SEW2871 Alleviates the Severity of Caerulein-Induced Acute Pancreatitis in Mice

Abstract

Sphingosine-1-phosphate type-1 receptor (S1P1) agonists have the potential to inhibit the egress of lymphocytes, and have been demonstrated to provide protective effects on some acute inflammatory diseases. However, the value of S1P1 agonists on acute pancreatitis (AP) remains unclear. The aim of this study was to explore the effect of SEW2871, a S1P1-selective agonist, on caerulein-induced AP in mice. AP was induced by giving eight intraperitoneal injections of caerulein (50 µg/kg/h) at hourly intervals. SEW2871 was administered by gavage, at a dose of 20 mg/kg, at 0 h and 12 h after the first intraperitoneal injection of caerulein. The mice were sacrificed at 24 h. Severity of AP, serum amylase and lipase activity, levels of serum cytokines, pancreatic myeloperoxidase (MPO) activity, CD45 CD4 T lymphocytes in blood, CD4 T cell infiltration in the pancreas, and proinflammatory cytokine production were assessed. Furthermore, the expression of signal transducer and activator of transcription (STAT) 3 and phospho-STAT3 (p-STAT3) in the pancreas was also evaluated. The results revealed that the administration of SEW2871 ameliorated the severity of AP, by a reduction of serum pancreatic enzyme activity and levels of cytokines, decreased pancreatic MPO activity, depletion of CD4 CD45 T lymphocytes in the blood and a reduction of CD4 T cell infiltration in the pancreas. Furthermore, the expression of proinflammatory cytokines mRNA and p-STAT3 were also suppressed by SEW2871 treatment. These results suggest that SEW2871 treatment attenuates the severity of caerulein-induced AP in mice, which may provide a new therapeutic approach for AP therapy.

Sinusoidal protection by sphingosine-1-phosphate receptor 1 agonist in liver ischemia-reperfusion injury

“…In sham groups, there were no significant differences between vehicle and SEW2871 groups. (AST at 4h: 31 [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] As shown in Figure 2A, IRI livers mostly demonstrated sinusoidal vascular congestion at 4 h; however, livers treated with SEW2871 showed suppressed congestion at 4 h. after IRI. IRI livers treated with only vehicle were mostly characterized by sinusoidal vascular congestion, whereas IRI livers with SEW2871 showed suppressed congestion at 4 h (panel A).…”

“…The development of the highly selective S1PR1 agonist, SEW2871, which was originally identified in 2004, 8 has enabled examination of S1PR1-mediated cell responses, using animal models such as renal IRI, 9,10 myocardial IRI, 11 heart transplant, 12 cardiopulmonary bypass, 13 and acute pancreatitis. 14 Using a renal IRI mouse model, Lien et al 9 revealed that SEW2871 administration significantly attenuated renal damage by reducing neutrophil/macrophage infiltration and cytokine production in the kidney. In hepatic IRI models, however, there have been few studies on the effect of selective S1PR1 agonists.…”