Wuxi Laboratory of Organ Transplantation, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 QingYang Road, Wuxi, 214023, Jiangsu, People's Republic of China.
Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 QingYang Road, Wuxi, 214023, Jiangsu, People's Republic of China.
Lung. 2023 Apr;201(2):235-242. doi: 10.1007/s00408-023-00608-8. Epub 2023 Feb 24.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by excessive extracellular matrix deposition. No effective treatments are currently available for IPF. High-temperature requirement A3 (HtrA3) suppresses tumor development by antagonizing transforming growth factor β (TGF-β) signaling; however, little is known about the role of HtrA3 in IPF. This study investigated the role of HtrA3 in IPF and underlying mechanisms.
Lung tissues were collected from patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis, and HtrA3 expression was measured in tissue samples. Then, HtrA3 gene knockout mice were treated with BLM to induce pulmonary fibrosis and explore the effects and underlying mechanism of HtrA3 on pulmonary fibrosis.
HtrA3 was up-regulated in the lung tissues of patients with IPF and the pulmonary fibrotic mouse model compared to corresponding control groups. HtrA3 knockout decreased pulmonary fibrosis-related protein expression, alleviated the symptoms of pulmonary fibrosis, and inhibited epithelial-mesenchymal transition (EMT) in BLM-induced lung tissue compared with BLM-induced wild-type mice. The TGF-β1/Smad signaling pathway was activated in fibrotic lung tissue, whereas HtrA3 knockout inhibited this pathway.
The expression level of HtrA3 is increased in fibrotic lungs. HtrA3 knockout alleviates the symptoms of pulmonary fibrosis probably via the TGF-β1/Smad signaling pathway. Therefore, HtrA3 inhibition is a potential therapeutic target for pulmonary fibrosis.
特发性肺纤维化（IPF）是一种慢性进行性间质性肺疾病，其特征是细胞外基质过度沉积。目前尚无有效的 IPF 治疗方法。高温需求 A3（HtrA3）通过拮抗转化生长因子β（TGF-β）信号抑制肿瘤发展；然而，关于 HtrA3 在 IPF 中的作用知之甚少。本研究探讨了 HtrA3 在 IPF 中的作用及其潜在机制。
收集特发性肺纤维化患者和博莱霉素（BLM）诱导的肺纤维化小鼠的肺组织，测量组织样本中的 HtrA3 表达。然后，用 BLM 处理 HtrA3 基因敲除小鼠以诱导肺纤维化，并探讨 HtrA3 对肺纤维化的影响及其潜在机制。
与相应的对照组相比，HtrA3 在特发性肺纤维化患者的肺组织和肺纤维化小鼠模型中上调。与 BLM 诱导的野生型小鼠相比，HtrA3 敲除减少了与肺纤维化相关的蛋白表达，减轻了肺纤维化的症状，并抑制了 BLM 诱导的肺组织中的上皮-间充质转化（EMT）。TGF-β1/Smad 信号通路在纤维化肺组织中被激活，而 HtrA3 敲除抑制了该通路。
HtrA3 的表达水平在纤维化肺中增加。HtrA3 敲除可能通过 TGF-β1/Smad 信号通路减轻肺纤维化的症状。因此，抑制 HtrA3 可能是治疗肺纤维化的一种潜在靶点。
