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Vincent van Gogh

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General Hospital

Clinicians examining a hospitalized patient

One consequence of major injury, whether from surgery, burns or trauma, is whole-body inflammation. In most injured patients, this whole-body inflammation resolves promptly with appropriate clinical attention in an intensive care unit. However, in certain patients the inflammation persists, increases in intensity and leads to serious complications that are very difficult to treat effectively. At this time, there is no proven method to identify, on an individual basis, which patients will develop complications and which patients will not.

While medical researchers know a considerable amount about whole-body inflammation, the genetic revolution has provided us with an opportunity to learn much more. The more we know, the better we will be able to predict which patients will suffer from serious complications of whole-body inflammation. Patients identified as being at risk can then be treated earlier and more aggressively, thus reducing morbidity and mortality.

Studies of actual injured patients are extremely valuable to extend our knowledge of whole-body inflammation, and such studies are a major focus of this grant. However, one major problem with these sorts of studies is that it is difficult to compare patients with different kinds of injuries: for instance, is a patient with a broken leg comparable to a patient with a blunt abdominal injury such as might occur in an automobile accident? Another difficulty from a statistical viewpoint is that one can never study a trauma or burn patient prior to the injury, and invariably, the duration of time between the injury and the study is not constant among patients.

One approach to avoid these limitations of studies in injured patients is to somehow induce whole-body inflammation in a non-injured, otherwise normal, person. This can be done by intravenously injecting a small amount of bacterial endotoxin. After endotoxin administration, human subjects manifest most of the signs and symptoms of whole body inflammation, albeit with reduced intensity and duration compared to actual injured patients. Each subject can be evaluatedprior to administering the endotoxin when there is no whole-body inflammation present. Each subject can serve as his or her own control.

Our studies using endotoxin have been very helpful to show that endotoxin administration produces changes in genes over time, and associated with these changes are not only changes in systems related to the innate immune response, but also other important pathways associated with the body’s biological processes.