Acute pancreatitis - Cellular response and dynamic inflammatory changes

Abstract: Acute pancreatitis (AP) is a common disorder where underlying mechanisms for the local initiating events in the pancreas, the systemic dissemination of the inflammatory response and the remote organ dysfunction still are unclear. The aim of the present study was to further characterize the dynamics and sequence of the immune response in AP, and to determine the cellular origin of the initiating events. A comparison with abdominal sepsis (AS) in a model with a slower and milder process also leading to systemic inflammation, was made. Our results showed an early increase in leakage index of human serum albumin (HSA) in the pancreas after induction of AP and later in AS compared to controls. A parallel and persistent increase in myeloperoxidase (MPO) activity in lungs occurred later (3 hours) in both AP and AS. Circulating levels of cytokines (TNF-a and MCP-1) increased 6 hours after both AP and AS with higher levels in AS. Hydrogen peroxide generation by circulating monocytes/ macrophages was high early on and then decreased in AP and AS, whereas superoxide production increased by time during both processes. The pancreatitis-associated lung injury showed expression of different adhesion molecules (PECAM-1, ICAM-1, L-selectin) at different time points and cells in the circulation, bronchoalveolar lavage fluid and lung tissue exhibited different expression pattern. Leukocyte recruitment increased early and persisted at all time points. Depletion of mast cells with the compound 48/80 administered 30 min prior to induction of AP resulted in a decrease of HSA leakage index in the pancreas and gut, while when given at the time of AP induction the HSA leakage index increased. The mast cell stabilizer cromolyn (sodium cormoglycate) reduced plasma exudation in the pancreas, gut and lungs, decreased plasma histamine levels, and reduced MPO activity in the colon and lungs. Pretreatment with different antihistamines was not effective in reducing HSA leakage index. The results imply that activation of mast cells is involved in the development of endothelial barrier dysfunction in both the pancreas and extrapancreatic organ/tissues. Histamine is one of the mediators involved, but other mediators also contribute and mast cell involvement might be direct or through activation of other immune cells.