Department of Emergency, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, 200438, China.
Department of Emergency, Shidong Hospital, Yangpu District, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, 200438, China.
Pulm Pharmacol Ther. 2023 Oct;82:102244. doi: 10.1016/j.pupt.2023.102244. Epub 2023 Jul 25.
This study mainly analyzes the mechanism of SIRT3 alleviating sepsis-induced acute lung injury (ALI) by regulating the deacetylation of FoxO3a and inhibiting pyroptosis.
SIRT3-overexpressing and silenced BEAS-2B cells were used to evaluate the effect of SIRT3 on apoptosis in LPS-treated lung epithelial cells. FoxO3a-silenced BEAS-2B cells were also used to verify the mechanism by which SIRT3 inhibited oxidative stress and pyroptosis in vitro in ALI. 3-TYP was used to inhibit the deacetylation function of SIRT3 in vivo. Pyroptosis was assessed by detecting GSDMD-N and LDH efflux.
In CLP-induced ALI mice, GSDMD-N and LDH levels were elevated, pyroptosis was induced. Silencing of SIRT3 exacerbated oxidative stress, NLRP3 activation and pyroptosis, and inhibited the deacetylation of FoxO3a. Overexpression of SIRT3 attenuated pyroptosis, induced deacetylation and restored the expression of FoxO3a and MnSOD. Silencing FoxO3a aggravated pyroptosis. Overexpression of SIRT3 restored the reduced FoxO3a expression and suppressed pyroptosis. 3-TYP blocked the promotion of FoxO3a by SIRT3 and the inhibitory effect of SIRT3 on pyroptosis.
The reduction of SIRT3 in sepsis caused hyperacetylation of FoxO3a, which in turn exacerbates oxidative stress and induces pyroptosis of ALI. Increasing the level of SIRT3 promotes FoxO3a through deacetylation, thereby inhibiting pyroptosis and relieving ALI.
本研究主要分析 SIRT3 通过调节 FoxO3a 的去乙酰化作用和抑制细胞焦亡来缓解脓毒症引起的急性肺损伤（ALI）的机制。
使用 SIRT3 过表达和沉默 BEAS-2B 细胞来评估 SIRT3 对 LPS 处理的肺上皮细胞凋亡的影响。还使用 FoxO3a 沉默的 BEAS-2B 细胞来验证 SIRT3 体外抑制 ALI 中氧化应激和细胞焦亡的机制。3-TYP 用于抑制体内 SIRT3 的去乙酰化功能。通过检测 GSDMD-N 和 LDH 外溢来评估细胞焦亡。
在 CLP 诱导的 ALI 小鼠中，GSDMD-N 和 LDH 水平升高，诱导细胞焦亡。沉默 SIRT3 加剧了氧化应激、NLRP3 激活和细胞焦亡，并抑制了 FoxO3a 的去乙酰化。SIRT3 的过表达减弱了细胞焦亡，诱导了去乙酰化，并恢复了 FoxO3a 和 MnSOD 的表达。沉默 FoxO3a 加重了细胞焦亡。SIRT3 的过表达恢复了减少的 FoxO3a 表达并抑制了细胞焦亡。3-TYP 阻断了 SIRT3 对 FoxO3a 的促进作用和 SIRT3 对细胞焦亡的抑制作用。
脓毒症中 SIRT3 的减少导致 FoxO3a 的过度乙酰化，进而加剧氧化应激并诱导 ALI 的细胞焦亡。增加 SIRT3 的水平通过去乙酰化促进 FoxO3a，从而抑制细胞焦亡并缓解 ALI。
