The arterial vasodilation seen in human septic shock is conventionally attributed to increased nitric oxide (NO) production, primarily by extrapolation of animal and cellular studies. Little is known of the cellular source of NO in human septic shock. Other mediators, such as carbon monoxide (CO), may modulate NO production, and could also directly contribute to vasodilation. This study has examined the NO and CO synthetic pathways in peripheral blood mononuclear cells and mesenteric arterial smooth muscle from patients with septic shock, and from non-septic controls. Peripheral blood mononuclear cells from septic patients had increased NO production, though this was perhaps more modest than expected. The transport of arginine, the substrate for NO synthase, into these cells was increased; this was due to an increase in the activity of one transporter system, y<sup>+</sup>. mRNA for a protein encoding y<sup>+</sup> activity, CAT2B, was increased in these cells. However, mRNA and protein for inducible and endothelial NO synthase was decreased in sepsis, while inducible heme oxygenase (the enzyme responsible for CO production) mRNA and protein was increased. NO production in arterial smooth muscle from septic patients was reduced, as was mRNA for inducible and endothelial NO synthase, and the arginine transporter CAT1. There was no increase in inducible NO synthase protein, though there were small increases in endothelial NO synthase protein and NO synthase activity. In contrast, both mRNA and protein for inducible heme oxygenase were increased. These results challenge the assumption that NO is central to the pathogenesis of human sepsis. Negative feedback systems for NO production have been demonstrated in cell models. These may be relatively more important in human sepsis. In addition to forming one of these feedback systems, it may be that CO, more than NO, is responsible for the hypotension observed in these patients.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:275376 |
| Date | January 2002 |
| Creators | Reade, Michael Charles |
| Contributors | Young, Duncan |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:abf881fc-3c9a-40b4-89e1-07b8df2067d1 |
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