Division of Chest Medicine, Department of Internal Medicine, Chi Mei Medical Center, Yongkang, Tainan, Taiwan.
Department of Respiratory Therapy, Fu Jen Catholic University, New Taipei City, Taiwan.
Mediators Inflamm. 2019 Mar 27;2019:7947596. doi: 10.1155/2019/7947596. eCollection 2019.
Weight loss due to skeletal muscle atrophy in patients with chronic pulmonary disease is negatively correlated with clinical outcome. Pulmonary fibrosis is a chronic and progressive interstitial lung disease characterized by the dysregulated deposition of the extracellular matrix (ECM) with the destruction of normal tissue, resulting in end-stage organ failure. BLM-induced fibrosis is one of several different experimental models of pulmonary fibrosis, characterized by inflammation and excessive ECM deposition. We directly induced mouse lung injury by the intratracheal administration of bleomycin and monitored the physiological and biochemical changes in lung and skeletal muscle tissues by using lung function testing, ELISA, Western blotting, and immunohistochemistry. Here, we found that BLM-induced lung fibrosis with thickened interstitial lung tissue, including fibronectin and collagen, was correlated with the increased serum concentrations of IL-6 and IL-33 and accompanied by reduced lung function, including FRC (functional residual capacity), C chord (lung compliance), IC (inspiratory capacity), VC (vital capacity), TLC (total lung capacity), and FVC (forced vital capacity) ( < 0.05). The activity of AKT in lung tissue was suppressed, but conversely, the activity of STAT3 was enhanced during lung fibrosis in mice. In addition, we found that the amount of sST2, the soluble form of the IL-33 receptor, was dramatically decreased in lung fibrosis tissues. The skeletal muscle tissue isolated from lung injury mice increased the activation of STAT3 and AMPK, accompanied by an increased amount of Atrogin-1 protein in BLM-induced lung fibrosis mice. The mouse myoblast cell-based model showed that IL-6 and IL-33 specifically activated STAT3 and AMPK signaling, respectively, to induce the expression of the muscle-specific proteolysis markers MuRF1 and Atrogin-1. These data suggested that increased levels of IL-6 and IL-33 in the serum of mice with BLM-induced lung injury may cause lung fibrosis with thickened interstitial lung tissue accompanied by reduced lung function and muscle mass through the activation of STAT3 and AMPK signals.
慢性肺部疾病患者因骨骼肌萎缩导致的体重减轻与临床结局呈负相关。肺纤维化是一种慢性进行性间质性肺疾病，其特征是细胞外基质（ECM）的失调沉积以及正常组织的破坏，导致终末期器官衰竭。博来霉素（BLM）诱导的纤维化是几种不同的肺纤维化实验模型之一，其特征是炎症和 ECM 的过度沉积。我们通过气管内给予博来霉素直接诱导小鼠肺损伤，并通过肺功能测试、ELISA、Western blot 和免疫组织化学监测肺和骨骼肌组织中的生理和生化变化。在这里，我们发现 BLM 诱导的肺纤维化伴有增厚的间质肺组织，包括纤维连接蛋白和胶原蛋白，与血清中白细胞介素-6（IL-6）和白细胞介素-33（IL-33）浓度的增加相关，并伴有肺功能下降，包括功能残气量（FRC）、肺顺应性（C 和弦）、吸气量（IC）、肺活量（VC）、总肺容量（TLC）和用力肺活量（FVC）（<0.05）。在小鼠肺纤维化过程中，肺组织中 AKT 的活性受到抑制，但相反，STAT3 的活性增强。此外，我们发现肺纤维化组织中 IL-33 受体的可溶性形式 sST2 的含量显著降低。从肺损伤小鼠分离的骨骼肌组织增加了 STAT3 和 AMPK 的激活，同时在 BLM 诱导的肺纤维化小鼠中增加了 Atrogin-1 蛋白的含量。基于小鼠成肌细胞的模型表明，IL-6 和 IL-33 分别特异性激活 STAT3 和 AMPK 信号通路，诱导肌肉特异性蛋白水解标志物 MuRF1 和 Atrogin-1 的表达。这些数据表明，BLM 诱导的肺损伤小鼠血清中 IL-6 和 IL-33 水平的升高可能通过激活 STAT3 和 AMPK 信号通路导致肺纤维化伴有增厚的间质肺组织，同时伴有肺功能和肌肉质量下降。
