Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B, mimicking pancreatitis-associated adult respiratory distress syndrome

Background. Select pancreatic enzymes, primarily elastase, precipitate pulm onary injury similar to pancreatitis-associated adult respiratory distress syndrome and stimulate leukocyte cytokine production in vitro via nuclear f actor kappa B (NF-kappa B) activation. This study explores the effect of sy stemic pancreatic enzymes on pulmonary NF-kappa B and inhibitory Kappa B (I kappa B) proteins and their rob in enzyme-induced pulmonary injury. Methods. Mice received pancreatic elastase, amylase, lipase, or trypsin int raperitoneally. Bronchoalveolar lavage I kappa B alpha/l kappa B beta prote ins were measured by immunoblot. Pulmonary, NF-kappa B activation, tumor ne crosis factor (TNF) gene expression, and neutrophil infiltration (myelopero xidase) were deter milled and myeloperoxidase experiments repeated in p55 T NF receptor-deficient (TNF KO) animals. Additional animals received pyrroli dine dithiocarbamate (PDTC), an inhibitor of NF-kappa B activation, and TNF protein and pulmonary microvascular permeability were measured after elast ase administration. Results. Pancreatic elastase induced pulmonary I kappa B alpha/I kappa B be ta degradation (30 minutes), NF-kappa B activation (60 minutes), and TNF ge ne expression (60 minutes) with subsequent neutrophilic inflammation (4 hou rs) and microvascular leakage (24 hours), whereas amylase, lipase, and tryp sin did not. Furthermore, lung injury was markedly reduced in TNF KO animal s and PDTC significantly attenuated TNF production and pulmonary microvascu lar leakage. Conclusions. Pancreatic elastase induces cytokine-mediated lung injury and this pathway involves the NF-kappa B second messenger system, further suppo rting elastase as a factor linking pancreatic inflammation to systemic illn ess during severe acute pancreatitis.