Nitric oxide protects against microcirculatory complications of malaria

一氧化氮可预防疟疾的微循环并发症

• 批准号: 7596233
• 负责人: Leonardo Jose de Moura Carvalho
• 金额: $ 42.62万
• 依托单位: LA JOLLA BIOENGINEERING INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596233
• 关键词: Address; Adhesions; Animals; Apoptosis; Arginine; Arts; Atherosclerosis; Biological Assay; Biological Availability; Blood; Blood - brain barrier anatomy; Blood Platelets; Blood Pressure; Blood Substitutes; Blood Vessels; Blood capillaries; Blood flow; Brain; Cell Adhesion; Cell Adhesion Molecules; Cells; Cerebral Malaria; Cessation of life; Child; Complex; Cyclic GMP; Data; Development; Disease; Doctor of Philosophy; Dyes; E-Selectin; Electrodes; Endothelial Cells; Erythrocytes; Evans blue stain; Exhibits; Extravasation; Functional disorder; Generations; Hemoglobin; Hemorrhage; Hypotension; Hypoxia; ICAM1 gene; Impaired cognition; Infection; Inflammation; Lactic Acidosis; Lead; Leukocytes; Location; Malaria; Malignant Neoplasms; Measurement; Measures; Mediating; Microcirculation; Microvascular Permeability; Molecular; Mus; NBL1 gene; Necrosis; Nitric Oxide; Nitric Oxide Donors; Organ failure; Oxygen; Parasite Control; Parasitemia; Parasites; Pathogenesis; Patients; Perfusion; Permeability; Plasmodium berghei; Production; Proteins; Radiolabeled; Reperfusion Injury; Research; Research Personnel; Role; Saline; Sepsis; Shock; Sickle Cell Anemia; Signal Transduction; Stroke; Superoxides; Techniques; Tissues; Toxic effect; Vascular Endothelial Growth Factors; Vascular Permeabilities; Venous; arteriole; base; brain tissue; capillary; density; in vivo; insight; intravital microscopy; killings; light microscopy; omega-N-Methylarginine; prevent; programs; radiotracer; response; tissue oxygenation; vasoconstriction; venule

DESCRIPTION (provided by applicant): We propose that low nitric oxide (NO) bioavailability mediates the microcirculatory complications of severe malaria; NO quenching by cell-free hemoglobin (Hb) released as an unavoidable consequence of parasite replication and low NO production due to hypoargininemia lead to low NO bioavailability. Vascular leak, petechial hemorrhaging, and hypotension are well recognized complications of experimental cerebral malaria (ECM), and the proposed studies will determine whether poor tissue oxygenation also functions in malaria pathogenesis by altering blood flow or functional capillary density. Our observations that (i) free hemoglobin (Hb) is markedly elevated during ECM, (ii) free Hb scavenges nitric oxide (NO) and (iii) marked hypoargininemia occurs during ECM indicate that, in contrast to sepsis, malaria shock is caused by low NO bioavailability. A major controversy in microcirculation research is the role of NO in mediating vascular leak and pathogenesis, and our proposed studies will define its role in vascular leak during ECM. A key prediction of our hypothesis is that exogenous NO should protect against ECM pathogenesis; indeed, NO donor administration significantly (P=0.003) protects animals from the development of disease. The markedly protected NO donor-treated mice abrogated the vascular leak, petechial hemorrhage, hypotension, and impaired NO mediated signaling (cGMP levels) that were detected in saline-injected controls with ECM. These studies will be extended to define whether NO donor administration protects against other microcirculatory dysfunction during ECM, such as low tissue perfusion and oxygenation (aim 1). Adhesion of parasitized erythrocytes (pRBCs), platelets, and leukocytes occur during ECM and deficiency of selected cell adhesion molecules protects against malaria pathogenesis. We will interrelate the results of the microcirculatory complications of ECM to cell adhesion and eCAM expression to define the cellular and molecular mechanisms whereby cell adhesion contributes to disruption of the blood brain barrier and pathogenesis and identify whether and how exogenous NO protects against ECM cell adhesion (aim 2). The final aim will assess by bioassay (arteriolar dilation, and venular leak) and actual measurement (NO electrode) whether NO bioavailability is impaired during ECM and restored by the protective NO donor. The response of eNOS to ECM and NO donor treatment will also be elucidated; a detailed understanding of in vivo eNOS responses to free Hb or to low NO bioavailability that occurs during other diseases (sickle cell anemia) is currently lacking. Besides providing new information about the microcirculation, the proposed studies may lead to adjunct therapy for malaria that rescues millions of children from death or impaired cognition. These studies will also address long standing controversies about malaria pathogenesis, such as whether pRBC adhesion leads to hypoxia and multi-organ failure (sequestration hypothesis).

描述（由申请人提供）：我们建议低一氧化氮（NO）生物利用度介导了严重疟疾的微循环并发症。无细胞血红蛋白（HB）释放的淬灭是寄生虫复制的不可避免的结果，而由于低脂蛋白血症引起的低产生导致低无生物利用度。血管泄漏，脊柱出血和低血压是实验性脑疟疾（ECM）的并发症，并且提出的研究将通过改变血流或功能性毛细管密度来确定较差的组织氧合性是否也会在疟疾发病机构中起作用。我们观察到（i）（i）在ECM期间（II）ECM中的游离HB氧化氧化物（NO）和（III）在ECM期间出现了游离HB一氧化氮（NO）和（III）在ECM期间出现的（II）显着升高（II）ECM中发生的（II）表明，与脓毒症相反，疟疾冲击导致疟疾震动引起的疟疾低。微循环研究中的一个重大争议是NO在介导血管泄漏和发病机理中的作用，我们提出的研究将定义其在ECM期间在血管泄漏中的作用。我们假设的关键预测是，外源性NO应该预防ECM发病机理。实际上，没有明显的供体给药（p = 0.003）可以保护动物免受疾病的发展。明显保护的没有供体治疗的小鼠废除了血管泄漏，petechial出血，低血压和受损的未介导的信号传导（CGMP水平），这些信号传导（CGMP水平）在用ECM注入盐水的对照中被检测到。这些研究将扩展以定义没有供体给ECM期间其他微循环功能障碍（例如低组织灌注和氧合）的其他微循环功能障碍（AIM 1）。 ECM期间发生寄生的红细胞（PRBC），血小板和白细胞的粘附，并且选定的细胞粘附分子的缺乏可预防疟疾发病机理。我们将相互关联ECM对细胞粘附和ECAM表达的微循环并发症的结果，以定义细胞和分子机制，从而使细胞粘附有助于干扰血液脑屏障和发病机理，并确定外源是否以及如何以及如何以及如何以及如何保护ECM细胞粘附（AIM 2）。最终目的将通过生物测定（小动脉扩张和静脉泄漏）和实际测量（无电极）评估，无论在ECM期间没有任何生物利用度损害并由保护性无供体恢复。 eNOS对ECM的反应和任何供体治疗也将得到阐明；目前缺乏对自由HB的体内eNOS反应的详细理解，或者对其他疾病期间（镰状细胞贫血）的无生物利用度的反应。除了提供有关微循环的新信息外，拟议的研究还可能导致疟疾的辅助治疗，从而使数百万儿童免于死亡或认知受损。这些研究还将解决有关疟疾发病机理的长期存在争议，例如PRBC粘附是否导致缺氧和多器官衰竭（隔离假设）。