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Heparin has shown benefits in severe acute pancreatitis (SAP) therapy, but the underlying mechanisms were unknown. Extracellular high-mobility group protein-1 (HMGB-1) has been regarded as a central mediator contributing to inflammation exacerbation and disease aggravation. We hypothesized heparin attenuated the disease by targeting HMGB-1-related pathways. In the present study, the possible therapeutic roles of heparin and its non-anticoagulant derivatives, 6-O-desulfulted heparin and N-acylated-heparin, were determined on mouse models induced by "Two-Hit" of L-arginine. The compounds exhibited potent efficiency by substantially decreasing the pancreatic necrosis, macrophage infiltration, and serum inflammatory cytokine (IL-6 and TNF-α) concentration. Moreover, they greatly reduced the rapidly increasing extracellular HMGB-1 levels in the L-arginine injured pancreases. As a result, multiple organ failure and mortality of the mice were inhibited. Furthermore, the drugs were incubated with the RAW264.7 cells activated with damaged pancreatic tissue of SAP mice in vitro. They were found to inhibit HMGB-1 transfer from the nucleus to the plasma, a critical step during HMGB-1 active secretion from macrophages. The results were carefully re-examined with a caerulein and LPS induced mouse model, and similar results were found. The paper demonstrated heparin alleviated SAP independent of the anti-coagulant functions. Therefore, non-anticoagulant heparin derivatives might become promising approaches to treat patients suffering from SAP.

Heparin Protects Severe Acute Pancreatitis by Inhibiting HMGB-1 Active Secretion from Macrophages