ABSTRACT
Acute pancreatitis [AP], especially its sever form, is a potential serious human disease with a limited specific therapy. Here, we assessed the therapeutic efficacy of interleukin-22 [IL-22], a newly emerged cytokine with unique biological activities, in the treatment of a rat model of severe AP induced by caerulein. For disease induction, the animals were intraperitoneally [i.p.] injected with nine doses of caerulein [50 micro g/kg/dose] at 1-h intervals. Recombinant rat IL-22 [rIL-22] was given [4 micro g/rat/dose; i.p.] after the 1[st], 5[th], and 9[th] caerulein injection. Twelve hours after the last caerulein injection, the animals were euthanized under anesthesia and their bloodd specimens and pancreases were collected and examined. Serum levels of pancreatic alpha-amylase and lipase, pancreatic weight/body weight ratio, histopathological feature of induced pancreatic injury, intrapancreatic expression of cyclooxygenase-2 [COX-2] and myeloperoxidase [MPO; an index of neutrophils infiltration], and concentrations of pro-inflammatory prostaglandin E2 [PGE2]; monocyte chemotactic protein-1 [MCP-1]; and interleukin-1 beta [IL-1beta] in the serum and pancreatic tissues were collectively analyzed as diagnostic parameters of the induced AP. Results showed that therapy with rIL-22 significantly repressed caerulein-induced severe injury and edema in the pancreatic tissues. Administration of rIL-22 significantly reduced caerulein-evoked substantial hyperamylasemia and hyperlipasemia, intrapancreatic over-expression of COX-2 and MPO, and the production of proinflammatory mediators [PGE2, MCP-1 and IL-1beta] in the pancreatic tissues and systemic circulation. These biochemical observations were also supported by the histopathological findings. In conclusion, these results indicate the favorable attenuating effect of IL-22 against the development of AP by acting as an anti-inflammatory agent
Subject(s)
Male , Animals, Laboratory , Interleukins , Rats , Male , alpha-Amylases/blood , Anti-Inflammatory AgentsABSTRACT
Autoimmune fulminant hepatic failure has a specific clinical and social importance. However, it still lacks its effective and targeting medication. Herein, we investigated the influence of rolipram, a selective PDE-IV inhibitor, on D-galactosamine/lipopolysaccharide [DGalN/ LPS]-induced immune-mediated and dose-dependent fulminant hepatitis and acute lethality in mice; in which tumor necrosis factor-alpha [TNF-alpha] plays a pivotal role. Two complementary sets of experiments were conducted in this work. Firstly, we assessed the distinct hepatoprotective effects of rolipram on this model. After an intraperitoneal [i.p.] injection of a single sub-lethal dose of D-GalN/LPS [0.2 mg/g + 5 microg/g] into mice a serious destructive hepatic injury was developed over a period of 4 days, and it was associated with abundant increases in the serum levels of liver enzymes [AST and ALT] and the concentrations of TNF-alpha in serum and hepatic tissues, as well as an over-production of vascular cellular adhesion mlocule-1 [VCAM-1] on liver tissues. Additionally, the histopathological findings showed the features of severely injured liver. Interestingly, treatment with rolipram [3 mg/kg, i.p.; at days +0, +1, +2, and +3] remarkably reversed all the aforementioned biochemical, immunological, and histopathological hallmarks of D-GalN/ LPS-induced hepatitis. Secondly, the prophylactic administration of rolipram [10 mg/kg, i.p.; at -24, -12, and -1 h] efficiently prevented the severe acute deaths and massive systemic TNF-alpha production that induced by a lethal dose of D-GalN/LPS [0.6 mg/g + 15 microg/g; i.p.] over 24-h period. The results reveal that rolipram; via, at least in part, inhibition of TNF-alpha production and VCAM-1 over-expression, has obvious hepatoprotective effects on D-GalN/LPS-induced lethal destructive hepatitis in mice. In addition, the beneficial role of rolipram in suppressing the progression of human hepatitis in which TNF-alpha is markedly involved could be considered