Systemic Nitric Oxide Production in Human Malaria

Abstract

As described in Chapter 42, niric oxide (NO) is synthesized from the amino acid l-arginine by the actions of a family of enymes, the NO synthases (NOS), each isoform of which is encoded by a separate gene. Two NOS isoforms are calcium-dependent and constitutively expressed and produce low levels of NO: NOS1 (neuronal NOS or nNOS), which is found mostly in neurons and skeletal muscle, and NOS3 (endothelial NOS or eNOS), which is found mostly in endothelial cells. NOS1 is critical for neurotransmission and learning, and NOS3 regulates vascular tone and adhesion of circulating cells. Inducible NOS (iNOS or NOS2) is transcriptionally induced by proinflammatory cytokines (such as tumor necrosis factor-α [TNF-α] and interferon-γ [IFN-γ]) and microbial products (e.g., lipoplysaccharide [LPS]). iNOS is calciumindependent, expressed by many cell types (especially mononuclear phagocytes, hepatocytes, chondrocytes and smooth muscle cells) and is responsible for high output NO production (1-3). While initial studies showed that iNOS expression within mouse macrophages resulted in high-output NO production, until recently there was doubt as to whether human macrophages were capable of producing NO. There is now clear evidence however that human monocytes and tissue macrophages can express iNOS and produce NO both in vitro and in vivo (3), including evidence from malaria-exposed Tanzanian children (4).