A novel diamino-pyridine derivative prevents excessive leukocyte infiltration in aggravation of acute necrotizing pancreatitis.

Leukocyte infiltration in the pancreas is involved in the aggravation of acute pancreatitis from edematous phase into necrotic change, and mild disease into severe disease; however, the mechanism responsible for leukocyte accumulation is not fully understood. This study was designed to clarify the mechanism underlying leukocyte accumulation into the pancreas and to elucidate the therapeutic efficacy of a novel diamino-pyridine derivative, IS-741 on leukocyte-endothelial cell interaction using rat necrotizing pancreatitis model. The number of adherent leukocytes to pancreatic collecting venules assessed by in vivo fluorescence microscopy increased significantly in necrotizing pancreatitis animals in a time-dependent manner. The expression of CD11b on circulating neutrophils determined by flow cytometric analysis was enhanced to approximately 500% after 2 h. IS-741 attenuated the leukocyte adherence significantly, accompanied by a lower up-regulation of CD11b. These findings were further supported by the histological examination that the accumulation of leukocytes in the pancreas was remarkably inhibited by IS-741. These results suggest that the leukocyte accumulation in the early phase of acute necrotizing pancreatitis may be mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18. IS-741 attenuated the leukocyte endothelial cell interaction as a consequence of its inhibitory effect on CD11b upregulation.