Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250062, China.
Erqi District Center for Disease Control and Prevention, Zhengzhou, Henan 450052, China.
Ecotoxicol Environ Saf. 2023 Nov 1;266:115575. doi: 10.1016/j.ecoenv.2023.115575. Epub 2023 Oct 14.
Exposure to toluene diisocyanate (TDI) can cause pulmonary diseases such as asthma. Inhibition of high mobility group box 1 protein (HMGB1) has been found to be protective against the toxic effects of TDI on human bronchial epithelial (HBE) cells. Here, we evaluated the in vivo positive roles of HMGB1 in the TDI-caused asthma mice and explored its underlying mechanisms in HBE cells. We found that suppression of HMGB1 obviously alleviated airway inflammation, airway hyperresponsiveness, and airway remodeling in the lung tissue of the asthma mice. The in vitro results showed that inhibition of HMGB1 ameliorated TDI-induced reactive oxygen species (ROS) release, inflammatory response, and activation of autophagy in HBE cells. At the molecular level, inhibition of HMGB1 decreased the expressions of HMGB1, Toll-like receptor 4, Vimentin and matrix metalloproteinase-9 proteins, activated NF-κB and NOD-like receptor protein 3 (NLRP3) inflammasome, and increased E-cadherin expression. Importantly, activation of autophagy could lead to the overactivation of NLRP3 inflammasome in TDI-induced asthma. These results suggest that inhibition of HMGB1 can alleviate TDI-induced asthma through ROS/AMPK/autophagy pathways, which may provide valuable evidence for the pathogenesis and therapeutic targets of TDI-induced asthma.
甲苯二异氰酸酯（TDI）暴露可引起哮喘等肺部疾病。已发现高迁移率族蛋白 B1（HMGB1）的抑制作用可防止 TDI 对人支气管上皮（HBE）细胞的毒性作用。在这里，我们评估了 HMGB1 在 TDI 引起的哮喘小鼠体内的积极作用，并探讨了其在 HBE 细胞中的潜在机制。我们发现，抑制 HMGB1 可明显减轻哮喘小鼠肺组织中的气道炎症、气道高反应性和气道重塑。体外结果表明，抑制 HMGB1 可改善 TDI 诱导的 HBE 细胞中活性氧（ROS）释放、炎症反应和自噬激活。在分子水平上，抑制 HMGB1 降低了 HMGB1、Toll 样受体 4、波形蛋白和基质金属蛋白酶-9 蛋白的表达，激活了 NF-κB 和 NOD 样受体蛋白 3（NLRP3）炎性小体，并增加了 E-钙黏蛋白的表达。重要的是，自噬的激活可导致 TDI 诱导的哮喘中 NLRP3 炎性小体的过度激活。这些结果表明，抑制 HMGB1 可通过 ROS/AMPK/自噬途径减轻 TDI 诱导的哮喘，这可能为 TDI 诱导的哮喘的发病机制和治疗靶点提供有价值的证据。
