Acute pancreatitis (AP) is a common and devastating inflammatory disorder of the pancreas. However, there are still no effective treatments available for the disease. Therefore, it is important to discover new therapeutic targets and strategies for better treatment and prognosis of AP patients. Toll-like receptor 3 (TLR3) ligand polyI:C is a double-stranded RNA mimic that can be used as an immune stimulant. Our current study indicates that polyI:C exerted excellent anti-inflammatory effects in a caerulein-induced AP mouse model and taurocholate-induced pancreatic acinar cell line injury model. We found that polyI:C triggers type I interferon (IFN) production and downstream IFN-α/β receptor (IFNAR)-dependent signaling, which play key roles in protecting the pancreas from inflammatory injury. Knockout of IFN-β and IFNAR in mice abolished the preventive effects of polyI:C on caerulein-induced AP symptoms, which include pancreatic edema, neutrophil infiltration, the accumulation of reactive oxygen species (ROS), and inflammatory gene expression. Treating pancreatic acinar 266-6 cells with an IFNAR inhibitor, which blocks the interaction between type I IFN and IFNAR, diminishes the downregulation of oxidative stress by polyI:C. Additionally, a subsequent transcriptome analysis on the role of polyI:C in treating pancreatitis suggested that chemotaxis of neutrophils and the production of ROS were inhibited by polyI:C in the pancreases damaged by caerulein injection. Thus, polyI:C may act as a type I IFN inducer to alleviate AP, and it has the potential to be a promising therapeutic agent used at the early stages of AP.
The changes of tumor necrosis factor-alpha (TNF-alpha) and brain ultrastructure during cardiopulmonary resuscitation and the effects of ulinastation injection were observed, and the mechanism was investigated. Twenty-four adult healthy Sprague-Dawley rats were randomly divided into control group (8 rats), resuscitation group (8 rats) and ulinastatin (UTI) group (8 rats). Rats in control group underwent tracheotomy without clipping the trachea to induce circulatory and respiratory standstill. Rats in resuscitation and ulinastatin group were subjected to the procedure of establishing the model of cardiopulmonary cerebral resuscitation (CPCR). Rats in ulinastatin group were given with UTI 104 U/kg once after CPCR. In the control group, the plasma was collected immediate, 30 min, 2 h, 4 h, and 6 h after tracheotomy. In resuscitation group and UTI group, plasma was collected immediate after tracheotomy, 30 min, 2 h, 4 h and 6 h after successful resuscitation. The plasma levels of TNF-alpha were determined by radioimmunoassay (RIA). At the end of the experiment, 2 rats were randomly selected from each group and were decapitated. The cortex of the brain was taken out immediately to observe the ultrastructure changes. In control group, there were no significant differences in the level of TNF-alpha among different time points (P>0.05). In resuscitation group, the level of TNF-alpha was increased obviously after resuscitation (P<0.01) and reached its peak 2 h later after resuscitation. An increasing trend of TNF-alpha showed in UTI group. There were no differences in TNF-alpha among each sample taken after successful resuscitation and that after tracheotomy. The utrastructure of brains showed the injury in UTI group was ameliorated as compared with that in resuscitation group. In early period of CPCR, TNF-alpha was expressed rapidly and kept increasing. It indicated that TNF-alpha might take part in the tissue injury after CPCR. The administration of UTI during CACR could depress TNF-alpha and ameliorate brain injury. By regulating the expression of damaging mediator, UTI might provide a protective effect on the tissue injury after CPCR.
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