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: 7837444
• 负责人: Leonardo Jose de Moura Carvalho
• 金额: $ 34.02万
• 依托单位: LA JOLLA BIOENGINEERING INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837444
• 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

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 eak, 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 inter relate 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).

我们认为低一氧化氮（NO）的生物利用度介导的微循环并发症