RESUMO
Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis.
Assuntos
Ácidos Docosa-Hexaenoicos , Inflamação , Lesão Pulmonar , Pancreatite Necrosante Aguda , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Ceruletídeo/farmacologia , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Fármacos Gastrointestinais/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite Necrosante Aguda/complicações , Pancreatite Necrosante Aguda/metabolismo , Pancreatite Necrosante Aguda/patologia , Peroxidase/metabolismo , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVES: The aim of the study was to explore the potential role of myeloid differentiation factor 88 (MyD88), which acts as an adaptor in the TLR4 signalling pathway, in immune responses of the pancreatic duct during acute pancreatitis. METHODS: Primary cultures of pancreatic duct epithelial cells from Wistar rats and cultures of the pancreatic ductal ARIP cell line were treated with lipopolysaccharide (LPS), and expression of toll-like receptor 4 mRNA was determined using real-time PCR, expression of MyD88 protein using Western blot, and levels of inflammatory cytokines using enzyme-linked immunosorbent assay. These experiments were repeated using ARIP cells in which MyD88 expression was stably knocked down. RESULTS: Toll-like receptor 4 and MyD88 expression were similar between pancreatic duct epithelial cells and ARIP cells after LPS stimulation. Myeloid differentiation factor 88 knockdown led to significantly lower levels of inflammatory cytokines after LPS induction in ARIP cells. CONCLUSIONS: Myeloid differentiation factor 88 knockdown attenuates LPS-induced inflammatory responses in pancreatic ductal cells, suggesting that the MyD88 pathway plays a critical role in their immune defense activity.