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Geranylgeranyl diphosphate synthase 1 knockout ameliorates ventilator-induced lung injury via regulation of TLR2/4-AP-1 signaling.
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2019-12-21 , DOI: 10.1016/j.freeradbiomed.2019.12.024 Bing Wan 1 , Wu-Jian Xu 2 , Mei-Zi Chen 3 , Shuang-Shuang Sun 1 , Jia-Jia Jin 1 , Yan-Ling Lv 2 , Ping Zhan 2 , Su-Hua Zhu 2 , Xiao-Xia Wang 2 , Tang-Feng Lv 2 , Yong Song 2
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2019-12-21 , DOI: 10.1016/j.freeradbiomed.2019.12.024 Bing Wan 1 , Wu-Jian Xu 2 , Mei-Zi Chen 3 , Shuang-Shuang Sun 1 , Jia-Jia Jin 1 , Yan-Ling Lv 2 , Ping Zhan 2 , Su-Hua Zhu 2 , Xiao-Xia Wang 2 , Tang-Feng Lv 2 , Yong Song 2
Affiliation
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OBJECTIVE
To investigate the role of geranylgeranyl diphosphate synthase 1 (GGPPS1) in ventilator-induced lung injury along with the underlying mechanism.
METHODS
A murine VILI model was induced by high-tidal volume ventilation in both wild-type and GGPPS1 knockout mice. GGPPS1 expression was detected in the bronchoalveolar lavage fluid (BALF) supernatants of acute respiratory distress syndrome (ARDS) patients and healthy volunteers, as well as in lung tissues and BALF supernatants of the VILI mice using enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase chain reaction (qRT-PCR), western bolt and immunohistochemical (IHC). The wet/dry ratio, total BALF proteins, and lung injury score were analyzed. The percentage of neutrophils was detected by flow cytometry and IHC. Inflammatory cytokine levels were measured by ELISA and qRT-PCR. The related expression of Toll-like receptor (TLR)2/4 and its downstream proteins was evaluated by western blot.
RESULTS
GGPPS1 in BALF supernatants was upregulated in ARDS patients and the VILI mice. Depletion of GGPPS1 significantly alleviated the severity of ventilator induced lung injury in mice. Total cell count, neutrophils and inflammatory cytokines (interleukin [IL]-6, IL-1β, IL-18 and tumor necrosis factor-α) levels in BALF were reduced after GGPPS1 depletion. Moreover, addition of exogenous GGPP in GGPPS-deficient mice significantly exacerbated the severity of ventilator induced lung injury as compared to the PBS treated controls. Mechanistically, the expression of TLR2/4, as well as downstream proteins including activator protein-1 (AP-1) was suppressed in lung tissues of GGPPS1-deficient mice.
CONCLUSION
GGPPS1 promoted the pathogenesis of VILI by modulating the TLR2/4-AP-1 signaling pathway, and GGPPS1 knockout significantly alleviated the lung injury and inflammation in the VILI mice.
中文翻译：
香叶基香叶基二磷酸合酶 1 敲除通过调节 TLR2/4-AP-1 信号传导来改善呼吸机诱导的肺损伤。
目的探讨香叶基香叶基二磷酸合酶1（GGPPS1）在呼吸机所致肺损伤中的作用及其机制。方法 在野生型和 GGPPS1 基因敲除小鼠中通过潮气量通气诱导小鼠 VILI 模型。使用酶联免疫吸附试验（ELISA），在急性呼吸窘迫综合征（ARDS）患者和健康志愿者的支气管肺泡灌洗液（BALF）上清液以及VILI小鼠的肺组织和BALF上清液中检测到GGPPS1的表达，定量逆转录聚合酶链反应 (qRT-PCR)、western bolt 和免疫组化 (IHC)。分析湿/干比、总BALF蛋白和肺损伤评分。通过流式细胞术和IHC检测中性粒细胞的百分比。通过ELISA和qRT-PCR测量炎症细胞因子水平。通过蛋白质印迹评估Toll样受体（TLR）2/4及其下游蛋白的相关表达。结果 BALF 上清液中的 GGPPS1 在 ARDS 患者和 VILI 小鼠中上调。GGPPS1的消耗显着减轻了呼吸机引起的小鼠肺损伤的严重程度。在 GGPPS1 耗竭后，BALF 中的总细胞计数、中性粒细胞和炎性细胞因子（白细胞介素 [IL]-6、IL-1β、IL-18 和肿瘤坏死因子-α）水平降低。此外，与 PBS 处理的对照相比，在 GGPPS 缺陷小鼠中添加外源 GGPP 显着加剧了呼吸机引起的肺损伤的严重程度。从机制上讲，TLR2/4 的表达，以及下游蛋白质，包括激活蛋白 1 (AP-1) 在 GGPPS1 缺陷小鼠的肺组织中被抑制。结论 GGPPS1通过调节TLR2/4-AP-1信号通路促进VILI的发病，敲除GGPPS1显着减轻VILI小鼠的肺损伤和炎症反应。
更新日期：2019-12-25
中文翻译：
香叶基香叶基二磷酸合酶 1 敲除通过调节 TLR2/4-AP-1 信号传导来改善呼吸机诱导的肺损伤。
目的探讨香叶基香叶基二磷酸合酶1（GGPPS1）在呼吸机所致肺损伤中的作用及其机制。方法 在野生型和 GGPPS1 基因敲除小鼠中通过潮气量通气诱导小鼠 VILI 模型。使用酶联免疫吸附试验（ELISA），在急性呼吸窘迫综合征（ARDS）患者和健康志愿者的支气管肺泡灌洗液（BALF）上清液以及VILI小鼠的肺组织和BALF上清液中检测到GGPPS1的表达，定量逆转录聚合酶链反应 (qRT-PCR)、western bolt 和免疫组化 (IHC)。分析湿/干比、总BALF蛋白和肺损伤评分。通过流式细胞术和IHC检测中性粒细胞的百分比。通过ELISA和qRT-PCR测量炎症细胞因子水平。通过蛋白质印迹评估Toll样受体（TLR）2/4及其下游蛋白的相关表达。结果 BALF 上清液中的 GGPPS1 在 ARDS 患者和 VILI 小鼠中上调。GGPPS1的消耗显着减轻了呼吸机引起的小鼠肺损伤的严重程度。在 GGPPS1 耗竭后，BALF 中的总细胞计数、中性粒细胞和炎性细胞因子（白细胞介素 [IL]-6、IL-1β、IL-18 和肿瘤坏死因子-α）水平降低。此外，与 PBS 处理的对照相比，在 GGPPS 缺陷小鼠中添加外源 GGPP 显着加剧了呼吸机引起的肺损伤的严重程度。从机制上讲，TLR2/4 的表达，以及下游蛋白质，包括激活蛋白 1 (AP-1) 在 GGPPS1 缺陷小鼠的肺组织中被抑制。结论 GGPPS1通过调节TLR2/4-AP-1信号通路促进VILI的发病，敲除GGPPS1显着减轻VILI小鼠的肺损伤和炎症反应。
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