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2001 Abstract: 1791 IL-10 Fusion Protein Reduces Pulmonary ICAM-1 Expression and Injury in Diet Induced Pancreatitis in Mice

2001 Digestive Disease Week

# 1791 IL-10 Fusion Protein Reduces Pulmonary ICAM-1 Expression and Injury in Diet Induced Pancreatitis in Mice
Andrew H. Lundberg, Xing X. Zheng, Terry Strom, Osama Gaber, Memphis, TN, Boston, MA

Lung injury is a major complication of Acute Pancreatitis (AP) and has been shown to result from cytokine over expression and leukocyte migration. This study examines the pathophysiological changes of lung tissue in response to influences of anti-inflammatory cytokines. We utilized a novel IL-10 molecule bound to an Fc antibody fragment (IL-10/Fc) which prolongs its half life from 8 hours to 48 hours. AP was induced by feeding mice a choline deficient-ethionine supplemented (CDE) diet. One group of mice, received IL-10/Fc at 0 and 48 hours. The second group of mice was fed the CDE diet and received non-functional antibody. A third group of mice was used as a normal control by feeding standard laboratory chow. Ninety-six hours after beginning the diet, animals were examined for pulmonary ICAM-1 expression by the radiolabeled dual monoclonal antibody method. Lung neutrophil sequestration was evaluated by the myeloperoxidase assay (MPO), and microvascular permeability was determined by measurement of accumulated radiolabeled albumin in pulmonary tissue. Finally, to examine the mechanism of IL-10/Fc during this study, the kinetic expression of serum and pulmonary tissue cytokines (TNFaand IL-1b) were measured by the ELISA method. The development of AP was associated with; increased pulmonary expression of ICAM-1 over control (122.2 ± 15.0 vs. 40.1 ± 2.9 mg mAb/g; p<0.0001), MPO activity (14.7 ± 2.9 vs. 5.8 ± 1.7 activity units/g; p<0.03), and microvascular permeability (0.131 ± 0.026 vs. 0.029 ± 0.002 lung 125I activity/blood 125I activity; p<0.007). In comparison to untreated mice, IL-10/Fc treated mice with AP had a significant reduction of pulmonary ICAM-1 expression (85.9 ± 9.6 vs. 122.2 ± 15.0 mg mAb/g; p<0.03), MPO activity (5.8 ± 1.8 vs. 14.7 ± 2.9 activity units/g; p<0.03), and microvascular permeability (0.062 ± 0.008 vs. 0.131 ± 0.026 lung 125I activity/blood 125I activity; p<0.03). The kinetic expression of serum TNFaand IL-1bover the 96 hour feeding period was significantly lower in IL-10/Fc treated mice; (p<0.03 and p<0.0001 respectively). Lung tissue TNFawas reduced in IL-10/Fc treated mice (p<0.01) during the 96 hour feeding period however no differences of tissue IL-1bwere apparent. IL-10/Fc protein alters proinflammatory cytokine expression, with resultant decrease in pulmonary ICAM-1 expression, leukocyte migration, and endothelial injury. The utilization of long acting anti-inflammatory cytokines may have a significant clinical relevance in the management of AP.

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