Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway.
Hydrogen attenuates postoperative pain through Trx1/ASK1/MMP9 signaling pathway.
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氢通过TRX1/ASK1/MMP9信号通路会减轻术后疼痛。
DOI：
10.1186/s12974-022-02670-0
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发表时间：
2023-02-03
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
术后疼痛是一个严重的临床问题，其机制知之甚少，缺乏有效的治疗。氢（H2）可以减少神经炎症;因此，我们假设H2可以减轻术后疼痛，并旨在研究其潜在机制。采用小鼠建立足底切口手术后疼痛模型。使用von Frey试验测量机械性异常性疼痛。使用明胶酶谱法、蛋白质印迹法、免疫组织化学和免疫荧光染色来测定细胞信号传导。动物或BV-2细胞接受有/没有ASK 1和Trx 1抑制剂，以研究H2对小胶质细胞的影响。足底切口手术增加了小鼠脊髓中MMP-9的活性和ASK 1的磷酸化。MMP-9敲除和ASK 1抑制剂NQDI-1可减轻术后疼痛。H2可增加Trx 1在脊髓和BV-2细胞中的表达。H2处理模拟NQDI 1降低ASK 1、p38和JNK的磷酸化。它还降低MMP-9活性，下调小鼠脊髓中pro-IL-1β成熟和IBA-1表达，并改善术后疼痛。H2的保护作用被Trx 1抑制剂PX 12所消除。在BV-2细胞中，H2也模拟NQDI 1抑制ASK 1、p38和JNK的磷酸化，并且还降低MMP-9活性和降低LPS诱导的IBA-1表达。Trx 1抑制剂PX 12可阻断H2对BV-2细胞的保护作用。我们的研究结果首次证实，H2可以作为一种治疗剂，通过Trx 1/ASK 1/MMP 9信号通路缓解术后疼痛。MMP-9和ASK 1可能是减轻术后疼痛的靶分子。
Postoperative pain is a serious clinical problem with a poorly understood mechanism, and lacks effective treatment. Hydrogen (H2) can reduce neuroinflammation; therefore, we hypothesize that H2 may alleviate postoperative pain, and aimed to investigate the underlying mechanism. Mice were used to establish a postoperative pain model using plantar incision surgery. Mechanical allodynia was measured using the von Frey test. Cell signaling was assayed using gelatin zymography, western blotting, immunohistochemistry, and immunofluorescence staining. Animals or BV-2 cells were received with/without ASK1 and Trx1 inhibitors to investigate the effects of H2 on microglia. Plantar incision surgery increased MMP-9 activity and ASK1 phosphorylation in the spinal cord of mice. MMP-9 knockout and the ASK1 inhibitor, NQDI-1, attenuated postoperative pain. H2 increased the expression of Trx1 in the spinal cord and in BV-2 cells. H2 treatment mimicked NQDI1 in decreasing the phosphorylation of ASK1, p38 and JNK. It also reduced MMP-9 activity, downregulated pro-IL-1β maturation and IBA-1 expression in the spinal cord of mice, and ameliorated postoperative pain. The protective effects of H2 were abolished by the Trx1 inhibitor, PX12. In vitro, in BV-2 cells, H2 also mimicked NQDI1 in inhibiting the phosphorylation of ASK1, p38, and JNK, and also reduced MMP-9 activity and decreased IBA-1 expression induced by LPS. The Trx1 inhibitor, PX12, abolished the protective effects of H2 in BV-2 cells. For the first time, the results of our study confirm that H2 can be used as a therapeutic agent to alleviate postoperative pain through the Trx1/ASK1/MMP9 signaling pathway. MMP-9 and ASK1 may be the target molecules for relieving postoperative pain.
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