Abstract
Severe acute pancreatitis (SAP) remains to be challenging for its unpredictable inflammatory progression from acute pancreatitis to SAP. Apoptosis is an important pathology of SAP. Fibrinogen-like protein 2 (FGL2) has been reported to be involved in apoptosis. The present study aimed to explore the therapeutic effect of an adenovirus-mediated artificial miRNA targetting FGL2 (Ad-FGL2-miRNA) in taurocholate-induced murine pancreatitis models. Sodium taurocholate was retrogradely injected into the biliopancreatic ducts of the C57/BL mice to induce SAP. FGL2 expression was measured with reverse transcription-PCR, Western blotting, and immunohistochemical staining. ELISA was used to detect the activity of amylase and the concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). In addition, the mRNA levels of TNF-α and IL-1β were also detected. Finally, apoptosis was assessed by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL) method and Western blotting. Ad-FGL2-miRNA significantly suppressed FGL2 expression and alleviated pancreatic injury. Also, Ad-FGL2-miRNA markedly inhibited a post-SAP increase in the activation of TNF-α and IL-1β. Finally, pretreatment with Ad-FGL2-miRNA ameliorated apoptosis at the early stage of SAP by modulating cleaved caspase-3 and therefore played a protective role. These results indicated that FGL2 might be a promising target for attenuating the severity of SAP and adenovirus-mediated artificial miRNAs targetting FGL2 represented a potential therapeutic approach for the treatment of SAP.
Highlights
Severe acute pancreatitis (SAP) is a potentially fatal pathogenic condition characterized by rapid progression and high mortality [1], but the underlying pathophysiological mechanisms remain incompletely defined
Recent studies have revealed that mild acute pancreatitis (MAP) is mainly associated with apoptotic acinar cell death, whereas necrosis plays a predominant role in SAP with a severe inflammatory response [2]
Our results apparently revealed the potential mechanisms that Fibrinogen-like protein 2 (FGL2) plays as a co-activator in inducing the toll-like receptor 4 (TLR4) and p38 mitogen-activatedprotein kinase (MAPK) signaling pathways in SAP mice
Summary
Severe acute pancreatitis (SAP) is a potentially fatal pathogenic condition characterized by rapid progression and high mortality [1], but the underlying pathophysiological mechanisms remain incompletely defined. The death of pancreatic acinar cell is the major pathophysiological change in early onset of acute pancreatitis, and the modalities of cell death generally contain necrosis and apoptosis [1,2,3]. The damage of pancreatic acinar cells during SAP is usually through the interaction of apoptosis and necrosis [2]. Recent studies have revealed that mild acute pancreatitis (MAP) is mainly associated with apoptotic acinar cell death, whereas necrosis plays a predominant role in SAP with a severe inflammatory response [2]. Cell death is unlikely to be favorable, a transformation from necrosis to apoptosis in response to a pathologic stimulus can attenuate experimental pancreatitis less severe and confers a beneficial effort [3]
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