635 Acute Pancreatitis (AP) in Aging Animals-Loss of PAP Protection?
Autor: | Nefertiti A. Brown, Ehab Hassanain, Albert Stanek, Cathy M. Mueller, Okiremute Oyiborhoro, Michael E. Zenilman, Chongmin Huan, Sophia L. Fu |
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Rok vydání: | 2009 |
Předmět: |
Chemokine
Hepatology biology Gastroenterology Inflammation Pharmacology Angiotensin II Proinflammatory cytokine chemistry.chemical_compound Losartan Pyrrolidine dithiocarbamate chemistry cardiovascular system medicine biology.protein medicine.symptom Signal transduction Receptor hormones hormone substitutes and hormone antagonists medicine.drug |
Zdroj: | Gastroenterology. 136:A-877 |
ISSN: | 0016-5085 |
Popis: | Background: Although acute inflammation is a critical protective response against injury and infection, persistent inflammation and the resulting oxidative stress drive the pathogenesis of numerous chronic degenerative diseases, including carcinogenesis. In human pancreatic ductal adenocarcinoma (PDA) and in animal models that recapitulate the disease progression, an intense fibroinflammatory reaction composed of stromal and immune cells accompanies the progression from normal histology to PDA. Angiotensin II (AngII), the principal hormone of the renin angiotensin system, is actively generated in the pancreas and has been proposed as a key mediator of inflammation. Monocyte chemoattractant protein(MCP)-1 is a chemokine that plays an important role in the recruitment of mononuclear cells into sites of inflammation. Objective: To investigate the potential proinflammatory role of AngII in PDA through studying its effect on MCP-1. Methods: PDA cells (AsPC-1, HS766T, MiaPaca) were cultured and treated with or without Ang II (10-8-10-6mol/L), in the presence or absence of AngII type 1 receptor blocker, losartan, or AngII type 2 receptor blocker, PD123319. MCP-1 mRNA was analyzed by real time PCR and its protein by ELISA. Luciferase-labeled promoter studies evaluated the effect of AngII on the transcription of MCP-1 and nuclear factor-κB (NF-κB). The effect of receptor blockers on the endogenous and AngII-induced activation and nuclear translocation of NF-kB was examined by luminescence assay and immunohistochemistry. Results: AngII significantly increased the expression ofMCP-1mRNA and protein in PDA cells, and induced its promoter activity. Constitutive and AngII-induced MCP-1 mRNA and promoter activity were significantly reduced in the presence of losartan but were unchanged by PD123319. AngII induced the activation and nuclear translocation of NF-kB, an effect that was inhibited by losartan, but not PD 1233319. Blocking NF-kB activation by pyrrolidine dithiocarbamate decreased the AngII-mediated increase in MCP1 mRNA. Conclusions: Our data provide a novel insight into an AngII-initiated signal transduction pathway that regulates MCP-1 as a possible inflammatory mechanism in PDA, and suggest that AngII blockade may regulate chemokine-induced signal transduction to prevent or reduce inflammation in PDA. |
Databáze: | OpenAIRE |
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