制:
Px 1在小鼠败血症(CLP或严重流感)和输血的死亡率、ALI和O2转运反应中的作用
使用遗传学和药理学方法。目标二。确定增加输血的影响
RBC ATP含量和/或输出对脓毒症小鼠器官功能和O2转运的影响RBC ATP导出可以
通过临床可用的方法增强:低氧RBC储存;用PIPA进行输注孵育
(磷酸盐,肌苷,丙酮酸盐,腺嘌呤)溶液,保存储存的红细胞ATP和DPG;或使用激活剂
红细胞丙酮酸激酶(PKR),增加红细胞ATP,对DPG或P50几乎没有影响。我们将测试这些
方法增加或保持红细胞ATP含量的ATP输出在小鼠输血期间败血症。目标3.
确定人脓毒症对离体RBC血管调节功能的影响,以及功能性的
脓毒症红细胞中ATP含量和输出候选调节剂的影响。我们验证了一种新的RBC
具有上级表型保真度的冷冻保存方案。我们建立了一个独特的红细胞样本生物库,
败血症儿童和成人。我们对150多名严重脓毒症患者进行了前瞻性抽样,大多数受试者
阿里我们将确定目标2中确定的准备就绪的主要候选人对增加RBC的影响
ATP输出对关键RBC呼吸功能的影响:血管活性、抗粘附性和O2运输。我们将模拟
在混合的败血性和储存的红细胞中输血干预的效果。我们的新焦点是通过
红细胞将产生新的,实用的,和相关的见解呼吸功能障碍败血症和输血。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ALLAN DOCTOR其他文献
ALLAN DOCTOR的其他文献
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{{ truncateString('ALLAN DOCTOR', 18)}}的其他基金
ErythroMer: Nanoscale Bio-Synthetic Red Cell Substitute
ErythroMer:纳米级生物合成红细胞替代品
- 批准号:
9347784 - 财政年份:2017
- 资助金额:
$ 73.14万 - 项目类别:
SEPSIS-INDUCED RED CELL DYSFUNCTION (SIRD)
脓毒症引起的红细胞功能障碍 (SIRD)
- 批准号:
9229050 - 财政年份:2015
- 资助金额:
$ 73.14万 - 项目类别:
SEPSIS-INDUCED RED CELL DYSFUNCTION (SIRD)
脓毒症引起的红细胞功能障碍 (SIRD)
- 批准号:
8803196 - 财政年份:2015
- 资助金额:
$ 73.14万 - 项目类别:
SEPSIS-INDUCED RED CELL DYSFUNCTION (SIRD)
脓毒症引起的红细胞功能障碍 (SIRD)
- 批准号:
9069918 - 财政年份:2015
- 资助金额:
$ 73.14万 - 项目类别:
SEPSIS-INDUCED RED CELL DYSFUNCTION (SIRD)
脓毒症引起的红细胞功能障碍 (SIRD)
- 批准号:
9273245 - 财政年份:2015
- 资助金额:
$ 73.14万 - 项目类别:
Erythrocyte Nitrosothiol Flux and Vasoregulation in Lung
红细胞亚硝基硫醇通量和肺血管调节
- 批准号:
6710786 - 财政年份:2004
- 资助金额:
$ 73.14万 - 项目类别:
Erythrocyte Nitrosothiol Flux and Vasoregulation in Lung
红细胞亚硝基硫醇通量和肺血管调节
- 批准号:
7350865 - 财政年份:2004
- 资助金额:
$ 73.14万 - 项目类别:
Erythrocyte Nitrosothiol Flux and Vasoregulation in Lung
红细胞亚硝基硫醇通量和肺血管调节
- 批准号:
6839438 - 财政年份:2004
- 资助金额:
$ 73.14万 - 项目类别:
Erythrocyte Nitrosothiol Flux and Vasoregulation in Lung
红细胞亚硝基硫醇通量和肺血管调节
- 批准号:
7250307 - 财政年份:2004
- 资助金额:
$ 73.14万 - 项目类别:
Erythrocyte Nitrosothiol Flux and Vasoregulation in Lung
红细胞亚硝基硫醇通量和肺血管调节
- 批准号:
7009990 - 财政年份:2004
- 资助金额:
$ 73.14万 - 项目类别:
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