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

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Abstract

Objective

Adult respiratory distress syndrome (ARDS) is responsible for a significant portion of the morbidity and mortality during severe acute pancreatitis. Because inflammatory mediators such as tumor necrosis factor (TNF)-α and nitric oxide (NO) produced within the lungs have been implicated in sepsis-induced ARDS, we aimed to determine the role of these mediators in pancreatitis-induced ARDS using a model whereby ascites from animals with pancreatitis is transferred to otherwise healthy animals resulting in pulmonary 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 tested for interleukin (IL)-1β, TNF-α, interferon-γ, 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 administered intravenous ascites were randomized to receive a single intraperitoneal 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 leukocyte and protein concentrations via bronchoalveolar lavage. Pulmonary TNF-α protein was detected by immunohistochemistry. Serum nitrite, as a measure of NO production, was measured utilizing the Griess reaction.

Main Results

After the intravenous administration of pancreatic ascites, the number of leukocytes and the protein concentration within the bronchoalveolar fluid were increased and pulmonary histology was worsened consistent with acute lung injury (all p < .001 vs. sham). Each of these variables of pulmonary injury was lessened in animals receiving CNI-1493 and intravenous ascites (p < .05 vs. vehicle). Pulmonary TNF-α protein and serum nitrites were decreased with the administration of CNI-1493 (p < .005 vs. vehicle).

Conclusions

A component of pancreatic ascites other than endotoxin, bacteria, or cytokines (IL-1β, TNF, interferon-γ, or IL-6) is capable of inducing ARDS in healthy animals. Inhibition of p38 mitogen activated kinase decreases the pulmonary injury through attenuated production of TNF-α and NO suggesting a primary role for these mediators in pancreatitis-induced ARDS.

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