Inhibition of p38 mitogen activate kinase attenuates the severity of pancreatitis-induced adult respiratory distress syndrome

Objective: Adult respiratory distress syndrome (ARDS) is responsible for a significant portion of the morbidity and mortality during severe acute panc reatitis, Because inflammatory mediators such as tumor necrosis factor (TNF )-alpha and nitric oxide (NO) produced within the lungs have been implicate d in sepsis-induced ARDS, we aimed to determine the role of these mediators in pancreatitis-induced ARDS using a model whereby ascites from animals wi th pancreatitis is transferred to otherwise healthy animals resulting in pu lmonary injury. Design: Prospective, randomized, controlled trial. Setting: Research laboratory at a university medical school. Subjects: Pathogen-free Sprague-Dawley rats weighing 225-250 g. Interventions: Sterile, endotoxin- and cytokine-free pancreatic ascites tes ted for interleukin (IL)-1 beta, TNF-alpha, interferon-gamma, and IL-6 was obtained from rats 18 hrs after the induction of severe, acute pancreatitis . Ascites was subsequently administered intravenously (20 mL/kg) to healthy rats. Sham animals were administered intravenous saline. Healthy animals a dministered intravenous ascites were randomized to receive a single intrape ritoneal injection of the p38 mitogen activated kinase inhibitor CNI-1493 ( 1 mg/kg) or vehicle. Measurements: Pulmonary injury was assessed at 24 hrs by histology and leuk ocyte and protein concentrations via bronchoalveolar lavage, Pulmonary TNF- alpha protein was detected by immunohistochemistry. Serum nitrite, as a mea sure of NO production, was measured utilizing the Griess reaction. Main Results:After the intravenous administration of pancreatic ascites, th e number of leukocytes and the protein concentration within the bronchoalve olar fluid were increased and pulmonary histology was worsened consistent w ith acute lung injury (all p < .001 vs. sham), Each of these variables of p ulmonary injury was lessened in animals receiving CNI-1493 and intravenous ascites (p < .05 vs. vehicle). Pulmonary TNF-alpha protein and serum nitrit es were decreased with the administration of CNI-1493 (p < .005 vs. vehicle ). Conclusions: A component of pancreatic ascites other than endotoxin, bacter ia, or cytokines (IL-1 beta, TNF, interferon-gamma, or IL-6) is capable of inducing ARDS in healthy animals, Inhibition of p38 mitogen activated kinas e decreases the pulmonary injury through attenuated production of TNF-alpha and NO suggesting a primary role for these mediators in pancreatitis-induc ed ARDS.