High Mobility Group Box 1 Promotes Small Intestinal Damage Induced by Nonsteroidal Anti-Inflammatory Drugs through Toll-Like Receptor 4

Abstract

Release of high mobility group box 1 (HMGB1) from damaged cells, which is involved in many types of tissue injuries, activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor 2 (TLR2), TLR4, and receptor for advanced glycation end-products (RAGE). Our objective was to determine the role of HMGB1 in nonsteroidal anti-inflammatory drug (NSAID)-induced damage of the small intestine. Oral indomethacin (10 mg/kg) induced damage to the small intestine and was associated with increases in intestinal HMGB1 expression and serum HMGB1 levels. In wild-type mice, recombinant human HMGB1 aggravated indomethacin-induced small intestinal damage; enhanced the mRNA expression levels of tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1, and KC; activated nuclear factor kappa B; and stimulated phosphorylation of the mitogen-activated protein kinases p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). In contrast, blocking HMGB1 action with neutralizing antibodies prevented damage and inhibited both inflammatory cytokine overexpression and activation of these intracellular signaling pathways. TLR2-knockout (KO) and RAGE-KO mice exhibited high sensitivities to indomethacin-induced damage, similar to wild-type mice, whereas TLR4-KO mice exhibited less severe intestinal damage and lower levels of TNF-α mRNA expression. Exogenous HMGB1 aggravated the damage in TLR2- and RAGE-KO mice but did not affect the damage in TLR4-KO mice. Thus, our results suggest that HMGB1 promotes NSAID-induced small intestinal damage through TLR4-dependent signaling pathways.

TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

“…8 Interestingly, HMGB1 was rapidly mobilized and released into system circulation by hepatocytes in the setting of liver I/R injury. 8,9 HMGB1 has also been reported to participate in ALI and lung inflammatory response induced by endotoxin, ventilator, and hemorrhage. [10][11][12] For example, HMGB1 expression in the lung was found to be increased within 4 h of hemorrhage, and then remained elevated for more than 72 h after blood loss.…”

“…27 The HMGB1-TLR4 signaling pathway has been strongly implicated in the pathogenesis of small intestinal damage induced by nonsteroidal anti-inflammatory drugs and other forms of ALI. 9,11 Thus, we hypothesized that HMGB1 may be involved in ALI and lung inflammation, and its downstream TLR4, p38MAPK, and AP-1 signaling pathways may act as potentially important mediators in the development of ALI. In this study, a rat liver I/R injury model was used to induce ALI.…”

Isoliquiritigenin Ameliorates Indomethacin-Induced Small Intestinal Damage by Inhibiting NOD-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation

“…where at least 10 random villi at the injured area were scored per mouse. For evaluation, we used a modified histological scoring system [11]. The histology score ranged from 0 to 13 and was subdivided into the following categories: epithelium (0 = normal, 1 = flattened, 2 = loss of epithelial continuity, 3 = severe denudation), villus shape (0 = normal, 1 = short and rounded, 2 = extremely short and thick), villus tip (0 = normal, 1 = damaged, 2 = severely damaged), stroma (0 = normal, 1 = slightly retracted, 2 = severely retracted), inflammation (0 = no infiltration, 1 = mild infiltration, 2 = severe infiltration), and crypt shape (0 = normal, 1 = mild crypt loss, 2 = severe crypt loss).…”

Non-Steroidal Anti-Inflammatory Drug (NSAID)-Induced Small Intestinal Injury

“…Combination of low-dose aspirin therapy and thienopyridine may exacerbate small bowel injury [27]. Other candidate mediators of NSAID-induced small intestinal injury are JNK pathway [28], Reg I (Regenerating gene I ) [29], MMP-9 (matrix metalloproteinase-9) [30], urocortin 1(a nonselective CRF receptor agonist) [31], IL-17A [32], enhanced platelets-bearing neutrophil migration [33], HMGB1(High mobility group box 1) [34], serotonin (5-HT) 3 receptors [35], and hemopexin [36]. If the contribution of any of these candidates to NSAID-induced injury of are enough high, they would be also candidates for treatment.…”