Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, 221002, Jiangsu Province, China,
Dig Dis Sci. 2013 Oct;58(10):2826-39. doi: 10.1007/s10620-013-2727-5. Epub 2013 Jun 7.
Toll-like receptor 4 (TLR4) contributes to ethanol-induced gastric mucosal injury. This study aimed to determine its precise role in this pathogenic state and the related signaling pathway.
Ethanol-induced gastric mucosal injury models were generated in TLR4(-/-) mice (C3H/HeJ: point mutation; C57BL/10ScNJ: gene deletion), their respective TLR4(+/+) wild-type counterparts, and heterozygous TLR4(+/-) mice. Lipopolysaccharide (LPS) or pyrrolidine dithiocarbamate (PDTC) was injected intraperitoneally 1 h or 30 min before ethanol administration. At 1 h post-ethanol treatment, gastric or serum specimens were evaluated.
Ethanol intra-gastric administration induced significant gastric mucosal injury in all mice, but the damaged area was larger in TLR4(-/-) mice. LPS preconditioning and up-regulated TLR4 expression led to significantly larger areas of gastric mucosal damage. Upon ethanol administration, TLR4(+/+), and not TLR4(-/-), mice showed significant increases in TLR4, myeloid differentiation factor 88 (MyD88), cytoplasmic high mobility group box 1 (HMGB1), and nuclear factor-kappa B p65 (NF-κB p65). PDTC pretreatment significantly attenuated the ethanol-induced gastric mucosal damaged areas, inhibited nuclear NF-κB p65 expression, and suppressed HMGB1 translocation out of the nucleus. In addition, PDTC pretreatment reduced ethanol-stimulated expression of the inflammatory modulators, interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), in serum.
Both deficient and excessive expression of TLR4 promotes ethanol-induced gastric mucosal injury. The underlying mechanism involves the MyD88/NF-κB signaling pathway and the HMGB1, TLR4 activator ligand. The increased expression of HMGB1 may lead to increased secretion and binding to TLR4, further stimulating the TLR4/MyD88/NF-κB signaling pathway and aggravating the ethanol-induced gastric mucosal injury.
Toll 样受体 4（TLR4）参与乙醇诱导的胃黏膜损伤。本研究旨在确定其在这种致病状态中的确切作用及其相关信号通路。
在 TLR4（-/-）小鼠（C3H/HeJ：点突变；C57BL/10ScNJ：基因缺失）、各自的 TLR4（+/+）野生型对照和杂合 TLR4（+/-）小鼠中生成乙醇诱导的胃黏膜损伤模型。在给予乙醇前 1 小时或 30 分钟，经腹腔内注射脂多糖（LPS）或吡咯烷二硫代氨基甲酸盐（PDTC）。在乙醇处理后 1 小时，评估胃或血清标本。
乙醇胃内给药在所有小鼠中均引起明显的胃黏膜损伤，但 TLR4（-/-）小鼠的损伤面积更大。LPS 预处理和 TLR4 表达上调导致胃黏膜损伤面积显著增大。给予乙醇后，TLR4（+/+）而不是 TLR4（-/-）小鼠中 TLR4、髓样分化因子 88（MyD88）、细胞质高迁移率族蛋白 B1（HMGB1）和核因子-κB p65（NF-κB p65）显著增加。PDTC 预处理显著减轻乙醇诱导的胃黏膜损伤面积，抑制核 NF-κB p65 表达，并抑制 HMGB1 从核内易位。此外，PDTC 预处理降低了血清中炎症调节剂白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的乙醇刺激表达。
TLR4 的缺乏和过度表达均促进乙醇诱导的胃黏膜损伤。其潜在机制涉及 MyD88/NF-κB 信号通路和 HMGB1、TLR4 激活配体。HMGB1 的表达增加可能导致其分泌增加并与 TLR4 结合，进而进一步刺激 TLR4/MyD88/NF-κB 信号通路，加重乙醇诱导的胃黏膜损伤。
