脂肪酸氧化在哮喘支气管平滑肌重构中的重要作用
2021/04/23
摘要
背景：哮喘患者支气管平滑肌（BSM）重构与哮喘患者线粒体生物合成增加和BSM细胞增殖增强有关。由于（i）线粒体产生最高水平的细胞能量和（ii）脂肪酸β氧化是产生ATP的最有效途径，我们假设在哮喘BSM细胞中，能量代谢向脂肪酸β氧化转移。
目的：研究哮喘患者体内外BSM细胞代谢特征，寻找一种新的抑制BSM细胞增殖的靶点。
方法：选择哮喘患者21例，非哮喘患者31例。我们使用代谢组学和蛋白质组学的方法来研究BSM细胞。在BSM细胞上评估氧化应激、ATP合成、脂肪酸内吞、代谢物产生、代谢能力、线粒体网络、细胞增殖和凋亡。用MALDI光谱成像法在体内测定脂肪酸含量。
结果：哮喘BSM细胞线粒体呼吸速率增加，ATP生成增加，线粒体β-氧化增加。在离体和体外，哮喘BSM的脂肪酸消耗均增加。哮喘BSM的蛋白质组重构是通过2条典型的线粒体途径实现的。在哮喘的BSM细胞中，分别通过线粒体和细胞膜吸收脂肪酸的CPT2和LDL受体水平均升高。阻断CPT2或LDL受体可显著降低哮喘BSM细胞增殖。
结论：本研究证实了哮喘BSM向线粒体β-氧化的代谢转换，并确定脂肪酸代谢是减少哮喘BSM重塑的一个新的关键靶点。
Crucial role of fatty acid oxidation in asthmatic bronchial smooth muscle remodelling
Pauline Esteves, Landry Blanc, Alexis Celle, Isabelle Dupin, Elise Maurat, Nivea Amoedo, Guillaume Cardouat, Olga Ousova, Lara Gales, Florian Bellvert, Hugues Begueret, Matthieu Thumerel, Jean-William Dupuy, Nicolas Desbenoit, Roger Marthan, Pierre-Olivier Girodet, Rodrigue Rossignol, Patrick Berger, Thomas Trian
Abstract
Background: Bronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since (i) mitochondria produce the highest levels of cellular energy and (ii) fatty acid beta-oxidation is the most powerful way to produce ATP, we hypothesized that, in asthmatic BSM cells, energetic metabolism is shifted towards the beta-oxidation of fatty acids.
Objectives: We aimed to characterize BSM cell metabolism in asthma both in vitro and ex vivo to identify a novel target for reducing BSM cell proliferation.
Methods: Twenty-one asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed in vivo using MALDI-spectrometry imaging.
Results: Asthmatic BSM cells were characterized by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both in vitro and ex vivo. Proteome remodelling of asthmatic BSM occurred via 2 canonical mitochondrial pathways. The levels of CPT2 and LDL-receptor, which internalize fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL-receptor drastically and specifically reduced asthmatic BSM cell proliferation.
Conclusion: This study demonstrates a metabolic switch towards mitochondrial beta-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma.
背景：哮喘患者支气管平滑肌（BSM）重构与哮喘患者线粒体生物合成增加和BSM细胞增殖增强有关。由于（i）线粒体产生最高水平的细胞能量和（ii）脂肪酸β氧化是产生ATP的最有效途径，我们假设在哮喘BSM细胞中，能量代谢向脂肪酸β氧化转移。
目的：研究哮喘患者体内外BSM细胞代谢特征，寻找一种新的抑制BSM细胞增殖的靶点。
方法：选择哮喘患者21例，非哮喘患者31例。我们使用代谢组学和蛋白质组学的方法来研究BSM细胞。在BSM细胞上评估氧化应激、ATP合成、脂肪酸内吞、代谢物产生、代谢能力、线粒体网络、细胞增殖和凋亡。用MALDI光谱成像法在体内测定脂肪酸含量。
结果：哮喘BSM细胞线粒体呼吸速率增加，ATP生成增加，线粒体β-氧化增加。在离体和体外，哮喘BSM的脂肪酸消耗均增加。哮喘BSM的蛋白质组重构是通过2条典型的线粒体途径实现的。在哮喘的BSM细胞中，分别通过线粒体和细胞膜吸收脂肪酸的CPT2和LDL受体水平均升高。阻断CPT2或LDL受体可显著降低哮喘BSM细胞增殖。
结论：本研究证实了哮喘BSM向线粒体β-氧化的代谢转换，并确定脂肪酸代谢是减少哮喘BSM重塑的一个新的关键靶点。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Eur Respir J. 2021 Apr 8;2004252. doi: 10.1183/13993003.04252-2020.)
(Eur Respir J. 2021 Apr 8;2004252. doi: 10.1183/13993003.04252-2020.)
Crucial role of fatty acid oxidation in asthmatic bronchial smooth muscle remodelling
Pauline Esteves, Landry Blanc, Alexis Celle, Isabelle Dupin, Elise Maurat, Nivea Amoedo, Guillaume Cardouat, Olga Ousova, Lara Gales, Florian Bellvert, Hugues Begueret, Matthieu Thumerel, Jean-William Dupuy, Nicolas Desbenoit, Roger Marthan, Pierre-Olivier Girodet, Rodrigue Rossignol, Patrick Berger, Thomas Trian
Abstract
Background: Bronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since (i) mitochondria produce the highest levels of cellular energy and (ii) fatty acid beta-oxidation is the most powerful way to produce ATP, we hypothesized that, in asthmatic BSM cells, energetic metabolism is shifted towards the beta-oxidation of fatty acids.
Objectives: We aimed to characterize BSM cell metabolism in asthma both in vitro and ex vivo to identify a novel target for reducing BSM cell proliferation.
Methods: Twenty-one asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed in vivo using MALDI-spectrometry imaging.
Results: Asthmatic BSM cells were characterized by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both in vitro and ex vivo. Proteome remodelling of asthmatic BSM occurred via 2 canonical mitochondrial pathways. The levels of CPT2 and LDL-receptor, which internalize fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL-receptor drastically and specifically reduced asthmatic BSM cell proliferation.
Conclusion: This study demonstrates a metabolic switch towards mitochondrial beta-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma.
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线粒体参与学龄前重度喘息者支气管平滑肌重构
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重症哮喘的免疫反应与急性发作
