Osa Sumika, Enoki Yuki, Miyajima Taichi, Akiyama Masahiro, Fujiwara Yukio, Taguchi Kazuaki, Kim Yun-Gi, Matsumoto Kazuaki
Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Shibakoen, Minato-ku, Tokyo, Japan.
Research Center for Drug Discovery, Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
Shock. 2023 Mar 1;59(3):417-425. doi: 10.1097/SHK.0000000000002053. Epub 2022 Nov 26.
Background: Patients with underlying skeletal muscle atrophy are likely to develop aggravated sepsis. However, no study has experimentally verified the association between the prognosis of sepsis and muscle atrophy, and the mechanism of aggravation of sepsis under muscle atrophy remains unclear. In this study, we investigated the effect of skeletal muscle atrophy induced by sciatic denervation (DN), an experimental muscle atrophy model, on sepsis prognosis. Methods: Skeletal muscle atrophy was induced by DN of the sciatic nerve in C57BL/6J male mice. Cecal ligation and puncture (CLP) was performed to induce sepsis. Results: The survival rates of the sham and DN groups 7 days after CLP were 63% and 35%, respectively, wherein an approximately 30% reduction was observed in the DN group ( P < 0.05, vs. sham-CLP). The DN group had a higher bacterial count in the blood 48 h after CLP ( P < 0.05, vs. sham-CLP). Notably, NOx (a metabolite of nitric oxide) concentrations in DN mice were higher than those in sham mice after CLP ( P < 0.05, vs. sham-CLP), whereas serum platelet levels were lower 48 h after CLP ( P < 0.05, vs. sham-CLP). In organ damage analysis, DN mice presented increased protein expression of the kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), a kidney injury marker, after CLP (NGAL 48 h after CLP, P < 0.05, vs. sham-CLP; KIM-1 24 h after CLP, P < 0.01, vs. sham-CLP). Furthermore, nitro tyrosine levels in the kidneys of DN mice were higher 48 h after CLP compared with those in sham-CLP mice, indicating the accumulation of nitrative stress ( P < 0.05, vs. sham-CLP). Serum cytokine levels were increased in both groups after CLP, but decreased in the sham group 48 h after CLP and remained consistently higher in the DN group (tumor necrosis factor [TNF]-α: P < 0.05, sham-CLP vs. DN-CLP; interleukin (IL)-1β: P < 0.01, sham-CLP vs. DN-CLP; IL-6: P < 0.05, DN vs. DN-CLP; IL-10: P < 0.05, sham-CLP vs. DN-CLP). Conclusions: We verified that skeletal muscle atrophy induced by DN is associated with poor prognosis after CLP-induced sepsis. Importantly, mice with skeletal muscle atrophy presented worsening sepsis prognosis at late onset, including prolonged infection, persistent inflammation, and kidney damage accumulation, resulting in delayed recovery.
患有潜在骨骼肌萎缩的患者可能会发生更严重的脓毒症。然而，尚无研究通过实验证实脓毒症预后与肌肉萎缩之间的关联，并且肌肉萎缩情况下脓毒症加重的机制仍不清楚。在本研究中，我们调查了坐骨神经去神经支配（DN）诱导的骨骼肌萎缩（一种实验性肌肉萎缩模型）对脓毒症预后的影响。方法：通过对C57BL/6J雄性小鼠坐骨神经进行去神经支配诱导骨骼肌萎缩。进行盲肠结扎和穿刺（CLP）以诱导脓毒症。结果：CLP术后7天，假手术组和DN组的生存率分别为63%和35%，其中DN组观察到约30%的降低（P<0.05，与假手术-CLP组相比）。CLP术后48小时，DN组血液中的细菌计数更高（P<0.05，与假手术-CLP组相比）。值得注意的是，CLP后DN小鼠中的NOx（一氧化氮的代谢产物）浓度高于假手术小鼠（P<0.05，与假手术-CLP组相比），而CLP术后48小时血清血小板水平较低（P<0.05，与假手术-CLP组相比）。在器官损伤分析中，CLP后DN小鼠的肾损伤分子（KIM-1）和肾损伤标志物中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的蛋白表达增加（CLP后48小时的NGAL，P<0.05，与假手术-CLP组相比；CLP后24小时的KIM-1，P<0.01，与假手术-CLP组相比）。此外，与假手术-CLP小鼠相比，CLP后48小时DN小鼠肾脏中的硝基酪氨酸水平更高，表明硝化应激积累（P<0.05，与假手术-CLP组相比）。CLP后两组血清细胞因子水平均升高，但假手术组在CLP后48小时降低，而DN组持续更高（肿瘤坏死因子[TNF]-α：P<0.05，假手术-CLP组与DN-CLP组相比；白细胞介素（IL）-1β：P<0.01，假手术-CLP组与DN-CLP组相比；IL-6：P<0.05，DN组与DN-CLP组相比；IL-10：P<0.05，假手术-CLP组与DN-CLP组相比）。结论：我们证实，DN诱导的骨骼肌萎缩与CLP诱导的脓毒症预后不良相关。重要的是，患有骨骼肌萎缩的小鼠在后期脓毒症预后恶化，包括感染延长、炎症持续和肾损伤积累，导致恢复延迟。
