Apocynin alleviates lung injury by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis.

Mounting evidence has demonstrated that acute pancreatitis (AP) is one of the causes of multiple organ damage. NADPH (nicotinamide adenine dinucleotide phosphate) act as a substrate of NADPH oxidase (NOX) to generate reactive oxygen species (ROS), but the role NADPH oxidase signaling pathway plays in AP-induced acute lung injury remains unclear. Apocynin, an inhibitor of NOX, is highly effective in suppressing the production of ROS. Here, we used rat model of severe acute pancreatitis (SAP) to explore whether the NOX inhibitor apocynin produced protective effects in against SAP-induced lung injury via inhibition of inflammation and oxidation. We observed that apocynin significantly attenuated severe acute pancreatitis-induced increase of NOX2, NOX4 and ROS expressions in lung tissues. In addition, the phosphorylation and degradation of IκBα, and the nuclear localization of NF-κB p65 in SAP-induced lung injury were also inhibited after using apocynin. Simultaneously, down-regulation of NOX suppressed the levels of inflammasome proteins including NLRP3, ASC, pro-Caspase-1 and cleaved-Caspase-1 in the lung. Serum levels of TNF-α, interleukin (IL)-1ß and IL-6 were also reduced. Our findings suggest that beyond anti-oxidative effects, apocynin may also have anti-inflammatory effects by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis. Therefore, apocynin may have therapeutic potential in the treatment of SAP and SAP-induced lung injury.

4-Phenylbutyric Acid Attenuates Endoplasmic Reticulum Stress-Mediated Intestinal Epithelial Cell Apoptosis in Rats with Severe Acute Pancreatitis.

OBJECTIVES: The present study aimed to determine whether intestinal epithelial cell (IECs) apoptosis could be induced by endoplasmic reticulum stress (ERS) in severe acute pancreatitis (SAP), and the role of chemical chaperone 4-phenylbutyric acid (4-PBA) in SAP-associated intestinal barrier injury. METHODS: Twenty-four male Sprague Dawley rats were randomly divided into three groups: the sham operation group, the SAP group, and the SAP model plus 4-PBA treatment group (4-PBA group). A rat model of SAP was induced by retrograde injection of 5% sodium taurocholate (STC) into the biliopancreatic duct; in the 4-PBA group, 4-PBA was injected intraperitoneally at a dose of 50 mg/kg body weight for 3 days before modeling. RESULTS: The results indicated that 4-PBA attenuated the following: (1) pancreas and intestinal pathological injuries, (2) serum TNF-α, IL-1ß, and IL-6, (3) serum DAO level, serum endotoxin level, (4) the apoptosis of IECs, (5) ER stress markers (caspase-12, CHOP, GRP78, PERK, IRE1α, ATF6) and caspase-3 expression in intestinal. However, the serum AMY, LIPA levels, and the expression of caspase-9, caspase-8 were just slightly decreased. CONCLUSIONS: ERS may be considered a predominant pathway, which is involved in the apoptosis of IECs during SAP. Furthermore, 4-PBA protects IECs against apoptosis in STC-induced SAP by attenuating the severity of ERS.

Inhibition of endoplasmic reticulum stress by 4-phenylbutyric acid prevents vital organ injury in rat acute pancreatitis.

This study was conducted to investigate the effect of 4-phenylbutyric acid (4-PBA) on vital organ injury following sodium taurocholate-induced acute pancreatitis (AP) in rats and the pertinent mechanism. The serum biochemical indicators and key inflammatory cytokines, histopathological damage and apoptosis of vital organs in rat AP, were evaluated in the presence or absence of 4-PBA. Moreover, mRNA and protein levels of endoplasmic reticulum stress (ERS) markers were assessed. 4-PBA significantly attenuated the structural and functional damage of vital organs, including serum pancreatic enzymes, hepatic enzymes, creatinine, and urea. The morphological changes and infiltration of neutrophils and macrophages were reduced as well. These effects were accompanied by decreased serum levels of proinflammatory TNF-α and IL-1ß. Furthermore, 4-PBA diminished the expression of ERS markers (glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein, protein kinase R-like ER kinase, activated transcription factor 6, and type-1 inositol requiring enzyme) in vital organs of AP rats. 4-PBA also reduced AP-induced apoptosis in lung, liver, and kidney tissues as shown by TUNEL assay. The present study demonstrated that 4-PBA protected pancreas, lung, liver, and kidney from injury in rat AP by regulating ERS and mitigating inflammatory response to restrain cell death and further suggested that 4-PBA may have potential therapeutic implications in the disease. NEW & NOTEWORTHY In this study, we suggest that endoplasmic reticulum stress (ERS) is an important player in the development of acute pancreatitis-induced multiorgan injury, providing additional evidence for the proinflammatory role of ERS. Because 4-phenylbutyric acid has been suggested to inhibit ERS in many pathological conditions, it is possible that this effect can be involved in alleviating inflammatory response and cell death to ameliorate vital organ damage following acute pancreatitis induced by sodium taurocholate in rats.

ß cells can be generated from cytokeratin 5-positive cells after cerulein-induced pancreatitis in adult mice.

Clinical studies have revealed that some patients will develop glucose tolerance dysfunction after recovering from acute pancreatitis (AP), which indicated the importance of investigating the potential therapies for restoration of islet ß cell function. Cytokeratin 5 (Krt5)-positive cells are considered to function as stem or progenitor cells in the regeneration of lung and salivary gland following injury. In the present study, AP was induced by six hourly intraperitoneal injections of 100 µg/kg cerulein for 4 consecutive days in adult mice, in order to determine the role of Krt5-positive cells in pancreatic regeneration, especially in the restoration of ß cell function and the underlying mechanisms. Results showed that glucose homeostasis were deteriorated partly during the recovery process after AP. Furthermore, clusters of Krt5-positive cells were significantly increased in the damaged pancreas marked by inflammatory cells infiltration and acinar cell eradication. In addition, cells co-labelling insulin and Krt5 were found in the injured region after cerulein administration, part of these cells were immunopositive for GLUT2. Taken together, our data demonstrated that Krt5-expressing cells could be involved in the natural pancreas self-healing process and the renewal of ß cells after AP in adult mice. It is promising that promoting conversion of Krt5-expressing cells into functional ß cells may be a novel method to mitigate the development of diabetes mellitus after AP in vivo.