氢气干预压力性溃疡的新机制：Nrf2/ARE信号通路调控皮肤成纤维细胞细胞早衰与功能稳态

Pressure ulcer is a serious public health problem in the elderly population. Premature senescence and dysfunction of fibroblast due to oxidative stress is a crucial pathogenic foundation for the chronicity and intractability of pressure ulcer, and thus becomes a hot spot at present. Our previous study found that hydrogen gas (H2) significantly reduced the oxidative stress and inflammation of ulcer lesions, and accelerated cutaneous collagen synthesis and wound closure in decubitus ulcer-like mouse model. Thus, hydrogen might be developed into a novel theraputic strategy against pressure ulcer. However, its molecular regulatory mechanism remains to be further explored. On the basis of preliminary work, we further hypothesized that H2 might inhibit premature senescence and dysfunction of fibroblast by activation of Nrf2/ARE pathway, and thus promote wound healing of pressure ulcer. To verify the above hypothesis, we try to explore the roles of H2 on fibroblast dysfunction and pressure ulcer formation via cell premature senescence models and animal experiments in this study. Furthermore, we will deeply explore the potential molecular and cellular mechanism of Nrf/ARE anti-oxidation pathway in regulating premature senescence and dysfunction of fibroblast by several methods, such as in-vitro phenotypes assays, histopathological and molecular biological methods. This study will provide new thoughts and theoretical basis for exploring novel theraputic strategies against pressure ulcer and finally overcoming chronic skin ulcers.

压力性溃疡（压疮）是威胁老年人群身心健康的重要疾病，氧化应激诱发的成纤维细胞早衰及功能紊乱是其迁延不愈的关键环节，是当前学界的研究热点。前期研究发现，氢气可显著降低压疮小鼠模型皮损中的氧化应激与炎症损伤水平，加速皮肤胶原合成，促进压疮皮损愈合，具备临床防治慢性皮肤溃疡的潜质，其潜在的分子调控机制亟待进一步明确。结合分子生物学实验，我们提出氢气可能通过Nrf2/ARE通路调控成纤维细胞早衰与功能修复，从而促进压力性溃疡的创口修复。本研究拟通过动物实验和早衰细胞模型，综合体外表型检测、组织病理学、分子生物学等多学科技术手段，从组织、细胞及分子水平论证氢气对压疮的干预效应，解析氢气对皮肤成纤维细胞的抗氧化、抗早衰和功能修复效应，揭示氧化应激调控通路Nrf2/ARE对成纤维细胞的细胞早衰与功能紊乱的分子调控机制, 为探索新型压疮防治策略提供理论依据，为最终攻克临床慢性皮肤溃疡疾病提供新的研究思路。

压力性溃疡（压疮）是威胁老年人群身心健康的重要疾病，氧化应激诱发的成纤维细胞早衰及功能紊乱是其迁延不愈的关键环节，是当前学界的研究热点。氢气具有良好的选择性抗氧化与抗炎效应，对皮肤缺血再灌注损伤具有显著的干预效应，其分子调控机制尚不甚明确。本研究发现氢气可显著降低压疮小鼠模型皮损中的氧化应激与炎症损伤水平，加速皮肤胶原合成，促进压疮皮损愈合。通过体外细胞实验，我们发现氢气对氧化损伤成纤维细胞具有显著的抗氧化、抗早衰及促功能修复效应，可显著抑制p16/p21/p53/pRb等衰老调控蛋白、NFκB通路调控蛋白的表达水平。与此同时，Sirt1基因沉默或Sirt1选择性抑制剂Ex527干预可显著阻断氢气对成纤维细胞的抗氧化、抗早衰与功能修复效应，同时也阻断了氢分子对p16等衰老调控蛋白、NFκB通路调控蛋白的抑制效应。我们的研究证实：氢气可能通过激活Sirt1通路调控成纤维细胞早衰与功能修复，从而促进压力性溃疡的创口修复。我们的研究为探索新型压疮防治策略提供理论依据，为最终攻克临床慢性皮肤溃疡疾病提供新的研究思路。

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