PDF(Pubmed)
Abstract：
BACKGROUND: Silicosis, characterized by interstitial lung inflammation and fibrosis, poses a significant health threat. ATII cells play a crucial role in alveolar epithelial repair and structural integrity maintenance. Inhibiting ATII cell senescence has shown promise in silicosis treatment. However, the mechanism behind silica-induced senescence remains elusive.
METHODS: The study employed male C57BL/6 N mice and A549 human alveolar epithelial cells to investigate silicosis and its potential treatment. Silicosis was induced in mice via intratracheal instillation of crystalline silica particles, with honokiol administered intraperitoneally for 14 days. Silica-induced senescence in A549 cells was confirmed, and SIRT3 knockout and overexpression cell lines were generated. Various analyses were conducted, including immunoblotting, qRT-PCR, histology, and transmission electron microscopy. Statistical significance was determined using one-way ANOVA with Tukey\'s post-hoc test.
RESULTS: This study elucidates how silica induces ATII cell senescence, emphasizing mtDNA damage. Notably, honokiol (HKL) emerges as a promising anti-senescence and anti-fibrosis agent, acting through sirt3. honokiol effectively attenuated senescence in ATII cells, dependent on sirt3 expression, while mitigating mtDNA damage. Sirt3, a class III histone deacetylase, regulates senescence and mitochondrial stress. HKL activates sirt3, protecting against pulmonary fibrosis and mitochondrial damage. Additionally, HKL downregulated cGAS expression in senescent ATII cells induced by silica, suggesting sirt3\'s role as an upstream regulator of the cGAS/STING signaling pathway. Moreover, honokiol treatment inhibited the activation of the NF-κB signaling pathway, associated with reduced oxidative stress and mtDNA damage. Notably, HKL enhanced the activity of SOD2, crucial for mitochondrial function, through sirt3-mediated deacetylation. Additionally, HKL promoted the deacetylation activity of sirt3, further safeguarding mtDNA integrity.
CONCLUSIONS: This study uncovers a natural compound, HKL, with significant anti-fibrotic properties through activating sirt3, shedding light on silicosis pathogenesis and treatment avenues.
METHODS: The study employed male C57BL/6 N mice and A549 human alveolar epithelial cells to investigate silicosis and its potential treatment. Silicosis was induced in mice via intratracheal instillation of crystalline silica particles, with honokiol administered intraperitoneally for 14 days. Silica-induced senescence in A549 cells was confirmed, and SIRT3 knockout and overexpression cell lines were generated. Various analyses were conducted, including immunoblotting, qRT-PCR, histology, and transmission electron microscopy. Statistical significance was determined using one-way ANOVA with Tukey\'s post-hoc test.
RESULTS: This study elucidates how silica induces ATII cell senescence, emphasizing mtDNA damage. Notably, honokiol (HKL) emerges as a promising anti-senescence and anti-fibrosis agent, acting through sirt3. honokiol effectively attenuated senescence in ATII cells, dependent on sirt3 expression, while mitigating mtDNA damage. Sirt3, a class III histone deacetylase, regulates senescence and mitochondrial stress. HKL activates sirt3, protecting against pulmonary fibrosis and mitochondrial damage. Additionally, HKL downregulated cGAS expression in senescent ATII cells induced by silica, suggesting sirt3\'s role as an upstream regulator of the cGAS/STING signaling pathway. Moreover, honokiol treatment inhibited the activation of the NF-κB signaling pathway, associated with reduced oxidative stress and mtDNA damage. Notably, HKL enhanced the activity of SOD2, crucial for mitochondrial function, through sirt3-mediated deacetylation. Additionally, HKL promoted the deacetylation activity of sirt3, further safeguarding mtDNA integrity.
CONCLUSIONS: This study uncovers a natural compound, HKL, with significant anti-fibrotic properties through activating sirt3, shedding light on silicosis pathogenesis and treatment avenues.
摘要：
背景：矽肺，以间质性肺部炎症和纤维化为特征，对健康构成重大威胁。ATII细胞在肺泡上皮修复和结构完整性维持中起着至关重要的作用。抑制ATII细胞衰老已在矽肺治疗中显示出希望。然而,二氧化硅诱导衰老背后的机制仍然难以捉摸。
方法：本研究采用雄性C57BL/6N小鼠和A549人肺泡上皮细胞研究矽肺及其潜在治疗方法。通过气管内滴注结晶二氧化硅颗粒在小鼠中诱发矽肺，与和厚朴酚腹膜内给药14天。证实了二氧化硅诱导的A549细胞衰老，产生SIRT3敲除和过表达细胞系。进行了各种分析，包括免疫印迹,qRT-PCR,组织学,和透射电子显微镜。使用单向ANOVA和Tukey事后检验确定统计显著性。
结果：本研究阐明了二氧化硅如何诱导ATII细胞衰老，强调mtDNA损伤。值得注意的是,和厚朴酚（HKL）作为一种有前途的抗衰老和抗纤维化剂，通过sirt3起作用。和厚朴酚有效地减弱了ATII细胞的衰老，依赖于sirt3表达，同时减轻mtDNA损伤。Sirt3，III类组蛋白脱乙酰酶，调节衰老和线粒体应激。HKL激活sirt3，保护免受肺纤维化和线粒体损伤。此外,HKL下调二氧化硅诱导的衰老ATII细胞中cGAS的表达，提示sirt3作为cGAS/STING信号通路的上游调节因子的作用。此外，和厚朴酚处理抑制NF-κB信号通路的激活,与减少氧化应激和mtDNA损伤有关。值得注意的是,HKL增强了SOD2的活性，对线粒体功能至关重要，通过sirt3介导的去乙酰化。此外,HKL促进sirt3的去乙酰化活性，进一步维护mtDNA完整性。
结论：这项研究揭示了一种天然化合物，HKL,通过激活sirt3具有显著的抗纤维化特性，揭示矽肺的发病机理和治疗途径。
方法：本研究采用雄性C57BL/6N小鼠和A549人肺泡上皮细胞研究矽肺及其潜在治疗方法。通过气管内滴注结晶二氧化硅颗粒在小鼠中诱发矽肺，与和厚朴酚腹膜内给药14天。证实了二氧化硅诱导的A549细胞衰老，产生SIRT3敲除和过表达细胞系。进行了各种分析，包括免疫印迹,qRT-PCR,组织学,和透射电子显微镜。使用单向ANOVA和Tukey事后检验确定统计显著性。
结果：本研究阐明了二氧化硅如何诱导ATII细胞衰老，强调mtDNA损伤。值得注意的是,和厚朴酚（HKL）作为一种有前途的抗衰老和抗纤维化剂，通过sirt3起作用。和厚朴酚有效地减弱了ATII细胞的衰老，依赖于sirt3表达，同时减轻mtDNA损伤。Sirt3，III类组蛋白脱乙酰酶，调节衰老和线粒体应激。HKL激活sirt3，保护免受肺纤维化和线粒体损伤。此外,HKL下调二氧化硅诱导的衰老ATII细胞中cGAS的表达，提示sirt3作为cGAS/STING信号通路的上游调节因子的作用。此外，和厚朴酚处理抑制NF-κB信号通路的激活,与减少氧化应激和mtDNA损伤有关。值得注意的是,HKL增强了SOD2的活性，对线粒体功能至关重要，通过sirt3介导的去乙酰化。此外,HKL促进sirt3的去乙酰化活性，进一步维护mtDNA完整性。
结论：这项研究揭示了一种天然化合物，HKL,通过激活sirt3具有显著的抗纤维化特性，揭示矽肺的发病机理和治疗途径。
