Protective effect of ebselen on bleomycin-induced lung fibrosis: analysis of the molecular mechanism of lung fibrosis mediated by oxidized diacylglycerol
Protective effect of ebselen on bleomycin-induced lung fibrosis: analysis of the molecular mechanism of lung fibrosis mediated by oxidized diacylglycerol
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DOI：
10.1080/10715762.2022.2092477
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发表时间：
2022-12-22
影响因子：
3.3
通讯作者：
Iwazaki，Masayuki
中科院分区：
文献类型：
--
作者：
Yagasaki，Hidehiko;Takekoshi，Susumu;Iwazaki，Masayuki
肺纤维化发生的分子机制尚不清楚，有效的治疗方法尚未开发出来。已有研究表明，氧化应激参与了肺纤维化。氧化应激产生的氧化二甘油(DAG)被认为在肺纤维化中起重要作用。本研究评价了氧化DAG在博莱霉素(BLM)肺吸入致肺纤维化动物模型中的作用。并观察依布硒对肺纤维化的抑制作用。在博莱曼诱导的肺纤维化组织中，脂质过氧化产物增多，胶原堆积。此外，在给予博莱姆后，具有较强蛋白激酶C(PKC)活性的氧化DAG的水平随着时间的推移而显著增加。Western blotting结果显示，博莱霉素可促进PKCα和δ亚型的磷酸化。口服依布硒可明显抑制博莱霉素所致的氧化DAG升高，改善肺纤维化。蛋白激酶Cα和δ的磷酸化也受到明显抑制。博莱曼可促进α-平滑肌肌动蛋白和I型胶原的表达，增加转化生长因子-β和肿瘤坏死因子-α的产生(这可能是纤维化过程中的一个重要因素)，而依布硒则显著降低其表达。博莱曼可诱导肺组织脂质过氧化，其产生的氧化DAG可诱导PKCα和δ的过度激活，从而导致肺纤维化的发生。
The molecular mechanisms underlying the development of pulmonary fibrosis remain unknown, and effective treatments have not yet been developed. It has been shown that oxidative stress is involved in lung fibrosis. Oxidized diacylglycerol (DAG) produced by oxidative stress is thought to play an important role in lung fibrosis. This study assessed the effect of oxidized DAG in an animal model of pulmonary fibrosis induced by aspiration of bleomycin (BLM) into the lungs. The inhibitory effect of ebselen on pulmonary fibrosis was also investigated. In lung fibrotic tissue induced by BLM, an increase in lipid peroxides and collagen accumulation was observed. Moreover, the levels of oxidized DAG, which has strong protein kinase C (PKC) activation activity, were significantly increased over time following the administration of BLM. Western blotting showed that phosphorylation of PKCα and δ isoforms was increased by BLM. Oral administration of ebselen significantly suppressed the increase in oxidized DAG induced by BLM and improved lung fibrosis. PKCα and δ phosphorylation were also significantly inhibited. The mRNA expression of α-smooth muscle actin and collagen I (marker molecules for fibrosis), as well as the production of transforming growth factor-β and tumor necrosis factor-α(a potentially important factor in the fibrotic process), were increased by BLM and significantly decreased by ebselen. The administration of BLM may induce lipid peroxidation in lung tissue, while the oxidized DAG produced by BLM may induce overactivation of PKCα and δ, resulting in the induction of lung fibrosis.