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首页> 外文期刊>Cellular Physiology and Biochemistry >Acid sphingomyelinase deficiency attenuates bleomycin-induced lung inflammation and fibrosis in mice
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Acid sphingomyelinase deficiency attenuates bleomycin-induced lung inflammation and fibrosis in mice

机译：酸性鞘磷脂酶缺乏症可减轻博来霉素诱导的小鼠肺部炎症和纤维化

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Background/Aims: The sphingomyelin/ceramide signaling pathway is an important component of many cellular processes implicated in the pathogenesis of lung disease. Acid sphingomyelinase (ASM) is a key mediator of this pathway, but its specific role in pulmonary fibrosis has not been previously investigated. Here we used the bleomycin model of pulmonary fibrosis to investigate fibrotic responses in normal and ASM knockout (ASM~(-/-)) mice, and in NIH3T3 fibroblasts with and without ASM siRNA treatment. Methods: Mice and cells with and without ASM activity were treated with bleomycin, and the effects on lung inflammation, formation of collagen producing myofibroblasts, and apoptosis were assessed. Results: The development of bleomycin-induced inflammation and fibrosis in wildtype mice correlated with the rapid activation of ASM, and was markedly attenuated in the absence of ASM activity. Along with the elevated ASM activity, there also was an elevation of acid ceramidase (AC) activity, which was sustained for up to 14 days post-bleomycin treatment. Studies in NIH3T3 fibroblasts confirmed these findings, and revealed a direct effect of ASM/AC activation on the formation of myofibroblasts. Cell studies also showed that a downstream effect of bleomycin treatment was the production of sphingosine-1-phosphate. Conclusions: These data demonstrate that the sphingomyelin/ceramide signaling pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis, and suggest that inhibition of ASM may potentially slow the fibrotic process in the lung.
机译：背景/目的：鞘磷脂/神经酰胺信号传导途径是许多参与肺部疾病发病机理的细胞过程的重要组成部分。酸性鞘磷脂酶（ASM）是该途径的关键介体，但先前尚未研究其在肺纤维化中的特定作用。在这里，我们使用了肺纤维化的博来霉素模型来研究正常和ASM基因敲除（ASM〜（-/-））小鼠以及有或没有ASM siRNA处理的NIH3T3成纤维细胞中的纤维化反应。方法：用博来霉素处理具有ASM活性和不具有ASM活性的小鼠和细胞，评估其对肺部炎症，产生胶原的成纤维细胞的形成以及细胞凋亡的影响。结果：博来霉素诱导的野生型小鼠炎症和纤维化的发生与ASM的快速活化有关，在没有ASM活性的情况下明显减弱。随着ASM活性的提高，酸性神经酰胺酶（AC）活性也有所提高，在博来霉素治疗后这种活性可持续长达14天。 NIH3T3成纤维细胞的研究证实了这些发现，并揭示了ASM / AC激活对成肌纤维细胞形成的直接影响。细胞研究还表明，博来霉素治疗的下游作用是产生1-磷酸鞘氨醇。结论：这些数据表明鞘磷脂/神经酰胺信号通路参与博来霉素诱导的肺纤维化的发病机理，并表明抑制ASM可能会减慢肺部纤维化过程。

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