Grant: Operating Grant

Shock is a group of cardiovascular diseases that kills 400,000 people a year in North America. All of the patients have activation of white cells which are thought to inappropriately stick in lungs, liver, brain and other organs. Also the white cells that get stuck cause damage leading to ultimately prolonged hospital stays or death. Some of the patients get septic shock which relates to the fact that uncontrolled bacterial infection is the initiating event. Endotoxin is a molecule that is found on certain types of bacteria (gram negative) and our body has learned to recognize this molecule. In small local doses endotoxin is essential for our ability to recognize and clear infections. In septic conditions it is thought that endotoxin is what activates the white cells to get stuck in lungs and liver. Recently, TLR4 has been identified as the molecule in mammals that can identify endotoxin and activate white cells. A second molecule TLR2 has been identified to detect gram positive bacteria. We will use mice that are deficient in these molecules and using a special microscope to look inside tiny blood vessels we will visualize white cell behaviour. We will determine how important TLR4 is in various tissues. Most scientists are studying TLR4 on white cells, but we believe that in fact TLR4 found on the endothelium (which lines all blood vessels) is important if not essential to get the white cells stuck in the lung, brain and liver. We have made a mouse that has no TLR4 or TLR2. We also have found that the body makes an inhibitor of TLR4 called Tollip which may dampen the inappropriate cell activation. Finally, almost all work by many labs is being done in test tubes, whereas we are proposing to examine infection response in animals where complexity is increased. We believe that learning more about these molecules in the animal will help us to better understand how white cells can be inappropriately activated to affect the cardiovascular system in disease.