Inositol possesses antifibrotic activity and mitigates pulmonary fibrosis.
Inositol possesses antifibrotic activity and mitigates pulmonary fibrosis.
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肌醇具有抗纤维化活性并减轻肺纤维化。
DOI：
10.1186/s12931-023-02421-6
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发表时间：
2023-05-16
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
--
作者：
肌醇（或肌醇）及其衍生物不仅是多种细胞过程的重要代谢物，而且在信号通路中作为辅助因子和第二信使。尽管补充肌醇已在各种临床试验中得到广泛研究，但对其对特发性肺纤维化（IPF）的影响知之甚少。最近的研究表明，IPF肺成纤维细胞由于精氨酸琥珀酸合成酶1 （ASS1）的缺失而表现出精氨酸依赖。然而，ASS1缺乏的代谢机制及其在纤维形成过程中的功能后果尚未阐明。从不同ASS1状态的原代肺成纤维细胞中提取的代谢物进行非靶向代谢组学分析。利用分子生物学方法评估了肺成纤维细胞中ASS1缺乏与肌醇及其信号传导的关系。补充肌醇对成纤维细胞表型和肺纤维化的治疗潜力分别在基于细胞的研究和博来霉素动物模型中进行了评估。我们的代谢组学研究表明，来自IPF患者的ass1缺陷肺成纤维细胞显著改变了肌醇磷酸代谢。我们观察到肌醇-4-单磷酸丰度的降低和肌醇丰度的增加与成纤维细胞中ASS1的表达有关。此外，在原代正常肺成纤维细胞中基因敲低ASS1表达导致肌醇介导的信号体激活，包括EGFR和PKC信号。肌醇治疗显著下调ASS1缺陷介导的信号通路，降低IPF肺成纤维细胞的细胞侵袭性。值得注意的是，补充肌醇还可以减轻博莱霉素引起的小鼠纤维化病变和胶原沉积。这些发现共同证明了肌醇在纤维代谢和肺纤维化中的新功能。我们的研究为这种代谢物的抗纤维化活性提供了新的证据，并表明补充肌醇可能是一种有希望的治疗IPF的策略。在线版本包含补充材料，可在10.1186/s12931-023-02421-6获得。
Myo-inositol (or inositol) and its derivatives not only function as important metabolites for multiple cellular processes but also act as co-factors and second messengers in signaling pathways. Although inositol supplementation has been widely studied in various clinical trials, little is known about its effect on idiopathic pulmonary fibrosis (IPF). Recent studies have demonstrated that IPF lung fibroblasts display arginine dependency due to loss of argininosuccinate synthase 1 (ASS1). However, the metabolic mechanisms underlying ASS1 deficiency and its functional consequence in fibrogenic processes are yet to be elucidated. Metabolites extracted from primary lung fibroblasts with different ASS1 status were subjected to untargeted metabolomics analysis. An association of ASS1 deficiency with inositol and its signaling in lung fibroblasts was assessed using molecular biology assays. The therapeutic potential of inositol supplementation in fibroblast phenotypes and lung fibrosis was evaluated in cell-based studies and a bleomycin animal model, respectively. Our metabolomics studies showed that ASS1-deficient lung fibroblasts derived from IPF patients had significantly altered inositol phosphate metabolism. We observed that decreased inositol-4-monophosphate abundance and increased inositol abundance were associated with ASS1 expression in fibroblasts. Furthermore, genetic knockdown of ASS1 expression in primary normal lung fibroblasts led to the activation of inositol-mediated signalosomes, including EGFR and PKC signaling. Treatment with inositol significantly downregulated ASS1 deficiency-mediated signaling pathways and reduced cell invasiveness in IPF lung fibroblasts. Notably, inositol supplementation also mitigated bleomycin-induced fibrotic lesions and collagen deposition in mice. These findings taken together demonstrate a novel function of inositol in fibrometabolism and pulmonary fibrosis. Our study provides new evidence for the antifibrotic activity of this metabolite and suggests that inositol supplementation may be a promising therapeutic strategy for IPF. The online version contains supplementary material available at 10.1186/s12931-023-02421-6.
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影响因子：
5.8
作者：
Fukushima S;Nishi H;Kumano M;Yamanaka D;Kataoka N;Hakuno F;Takahashi SI
通讯作者：
Takahashi SI
DOI：
10.1165/rcmb.2019-0051oc
发表时间：
2019-10-01
影响因子：
6.4
作者：
Cui, Huachun;Xie, Na;Liu, Gang
通讯作者：
Liu, Gang
影响因子：
3.3
作者：
Han, Wei;Gills, Joell J.;Dennis, Phillip A.
通讯作者：
Dennis, Phillip A.
影响因子：
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作者：
Kreuter M;Bonella F;Wijsenbeek M;Maher TM;Spagnolo P
通讯作者：
Spagnolo P
影响因子：
16.6
作者：
Chakraborty D;Šumová B;Mallano T;Chen CW;Distler A;Bergmann C;Ludolph I;Horch RE;Gelse K;Ramming A;Distler O;Schett G;Šenolt L;Distler JHW
通讯作者：
Distler JHW