Rac-1 Inhibitor Attenuates Neutrophil Infiltration and Tissue Damage in Severe Acute Pancreatitis

Background: Acute pancreatitis is a common inflammatory disease of the exocrine pancreas, characterized by a mortality rate ranging from 1% to 5%. This condition has the potential to lead to organ dysfunction, pancreatic necrosis, and subsequent organ failure. Aim: Rac1, a G-protein with a molecular weight of approximately 21 kD, has been demonstrated to govern various platelet functions. We hypothesized that the inhibition of Rac-1 signaling could be implicated in severe acute pancreatitis (AP). Our study aimed to explore the impact of a Rac- 1 inhibitor on neutrophil release and its potential in safeguarding against tissue damage associated with severe acute pancreatitis. Method: In this experimental study, Swiss albino mice were employed, and the mice received pretreatment with a specific Rac1 inhibitor, NSC23766, at a dosage of 5 mg/kg. Subsequently, a midline laparotomy was performed on the anesthetized animals, followed by taurocholate perfusion. Blood amylase levels were measured, and the concentration of serum chemokines (CXCL2 and IL6) was assessed using ELISA. Additionally, leukocyte counting, myeloperoxidase (MPO) activity, and histopathological examination were conducted to analyze morphological changes in the pancreas. Results: The blood amylase levels were notably elevated in mice with acute pancreatitis compared to the sham mice. Our findings indicated that acute pancreatitis was induced in mice through taurocholate perfusion. Rac1 expression was upregulated in mice with acute pancreatitis, and pre-treatment with NSC23766 led to a significant decrease in myeloperoxidase (MPO) levels compared to the acute pancreatitis group. Furthermore, the levels of CXCL2 and IL6 were significantly higher in acute pancreatitis compared to the control group, with a P-value < 0.05. Conclusion: Our investigation underscores the pivotal role of Rac-1 in regulating amylase activity during severe acute pancreatitis (AP). Additionally, it highlights the involvement of Rac-1 in platelet activation and the secretion of chemokines, namely CXCL2 and IL6, attributed to inflammation in organ tissues during acute pancreatitis. Targeting Rac1 emerges as a promising and innovative approach for the treatment of severe acute pancreatitis, offering potential control over inflammation and tissue damage.