Inflammation is important and cytokines represent critical elements in the inflammatory process. This application will determine the mechanisms which control the inflammatory response. One of the major thrusts of this competing renewal is to understand the regulation of ongoing inflammation. Many studies have determined treatments that will prevent the initiation of inflammation, but there are far fewer studies which investigate how to halt an ongoing inflammatory response. In most patients, inflammation will be treated after it has started. Our central hypothesis is that anti-oxidant (and NO inhibitor) regulation of ongoing inflammation occurs through multiple mechanisms including depressing chemokine production and blocking chemokine biological activity. We will examine if anti-oxidants not only modulate the initiation of the inflammatory response, but also if they will depress chemokine production once it has already been started. The mechanism of this suppression will also be tested.
Four specific aims comprise this application. In the first we will build on our previous work investigating the IL-8 gene by identifying regulatory sequences in the 5'end of cytokine genes which are important in ongoing inflammation. In the second aim the contribution of reactive oxygen intermediates as compared to reactive nitrogen intermediates will be detailed.
The third aim will use a whole blood stimulation model as well as isolated cells to determine the mechanisms of halting an ongoing inflammatory response. The last aim will look at methods of how the biological activity of chemokines may be inhibited, with a view towards determining both if this is advantageous to the host or may actually be injurious. Successful completion of each of these specific aims will help to determine both the optimal method to regulate ongoing inflammation and the precise mechanisms of how this regulation occurs.
