The morbidity and mortality of acute pancreatitis is directly related to its severity but, at present, no specific therapy is available for this frequently devastating disease. The current project is based on a vast array of preliminary studies that employed a conditional and targeted technique for selectively depleting mouse monocytes-macrophges by administering diphtheria toxin (DT) to mice transgenically modified to express the human receptor for DT (hDTR). Using two dissimilar experimental models of acute pancreatitis, we found that administering DT to hDTR mice during the development of pancreatitis markedly diminishes the severity of pancreatitis but that persistent inflammation as well as extensive fibrosis i.e. changes suggestive of chronic pancreatitis-- are observed when DT is administered to hDTR mice during the recovery phase of acute pancreatitis. These observations indicate that the monocyte-macrophage system plays a critical role in regulating the severity of, and recovery from, acute pancreatitis. The proposed studies will pursue two specific aims: (1) to define the mechanisms by which monocytes-macrophages regulate the severity of acute pancreatitis and (2) to define the mechanisms by which monocytes-macrophages regulate recovery from pancreatitis. The studies pursuing the first specific aim will (a) define the monocyte sub-set which is responsible for regulating the severity of pancreatitis, (b) test our novel hypothesis that pancreatitis severity is worsened by bone marrow cells that traffic to the pancreas in response to signals arising in the pancreas but transduced by elements in the circulating blosod, and (c) identify the mediators, generated by those cells which promote worsening of pancreatitis severity. Studies pursuing the second specific aim will (a) define the time-dependence of events triggered by monocyte-macrophage depletion during recovery from pancreatitis, (b) examine the effects of pancreatic inflammatory macrophages on pancreatic myofibroblasts (PSCs) and PSC- mediated fibrosis during recovery from acute pancreatitis, and (c) elucidate the effects of pancreatic inflammatory macrophages on pancreatic matrix metalloproteinase (MMP) activity and matrix remodeling during recovery from acute pancreatitis. The knowledge gained from these proposed studies will elucidate the pathways involved in the trafficking of monocytes-macrophages to the pancreas during pancreatitis, define events and mechanisms which are responsible for determining the severity of acute pancreatitis, and elucidate the events and mechanisms which are responsible for recovery from acute pancreatitis. This knowledge will prove critical in subsequent efforts to reduce the severity and hasten recovery from clinical pancreatitis. Public Health Relevance: The proposed studies will focus on the role of a specific subset of white blood cells in the pathogenesis and resolution of acute pancreatitis. We use two dissimilar models of experimental acute pancreatitis and genetically modified mice to perform our studies.