State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510030, PR China.
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510030, PR China; Department of Respiratory Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550001, PR China.
Biochem Biophys Res Commun. 2020 Nov 19;532(4):598-604. doi: 10.1016/j.bbrc.2020.08.094. Epub 2020 Sep 6.
Pulmonary fibrosis is a fatal interstitial lung disease that is characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of lung. The precise mechanisms underlying pulmonary fibrosis still remain unclear. In the current study, we aimed to investigate the alteration and function of serine (or cysteine) peptidase inhibitor, clade A, member 3 N (Serpina3n) in pulmonary fibrotic models and explore the potential mechanisms.
We induced pulmonary fibrosis in mice by silica and bleomycin respectively and determined Serpina3n in lung tissues, and then verified the expression of Serpina3n and its correlation with pulmonary fibrosis at seven time points in a bleomycin longstanding model. Moreover, adeno-associated virus type 9 (AAV9)-mediated Serpina3n knockdown was used to treat pulmonary fibrosis in the bleomycin model, whose possible mechanisms would be preliminarily explored by detecting chymotrypsin C as an example.
Serpina3n was up-regulated significantly in lungs of both models at mRNA and protein levels relative to control. Notably, the expression of Serpina3n peaked during the 3rd week and then decreased until nearly normal levels during the 10th week, which was closely related to fibrotic procession in bleomycin-treated mice. AAV-mediated Serpina3n knockdown in the lung tissues alleviated bleomycin-induced fibrotic symptoms at various levels and disinhibit chymotrypsin C.
Our study revealed that Serpina3n is a critical regulator in pulmonary fibrosis and suggested Serpina3n inhibition as a potential therapeutic strategy in chronic pulmonary injuries.
肺纤维化是一种致命的间质性肺疾病，其特征是细胞外基质（ECM）过度积累和肺重塑。肺纤维化的确切机制仍不清楚。在本研究中，我们旨在研究丝氨酸（或半胱氨酸）蛋白酶抑制剂 A 族成员 3N（Serpina3n）在肺纤维化模型中的改变和功能，并探讨其潜在机制。
我们分别用二氧化硅和博来霉素诱导小鼠肺纤维化，并测定肺组织中 Serpina3n 的含量，然后在博来霉素长期模型中七个时间点验证 Serpina3n 的表达及其与肺纤维化的相关性。此外，用腺相关病毒 9（AAV9）介导的 Serpina3n 敲低来治疗博来霉素模型中的肺纤维化，通过检测糜蛋白酶 C 作为一个例子来初步探讨其可能的机制。
与对照组相比，两种模型的肺组织中 Serpina3n 的 mRNA 和蛋白水平均显著上调。值得注意的是，Serpina3n 的表达在第 3 周达到峰值，然后在第 10 周降至接近正常水平，这与博来霉素处理小鼠的纤维化过程密切相关。AAV 介导的肺组织中 Serpina3n 的敲低在多个水平上缓解了博来霉素诱导的纤维化症状，并抑制了糜蛋白酶 C。
我们的研究表明，Serpina3n 是肺纤维化的一个关键调节因子，并提示 Serpina3n 抑制可能是慢性肺损伤的一种潜在治疗策略。
