Blockade of high-mobility group box 1 attenuates intestinal mucosal barrier dysfunction in experimental acute pancreatitis

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.

Drug discovery and formulation development for acute pancreatitis

“…Research showed that HMGB1 level in pancreatic tissues is abnormally increased in experimental SAP model (Li et al., 2016 ). Additionally, HMGB-1 participated in the intestinal mucosal damage and dysbacteriosis, which often occurs in the SAP induced multiple organ inflammation (Chen et al., 2017 ). Inhibition of HMGB-1 played a protective role in intestinal mucosal barrier dysfunction by significantly reducing the serum levels of many pro-inflammatory cytokines, e.g.…”

“…By observing the diverse environmental factors in the inflammatory sites, such as acidity and elevated enzyme, a few responsive drug delivery systems have been constructed to increase the efficacy and decrease the side effects through elevating the drug distribution in the inflamed site (Yao, Chen, et al., 2017 ; Yao, Huang, et al., 2017; Kou et al., 2020 ; Yao et al., 2020 ). Responsive nanoparticles have shown significant potential for delivering antibiotics to the site of infection, which is beneficial to relieve necrosis in acute pancreatitis.…”

The Role of TLR-4 and Galectin-3 Interaction in Acute Pancreatitis

“…The other proposed factors that trigger TLR4 are PAMPS from translocated bacteria (2). Namely, bacterial translocation is an event that precedes bacterial infection of pancreatic necrosis (61). After activation TLR4 by PAMPs derived from invading bacteria, expression of several cytokines and costimulatory molecules is increased in the antigen-presenting cells and therefore promote activation of the specific immune response (2).…”

Combinatory antibiotic treatment protects against experimental acute pancreatitis by suppressing gut bacterial translocation to pancreas and inhibiting NLRP3 inflammasome pathway

“…During AP, gut bacteria translocation is usually caused by an impaired gut barrier, gut bacterial overgrowth, and increased inflammation. [11][12][13] In the later stage of AP, bacteria in the blood and other organs account for multiple organ failure, sepsis and other serious complications. However, how the escaped gut bacteria participate in amplifying inflammation in the blood, pancreas and adjacent organs remains unknown.…”