程序性死亡-1和肌肉先天性淋巴细胞衍生白细胞介素13在败血症诱发的重症监护室获得性虚弱中的作用。

IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY
Yuichi Akama, Eun Jeong Park, Naoko Satoh-Takayama, Atsushi Ito, Eiji Kawamoto, Arong Gaowa, Eri Matsuo, Satoshi Oikawa, Masafumi Saito, Shigeaki Inoue, Takayuki Akimoto, Kei Suzuki, Motomu Shimaoka
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Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15–17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). 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引用次数: 0

摘要

背景:重症监护室获得性肌无力(ICU-AW)是一种综合征,其特点是脓毒症存活患者在慢性期经常出现长期肌无力。虽然 ICU-AW 与死亡率的增加有独立关联,但有效的治疗方法尚未确立。程序性死亡-1(PD-1)抑制剂作为逆转脓毒症免疫衰竭的潜在治疗方法引起了人们的关注;然而,它对 ICU-AW 的影响仍有待阐明。在此,我们研究了在临床前脓毒症模型中,PD-1缺陷如何影响脓毒症诱发的骨骼肌功能障碍:方法:用粪便处理野生型(WT)和 PD-1 基因敲除(KO)小鼠,然后用抗生素和生理盐水复苏,建立慢性败血症模型。小鼠在第15-17天安乐死。测量体重、肌肉重量和四肢肌肉力量。通过流式细胞术检测白细胞介素 13 (IL-13) 和 PD-1 的表达。通过逆转录和定量聚合酶链反应(RT-qPCR)测定了慢肌的信使 RNA(mRNA)表达。在体外研究中,用脂多糖(LPS)和重组 IL-13 处理 C2C12 肌管,然后测量基因表达:结果:WT 败血症小鼠的肌肉重量减轻(股四头肌、PPD-1 KO 小鼠在实验性 ICU-AW 中的长期肌无力症状得到了改善。PD-1 KO 小鼠骨骼肌中 ILC2 衍生的 IL-13 生成增加,从而表明 IL-13 可缓解败血症期间的肌肉无力。这项研究证明了 PD-1 阻断可通过增加 ILC2 衍生的 IL-13 来保护脓毒症期间的肌肉力量,这可能是脓毒症引起的 ICU-AW 的一个有吸引力的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Roles of programmed death-1 and muscle innate lymphoid cell-derived interleukin 13 in sepsis-induced intensive care unit-acquired weakness

Roles of programmed death-1 and muscle innate lymphoid cell-derived interleukin 13 in sepsis-induced intensive care unit-acquired weakness

Background

Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model.

Methods

Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15–17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements.

Results

WT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long-term muscle weakness (P < 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2-derived IL-13 was increased by PD-1 KO septic mice and thought to protect the muscles from experimental ICU-AW.

Conclusions

Long-term muscle weakness in experimental ICU-AW was ameliorated in PD-1 KO mice. ILC2-derived IL-13 production in skeletal muscles was increased in PD-1 KO mice, thereby suggesting that IL-13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD-1 blockade in preserving muscle strength during sepsis through an increase in ILC2-derived IL-13 and may be an attractive therapeutic target for sepsis-induced ICU-AW.

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来源期刊
Journal of Cachexia Sarcopenia and Muscle
Journal of Cachexia Sarcopenia and Muscle MEDICINE, GENERAL & INTERNAL-
CiteScore
13.30
自引率
12.40%
发文量
234
审稿时长
16 weeks
期刊介绍: The Journal of Cachexia, Sarcopenia and Muscle is a peer-reviewed international journal dedicated to publishing materials related to cachexia and sarcopenia, as well as body composition and its physiological and pathophysiological changes across the lifespan and in response to various illnesses from all fields of life sciences. The journal aims to provide a reliable resource for professionals interested in related research or involved in the clinical care of affected patients, such as those suffering from AIDS, cancer, chronic heart failure, chronic lung disease, liver cirrhosis, chronic kidney failure, rheumatoid arthritis, or sepsis.
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