The 3 intervention time points reported in most experimental pancreatitis studies are 1,6 hours before induction, immediately after the induction, and 1,6 hours after the induction. 2) In the above literature, studies on the role of netrin-1 in protecting kidney, lung, colon, or peritoneum from inflammatory injury have found netrin-1 can effectively protect these organs/tissues if it is administrated at 2 hours before or immediately after the induction and once every 24 hours thereafter at the dosage of 1 mg/mouse. The present study showed that our netrin-1 administration has protective and beneficial effects on the pancreas and lung in L-Arginin-induced pancreatitis model, as measured both biochemically and histologically. As expected, acute pancreatitis was successfully and consistently induced in C57BL/6 mice following the administration of two doses of L-Arginin, 4 g/kg each, and 1 h apart. Both plasma amylase and MPO levels in pancreas and lung significantly increased at 24 h after induction of pancreatitis compared to levels in normal animals. Histopathological changes observed in pancreatic acinar cells concurred with the time point at which both plasma amylase and MPO activities started to increase. LArginine administration resulted in significant inflammatory cells infiltration and tissue damage in both pancreas and lung. The infiltration of inflammatory cells, with the majority being neutrophils, was also observed at 24 h after L-arginine administration, and was most prominent after 72 h in both pancreas and lung. Netrin-1 treatment significantly reduced neutrophil infiltration both in pancreas and lung as evidenced by MPO levels and histological manifestations compared to untreated animals. Our study shows that netrin-1 treatment significantly ameliorates the severity of L-Arginin-induced AP and the protective effect of netrin-1 against AP was positively related to its ability to inhibit leukocyte infiltration. Accumulating evidence has shown that pro-inflammatory cytokines, especially TNF-a, IL-1ß, and IL-6, are pivotal in explaining why local pancreatic damage evolves to a systemic disease. In experimental pancreatitis, the plasma levels of TNF-a, IL-1ß, and IL-6 are elevated and their blockade attenuates the disease process. In the present study, plasma levels of TNF-a, IL-1ß, IL-6, and IL-10 gradually increased after induction of pancreatitis, with peak levels occurred after 48 or 72 h. We observed that netrin-1 treatment resulted in significant reduction in plasma levels of TNF-a, IL- 1ß, and IL-6. Furthermore, netrin1 treatment led to a significant increase in plasma IL-10 levels. Our results demonstrate that Netrin-1 can regulate inflammatory cytokines and suppress the pro-inflammatory response in AP. The signaling pathway responsible for the role of netrin-1 in regulating leukocyte infiltration and cytokine GDC-0941 production during the course of AP has been of interest. One important signaling molecule, NF-kB, was identified as an important regulator of the expression of many inflammatory mediators in the pancreas. NF-kB is a nuclear transcription factor responsible for regulating the transcription of a wide variety of genes involved in immunity and inflammation. There is an emerging body of evidence which suggests that NF-kB plays an important role in the early stage of acute pancreatitis, and that inhibiting this transcription factor reduces the disease severity. Although most researchers agree that blocking NF-kB activation is beneficial in acute experimental pancreatitis.