The acute-phase protein serum amyloid A1 plays a key role in inflammation induced skeletal muscle atrophy in critically ill patients.

急性时相蛋白血清淀粉样蛋白 A1 在危重患者炎症引起的骨骼肌萎缩中发挥关键作用。

• 批准号: 249567787
• 负责人: Professor Dr. Jens Fielitz
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin B
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/249567787?language=en
• 关键词: acute; phase; protein; serum; amyloid

Intensive care unit (ICU)-acquired weakness is a devastating complication during critical illness, characterized by muscle atrophy, loss of muscle mass and weakness often resulting in protracted rehabilitation and permanent disability. Inflammation and acute phase response are important contributors leading to ICU-acquired weakness. The acute phase-response protein serum amyloid A (SAA) 1 accumulates in muscle of critically ill patients and is associated with reduced muscle membrane excitability and muscle force. However, SAA1 activated signaling pathways in myocytes were unknown. We tested and confirmed the hypothesis that SAA1 plays a key role in pathogenesis of inflammatory muscle atrophy. We show that SAA1 acts direct on myocytes via activation of toll-like receptors (Tlr) 2 and 4 leading to an activation of the transcription factor NF-kB. We found that SAA1 mediates atrophy not directly but rather indirect via interleukin 1 beta. We identified Toll-like receptor 2, NF-kB and interleukin 1 beta as possible targets to treat inflammation induced atrophy. Now we want to test if inhibition of these proteins inhibits inflammatory atrophy and preserves muscle function. We also want to describe the kinetics of SAA1 synthesis, secretion and accumulation during inflammation in muscle. We aim to investigate the importance of additional muscular SAA1 receptors and downstream signalling pathways. We aim to describe the function of SAA1 in inflammation induced atrophy in further detail. We want to investigate if inhibition of the SAA1 signalling pathway is a suitable target to combat muscle failure in critically ill patients.

重症监护室（ICU）获得性虚弱是危重病期间的一种毁灭性并发症，其特征是肌肉萎缩、肌肉质量损失和虚弱，通常导致长期康复和永久残疾。炎症和急性期反应是导致ICU获得性虚弱的重要因素。急性相反应蛋白血清淀粉样蛋白A（SAA）1在危重患者的肌肉中积累，并与肌膜兴奋性和肌肉力量降低有关。然而，SAA 1在心肌细胞中激活的信号通路是未知的。我们测试并证实了SAA 1在炎性肌萎缩的发病机制中起关键作用的假设。我们表明，SAA 1直接作用于肌细胞通过激活Toll样受体（TLR）2和4，导致激活的转录因子NF-κ B。我们发现SAA 1不是直接介导萎缩，而是通过白细胞介素1 β间接介导萎缩。我们确定了Toll样受体2、NF-kB和白细胞介素1 β作为治疗炎症诱导的萎缩的可能靶点。现在我们想测试抑制这些蛋白质是否能抑制炎症性萎缩并保持肌肉功能。我们还想描述肌肉炎症过程中SAA 1合成、分泌和积累的动力学。我们的目的是调查的重要性，额外的肌肉SAA 1受体和下游信号通路。我们的目的是进一步详细描述SAA 1在炎症诱导的萎缩中的功能。我们想研究抑制SAA 1信号通路是否是治疗重症患者肌肉衰竭的合适靶点。

项目成果

Myeloid differentiation factor‐2 activates monocytes in patients with dilated cardiomyopathy

• DOI: 10.1111/imm.13490
• 发表时间: 2022-05
• 期刊: Immunology
• 影响因子: 6.4
• 作者: R. Feldtmann;Andreas Kümmel;B. Chamling;A. Strohbach;K. Lehnert;S. Gross;Lisa Loerzer;A. Riad;D. Lindner;D. Westermann;J. Fielitz;M. Dörr;S. Felix