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SEPTIC SHOCK - the NO problem

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Blood poisoning or sepsis, the general invasion of the blood system by bacteria, is still a major hazard, particularly of abdominal surgery or burns injuries. There are about 37,000 cases of sepsis per year in the UK alone and mortality rates are approximately 40%. The major danger comes from septic shock which is caused by the release of endotoxins associated with bacterial cell walls. These toxins cause an inflammatory response by over-exciting the immune system. The immune response deals well with relatively minor invasions but, with such a massive overload, can cause major shock in which the blood pressure falls dramatically with associated kidney and liver failure. In addition, there is a profound disturbance in the regulation of blood sugar. Stored carbohydrate is mobilised by the liver (causing increased blood sugar) until it runs out; this happens within 24 hours, causing blood sugar levels to fall to catastrophically low levels. Once sepsis has set in, treatments which kill the bacteria make the problem worse by causing the release of more bacterial endotoxins from the dying bacteria.

Mike Titheradge and colleagues in BIOLS are working on the mechanisms involved in septic shock and how endotoxins affect the mobilisation of carbohydrate by the liver, as there is evidence that survival is greatly enhanced if the effects on blood glucose can be prevented or reversed. Their aim is to pinpoint targets for new methods of therapy, in particular the possible involvement of nitric oxide (NO) in this process. Nitric oxide is normally produced in minute amounts within the body and plays an important role in the central nervous system, in signalling throughout the body and in the regulation of blood pressure. However in response to bacterial endotoxins there is a large-scale release of nitric oxide within the cells of the body, reaching toxic levels which cause cell and tissue damage and a dramatic fall in blood pressure.

Fortunately the enzyme which produces nitric oxide in response to bacterial endotoxins is different from those involved in its normal function. A search is under way for drugs capable of discriminating between these enzymes, which may be able to reduce some of the effects of endotoxic shock without affecting normal signalling. Whether excess nitric oxide production underlies the changes in the control of carbohydrate mobilisation and blood sugar levels in sepsis, and therefore whether these will be amenable to treatment by these drugs, is an important question which remains to be answered.

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Friday May 2nd 1997