A prominent feature of severe acute systemic inflammatory response syndrome (SIRS) including acute respiratory distress syndrome (ARDS). The physiology of these responses appears remarkably similar to responses to direct liver injury in other settings. Cytokines produced in the liver and lungs, including tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL-1), are implicated in the pathogenesis of SIRS and animal experiments have demonstrated them capable of precipitating acute lung injury. During acute pancreatitis, proteases are released into the portal system, exposing the liver to high levels of activated enzymes. Nuclear factor kappa-B (NF-kappaB), a transcriptional regulator of TNF- alpha, IL-1 and other cytokines, is activated in the pancreas within 30 minutes of inducing experimental acute pancreatitis and subsequently within the liver and lung within 24 hours of acute liver injury. Our central hypothesis is that NF-kappaB activation in the pancreas and liver mediates acute lung injury associated with pancreatitis. Using the biliary cerulein/glycodeoxycholic acid model of acute pancreatitis will address two specific aims: 1) to determine whether altering NF-kappaB activation in the liver affects the pulmonary response to severe acute pancreatitis; 2) to determine the role of Kupffer cells in mediating the multi-system effects of pancreatitis by depleting Kupffer cells prior to induction of pancreatitis. These studies may allow the development of strategies to ameliorate multi-system to ameliorate multi-system injury including pulmonary failure,, which can be devastating during this illness.
