Abstract
The release of inflammatory cytokines, that plays a dominant role in local pancreatic inflammation and systemic complications in severe acute pancreatitis (SAP). High-mobility group box 1 (HMGB1) is implicated in the mechanism of organ dysfunction and bacterial translocation in SAP. This current study aims to investigate possible role of HMGB1 in the intestinal mucosal barrier dysfunction of SAP, and the effect of anti-HMGB1 antibody treatment in intestinal mucosal injury in SAP. Our data revealed that the HMGB1 expression was significantly increased in AP mice induced by caerulein and LPS, and the inhibition of HMGB1 played a protective role in intestinal mucosal barrier dysfunction, reduced the serum level of other proinflammatory cytokines include IL-1β, IL-6, TNF-α. Next we investigated the downstream receptors involving in HMGB1 signaling. We found that the expressions of toll-like receptor (TLR) 4 and TLR9 were elevated in ileum of AP mice, the administration of HMGB1 neutralizing antibody significantly reduced the TLR4 and TLR9 expression. It was concluded that HMGB1 contributed the mechanism to the intestinal mucosal barrier dysfunction during AP. Blockade of HMGB1 by administration of HMGB1 neutralizing antibody may be a beneficial therapeutic strategy in improving intestinal mucosal barrier dysfunction in SAP.
Highlights
Severe acute pancreatitis (SAP) is a local inflammatory disease of the pancreas, and a systemic disease involving multiple organs
The translocation of gut bacteria and endotoxin following intestinal mucosal barrier injury is a key event contributing to the severity of AP, even more, initiate and aggravate systemic inflammatory response syndrome (SIRS) or multiple organ dysfunction syndrome (MODS), which are important factors influencing severity and mortality of AP16
Serum levels of Diamine oxidase (DAO) and endotoxin core body were increased in mice with acute necrotizing pancreatitis (ANP), together with the histopathologic changes of ileal mucosal impairment, indicating the presence of intestinal mucosal barrier dysfunction during the development of AP
Summary
Severe acute pancreatitis (SAP) is a local inflammatory disease of the pancreas, and a systemic disease involving multiple organs. Activation of polymorphonuclear granulocytes (PMNs) and of monocytes/ macrophages is an early event during SAP Cytokines such as TNF-α is rapidly cleared from the bloodstream, and sensitivity of its measurement seem strictly time dependent only in the onset of the disease[4]. Whether the blockade of HMGB1 with a polyclonal antibody could ameliorate intestinal mucosal barrier dysfunction and its possible mechanism were explored. These data would provide more information to understand the possible therapeutic potential of HMGB1 targeted intervention in intestinal barrier dysfunction in SAP
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