Defects in cell-mediated immunity and the inflammatory and antibody responses undoubtedly contribute to infections and mortality in patients undergoing surgery and who suffer major trauma and burn injury. There has been limited progress in controlling the immune responses and preventing immune depression after such injuries. In our previous studies we have documented specific immune deficits in mice following burn injury and following skeletal trauma; we have also demonstrated that specific pharmacologic therapy can improve immune functions in such animals after injury (delayed hypersensitivity, splenic lymphocyte """"""""helper/suppressor"""""""" ratios, and resistance to septic challenge). Pilot clinical studies have shown that some of the same drugs appear to prevent alterations in circulating lymphocyte subpopulations after major surgical procedures. This project will determine if specific pharmacologic therapy can improve additional immune functions in animals after burn injury and in patients after burn injury, trauma and major surgical procedures. The drugs utilized will be those which we have shown in previous experiments to improve immunity following burns (mice), skeletal trauma (mice) and major surgery (humans). We suspect that these drugs, which we have termed immunmodulating drugs in this proposal, exert their effects by blocking activation or proliferation of suppressor lymphocyte populations after injury. Experiments are designed to provide the following information: 1) Determine the ability of histamine-2 receptor antagonists, prostaglandin blockers, cyclophosphamide, and cerium nitrate to affect multiple immune functions in burned mice, using varying drug dosages; 2) Determine the ability of cimetidine (a histamine-2 blocker) and ibuprofen (a prostaglandin blocker) to affect immune functions after major surgical procedures in humans, using multiple measures of immune function; 3) Determine effects of the same drugs on similar immune functions after major non-burn trauma in humans, correlating severity of injury with specific immune responses; 4) Determine effects of the same drugs on similar immune functions after burn injury, correlating the magnitude of burn injury with specific immune responses.
