肩袖修复术后继发性冻结肩患者的血清可诱导关节囊纤维化并促进巨噬细胞极化和成纤维细胞活化。
The Serum from Patients with Secondary Frozen Shoulder Following Rotator Cuff Repair Induces Shoulder Capsule Fibrosis and Promotes Macrophage Polarization and Fibroblast Activation.
作者信息
Sun Yaying, Lin Jinrong, Luo Zhiwen, Zhang Yuhan, Chen Jiwu
机构信息
Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
出版信息
J Inflamm Res. 2021 Mar 23;14:1055-1068. doi: 10.2147/JIR.S304555. eCollection 2021.
PURPOSE
Disorders with systematic inflammation were prognostic for secondary frozen shoulder (sFS) following rotator cuff repair (RCR); however, how systematic inflammation affects sFS remains unclear. The aim of this study was to observe the effect of pre-operative serum from patients with sFS and the serum from those without on shoulder capsule in mice, and on macrophages and fibroblasts in vitro.
METHODS
Serum samples of a consecutive cohort of patients for RCR were collected pre-operatively. Three months after RCR, patients who developed sFS (Group S) were identified. Serum samples from gender- and age-matched controls without sFS (group NS) were also picked out. Firstly, the effect of serum on shoulder capsule fibrosis was observed histologically and biomechanically in a mouse model of RCR. Secondly, the roles of the serum on macrophage polarization and fibroblast activation were investigated, and the potentially involved signaling pathways were identified. Finally, inflammation and fibrosis-related cytokines in serum were quantified.
RESULTS
In our cohort, all patients had free pre-operative shoulder range of motion. Seven patients developed sFS at 3 months after surgery. Seven matched patients without sFS were selected as control. The inter-group difference of basic characteristics was not significant. Compared to the serum of group NS, the serum of group S significantly induced hypercellularity, capsular thickening, and range of motion deficiency in mice shoulders after RCR. Compared to the serum of group NS, samples of group S significantly promoted M2 polarization of THP-1 human macrophages and the activation of human capsule-derived fibroblasts. Meanwhile, Smad3 and p-Smad3 in macrophages and fibroblasts were significantly up-regulated. On the other hand, levels of inflammation and fibrosis-related cytokines were not significantly different between serum in group S and group NS.
CONCLUSION
Although all patients in this cohort had free range of motion pre-operatively, the pre-operative serum from patients with sFS at 3 months after RCR could act as a trigger of shoulder capsule fibrosis post-operatively. This effect may be related to its promotion on macrophage polarization to M2 phenotype and fibroblast activation.
目的
系统性炎症性疾病对肩袖修复术后继发性冻结肩（sFS）具有预后意义；然而，系统性炎症如何影响sFS仍不清楚。本研究的目的是观察sFS患者术前血清和非sFS患者血清对小鼠肩袖的影响，以及对体外巨噬细胞和成纤维细胞的影响。
方法
术前收集连续队列中接受肩袖修复术患者的血清样本。肩袖修复术后3个月，确定发生sFS的患者（S组）。还挑选了年龄和性别匹配的无sFS对照患者的血清样本（非S组）。首先，在肩袖修复术的小鼠模型中，通过组织学和生物力学方法观察血清对肩袖纤维化的影响。其次，研究血清对巨噬细胞极化和成纤维细胞活化的作用，并确定潜在的相关信号通路。最后，对血清中炎症和纤维化相关细胞因子进行定量分析。
结果
在我们的队列中，所有患者术前肩部活动范围均正常。7例患者在术后3个月发生sFS。选择7例匹配的无sFS患者作为对照。两组基本特征的组间差异无统计学意义。与非S组血清相比，S组血清在肩袖修复术后显著诱导小鼠肩部细胞增多、关节囊增厚和活动范围受限。与非S组血清相比，S组样本显著促进THP-1人巨噬细胞向M2极化以及人关节囊来源成纤维细胞的活化。同时，巨噬细胞和成纤维细胞中的Smad3和p-Smad3显著上调。另一方面，S组和非S组血清中炎症和纤维化相关细胞因子水平无显著差异。
结论
尽管该队列中的所有患者术前活动范围均正常，但肩袖修复术后3个月发生sFS的患者术前血清可作为术后肩袖纤维化的触发因素。这种作用可能与其促进巨噬细胞向M2表型极化和成纤维细胞活化有关。
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