Blockade of C3a/C3aR axis alleviates severe acute pancreatitis-induced intestinal barrier injury

Severe acute pancreatitis (SAP) contributes to multiple organ dysfunction and intestine is one of the most susceptible targets. This study aims to explore the role of C3a/C3aR axis in SAP-induced intestinal barrier injury. Adult male Sprague Dawley rats were randomly divided into control, SAP, C3aRA (0.06 mg/kg) and C3aRA (0.12 mg/kg) groups. SAP rat models were established by retrograde injection of 3.5% sodium taurocholate solutions into pancreatic ducts. Histopathological changes and dysfunction in pancreatitis and intestine were measured by hematoxylin and eosin (H&E) staining and detection of amylase (AMY), lipase (LIPA), endotoxins and diamine oxidase (DAO) levels in serum. Cell apoptosis was evaluated by TUNEL assay and western blot analysis. In addition, the expressions of caudin-1, caudin-2, occludin and ZO-1 were detected by western blot assay and immunohistochemical staining. Inflammatory cytokines and oxidative stress levels in SAP rats were determined. The C3a/C3aR expression was increased in pancreatic and intestinal tissues of successfully established SAP rat models. C3a receptor antagonist (C3aRA) alleviated pancreatic and intestinal pathological lesions and dysfunction induced by SAP. C3aRA inhibited cell apoptosis and promoted the expressions of caudin-1, caudin-2, occludin and ZO-1 in intestinal tissues. Moreover, C3aRA repressed inflammatory cytokines by reduction of TNF-α, IL-1β, IL-6 and MCP-1 levels, and ameliorated oxidative stress through regulation of ROS, MPO and SOD activity in rats with SAP-induced intestinal barrier injury. Our findings suggested that inhibition of C3a/C3aR axis diminished pancreatic damage and SAP-induced intestinal barrier injury in vivo, which may provide a new therapeutic strategy for SAP-induced intestinal injury.