Role of Nitric Oxide in Malaria
Condition: Malaria; Pulmonary Hypertension
MeSH terms: Malaria; Hypertension, Pulmonary; Hypertension
Study type: Observational

Summary: 
      This study, conducted by NIH, the University of Bamako in Mali, Africa, and Tulane University
      will examine the relationships between hemolysis (breakdown of red blood cells), nitric oxide
      (a gas important in regulating blood vessel dilation and blood flow) and pulmonary
      hypertension in patients with malaria. Malaria is among the leading causes of death in many
      of the world s poorest countries. It is caused by a parasite that is transmitted to humans by
      mosquitoes.

      Malian children ages 1-5 years are eligible for participation in this study. They include
      children with asymptomatic infection, uncomplicated disease, and severe disease. Uninfected
      controls are also included.

      Upon enrollment, participants have a medical history and physical examination, echocardiogram
      (ultrasound test of heart function) and blood tests. In addition, all participants (infected
      children and controls) have repeat evaluations when healthy, approximately 7 to10 days
      following successful therapy.
    

Detailed description: 
      Malaria is among the leading infectious causes of death in many of the world s poorest
      countries. This parasitic mosquito-borne illness produces massive hemolysis in many infected
      human hosts. While much is known about parasite replication and cytoadherence, very little is
      known about the impact of hemolysis per se on vascular tone and endothelial function.
      Crossing a number of medical disciplines beyond the scope of malaria, intriguing new research
      on inherited hemolytic disorders such as sickle cell disease (SCD) provides clues to
      pathogenic mechanisms that may be relevant to malaria. Dr. Gladwin (NHLBI) and colleagues
      have characterized a mechanism of disease, hemolysis-associated endothelial dysfunction, in
      which red blood cell hemoglobin spills into plasma and reacts with and oxidatively destroys
      nitric oxide (NO). Additionally, erythrocyte arginase I is released into plasma and
      catabolizes arginine, the substrate for endothelial NO synthesis. As a result, the profound
      reduction in NO bioavailability produces vasomotor instability, oxidant stress, inflammation,
      endothelial adhesion molecule expression, activation of tissue factor, and platelet
      aggregation. Consistent with shared mechanisms, these same pathways are found to be activated
      during malarial infection. Chronic hemolysis in hemoglobinopathies also leads to a disease
      syndrome, hemolysis associated pulmonary hypertension, which develops in all chronic
      hereditary and acquired hemolytic conditions and is associated with excessive morbidity and
      mortality. Despite the recent appreciation of these mechanisms, not one study can be found in
      the literature evaluating pulmonary hypertension in human malaria.

      This protocol therefore aims to evaluate mechanisms governing interrelationships among
      malaria, intravascular hemolysis, NO bioavailability, endothelial function, pulmonary
      hypertension, and evolutionarily selected host polymorphisms that regulate the host response
      to hemolysis. We will correlate our clinical observations in the field with laboratory assays
      of hemolysis and nitric oxide bioavailability related to scavenging by cell-free hemoglobin
      and arginine catabolism. Using a candidate gene approach, we will identify and selectively
      characterize polymorphisms in genes important for endothelial function, vascular inflammation
      and disease phenotype. Finally, the characterization of this mechanism in malaria may
      catalyze the development of novel therapies targeting this pathway, such as sodium nitrite,
      inhaled nitric oxide gas, and/or recombinant haptoglobin infusions.

      This international collaboration between scientists at the NIH, University of Bamako, and
      Tulane University will provide an exclusive opportunity for the rapid transfer of appropriate
      technology and expertise relevant to the provision of the highest quality care to malaria
      patients in Mali and the world.
    

Time perspective: Prospective
Keywords: Echocardiogram; Endothelial Dysfunction; Malaria; Mali; Screening