Department of Endoscopy (the bronchoscope group), Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia 19104, USA.
Theranostics. 2022 Jul 4;12(11):5125-5137. doi: 10.7150/thno.74809. eCollection 2022.
Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) has a poor prognosis and lacks effective therapy. Animal models that mimic AE-IPF can greatly accelerate investigation of its pathogenesis and development of effective therapy. However, there are few reports of animal models of AE-IPF caused by bacteria. Thus, our study aimed to establish a mouse model of bacterium-induced AE-IPF and explore the potential pathogenic mechanism of AE-IPF. Mice were instilled intranasally with bleomycin (BLM) followed by non-typeable (NTHi) strain NT127. Murine survival, bacterial load, body weight and pulmonary histopathological changes were evaluated. We analyzed the T cell and inflammatory cell responses in the lungs. Infection with 10 CFU NT127 triggered AE in mice with PF induced by 30 μg BLM. Compared with BLM-instilled mice, the BLM/NT127-treated mice showed more obvious airway inflammation, lower survival rate, higher inflammatory cell response, and increased proportions and numbers of IL-17CD4, IL-17 γδ T, IL-22CD4 and regulatory T (Treg) cells in lungs. γδ T cells were the predominant source of IL-17. IL-17 gene knockout mice with AE-IPF had quicker body weight recovery, milder pulmonary inflammation and fibrosis, stronger IL-22CD4T, TGF-β γδ T and Treg cell responses, and weaker neutrophil and eosinophil responses than wild-type mice with AE-IPF. NTHi infection after BLM-induced IPF can cause AE-IPF in a murine model. This novel model can be used to investigate the pathogenesis of AE-IPF and develop new therapies for AE-IPF caused by bacteria. IL-17 is essential for the development of AE-IPF, and it may be a new therapeutic target for bacteria-induced AE-IPF.
特发性肺纤维化（IPF）的急性加重（AE）预后不良，缺乏有效治疗方法。模拟 AE-IPF 的动物模型可以极大地加速对其发病机制和有效治疗方法的研究。然而，很少有关于细菌引起的 AE-IPF 动物模型的报道。因此，我们的研究旨在建立一种由细菌引起的 AE-IPF 小鼠模型，并探讨 AE-IPF 的潜在发病机制。 我们通过鼻腔内滴注博莱霉素（BLM），然后滴注非定型（NTHi）菌株 NT127，建立了 AE-IPF 小鼠模型。评估了小鼠的存活率、细菌负荷、体重和肺组织病理学变化。我们分析了肺部 T 细胞和炎症细胞的反应。 与 BLM 处理的小鼠相比，用 30μg BLM 诱导 PF 后感染 10 CFU NT127 的小鼠出现更明显的气道炎症、更低的存活率、更高的炎症细胞反应以及肺内 IL-17CD4、IL-17γδ T、IL-22CD4 和调节性 T（Treg）细胞比例和数量增加。γδ T 细胞是 IL-17 的主要来源。AE-IPF 时的 IL-17 基因敲除小鼠比野生型小鼠更快地恢复体重，肺部炎症和纤维化程度更轻，IL-22CD4T、TGF-βγδ T 和 Treg 细胞反应更强，中性粒细胞和嗜酸性粒细胞反应更弱。 在 BLM 诱导的 IPF 后感染 NTHi 可导致 AE-IPF 在小鼠模型中发生。这种新型模型可用于研究 AE-IPF 的发病机制，并为细菌引起的 AE-IPF 开发新的治疗方法。IL-17 是 AE-IPF 发展所必需的，它可能是细菌诱导的 AE-IPF 的新治疗靶点。
