Searching for NF-kappaB-based treatments of ischemia reperfusion injury.

When a tissue becomes ischemic, a host of changes occur at the cellular level that lead to a shift in transcriptional activity of many inflammatory and cytoprotective compounds, a process which is extensively controlled through a family of transcription factors known as nuclear factor kappa-B (NF-kappaB). This shift in activity paradoxically results in both a cytoprotective effect at the cellular level and upon reperfusion, a generally destructive inflammatory response, a phenomenon referred to as ischemia reperfusion (IR) injury. To date, a number of methods of modifying the activity of NF-kappaB through either physiologic or pharmacologic manipulation have been developed and studied in animal models of IR injury and in some cases in human clinical trials. Nearly every method of NF-kappaB antagonism has demonstrated a discrete protective effect allowing investigators to reduce myocardial infarct sizes by 60% and cerebral infarct sizes by 57% relative to untreated control animals. The problem of IR injury is all too common and represents a discrete threat not only to the tissues directly involved in the ischemic event, but also to distal sites as well as is seen in the evolution of acute respiratory distress and severe inflammatory response syndromes. In the course of this review, the nature of NF-kappaB and its involvement in IR injury is examined along with the efficacy of the various NF-kappaB-based investigational treatment developed to date.