A Novel Diamino-Pyridine Derivative Prevents Excessive Leukocyte Infiltration in Aggravation of Acute Necrotizing Pancreatitis

Abstract

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.

Pancreatic proteases in serum induce leukocyte-endothelial adhesion and pancreatic microcirculatory failure

“…We and others have previously demonstrated the importance of MAC-1 and ICAM-1 for the progression of acute pancreatitis [33][34][35]. In a murine model of acute necrotizing pancreatitis, Yamauchi et al [36] demonstrated a 500% increase of MAC-1 expression on circulating leukocytes in acute pancreatitis. Interruption of neutrophil adherence by using ICAM-1-deficient animals [34] or antibodies against ICAM-1 [33,35,37] in different models of acute pancreatitis has demonstrated that adhesion of leukocytes to endothelium is of essential importance for the evolution of severe acute pancreatitis.…”

A novel diamino-pyridine derivative (IS-741) attenuates rat ileitis induced by trinitrobenzene sulfonic acid

“…In both these models, the neutrophil infiltration into the inflamed tissues was significantly reduced by the administration of IS-741. It has also been reported that this new agent decreased the number of adherent leukocytes along pancreatic collecting venules, as well as reducing the expression of Mac-1 (CD11b/CD18) on circulating neutrophils, in an acute pancreatitis model, 15 and it also decreased the number of neutrophils and Mac-1-positive cells accumulated in the injured lung. 17 Based on these results, it appears that the leukocyte accumulation during the early phase of pancreatitis and lung injury may be mediated by leukocyte-endothelial cell interactions via the leukocyte integrin Mac-1, and that this new anti-inflammatory agent attenuated the leukocyteendothelial interactions as a consequence of its inhibitory effect on Mac-1 expression in the inflamed lesions.…”

“…[15][16][17][18] However, there are only few reports about the efficacy of leukocyte-endothelial interaction inhibitors against intestinal inflammation. 19 In the present study, we investigated the effects of oral IS-741 on rat experimental ileitis.…”

Efficacy of tocilizumab treatment in cerulein-induced experimental acute pancreatitis model in rats

“…Through the interaction of adhesion molecules on the surface of neutrophils via vascular endothelium, many more cytokine, chemokine, and free oxygen radicals release (20,21). The deterioration of the microcirculation results as increased permeability of the endothelial layer of the arterioles and venules, leading to extravasation of plasma and erythrocytes presented as edema and microhemorrhagia (19).…”