Zhao Xinyu, Li Yupeng, Yang Shengnan, Chen Yicong, Wu Kaiwei, Geng Jing, Liu Peipei, Wang Zai, Dai Huaping, Wang Chen
The Second Affiliated Hospital of Harbin Medical University, Heilongjiang, China.
Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.
J Cell Mol Med. 2025 Jan;29(1):e70321. doi: 10.1111/jcmm.70321.
Pulmonary fibrosis is a pathological manifestation that occurs upon lung injury and subsequence aberrant repair with poor prognosis. However, current treatment is limited and does not distinguish different disease stages. Here, we aimed to study the differential functions of Axl, a receptor tyrosine kinase expressing on both macrophages and fibroblasts, in the whole course of pulmonary fibrosis. We used mice with Axl total knockout, conditionally knockout in macrophages or fibroblasts, or treating with Axl inhibitors in inflammation or fibrosis stages to examine the effect of temporary dysfunction of Axl on bleomycin (BLM)-induced pulmonary fibrosis. Primary bone marrow-derived monocytes and primary fibroblasts from mice were used for cell-type-specific studies. Lung tissue and plasma samples were collected from idiopathic pulmonary fibrosis (IPF) patients and healthy controls to assess the Axl levels. We found that Axl inhibited the M1 polarisation of macrophages; inhibition of Axl during acute phase exacerbated inflammatory response and subsequent pulmonary fibrosis. On the other hand, Axl promoted the proliferation and invasion of the fibroblasts, partially by accelerating the focal adhesion turnover; inhibiting Axl during the fibrotic phase significantly alleviated pulmonary fibrosis. Consistently, phosphorylated Axl levels increased in fibrotic foci in the lung sample of IPF patients. In contrast, the soluble Axl (sAxl) level decreased in their plasma as compared to healthy controls. These results indicate that Axl may sequentially and differentially regulate macrophages and fibroblasts in acute and fibrosis phases, implying the necessity of a stage-specific treatment for pulmonary fibrosis. In addition, the activated Axl on fibroblasts may be reflected by the lowered plasma sAxl level, which may act as a biomarker for IPF. Trial Registration: ClinicalTrials.gov identifier: NCT03730337.
肺纤维化是肺损伤后发生的病理表现，随后异常修复，预后不良。然而，目前的治疗方法有限，且未区分不同的疾病阶段。在此，我们旨在研究巨噬细胞和成纤维细胞上均表达的受体酪氨酸激酶Axl在肺纤维化全过程中的不同功能。我们使用Axl完全敲除、在巨噬细胞或成纤维细胞中有条件敲除的小鼠，或在炎症或纤维化阶段用Axl抑制剂进行处理，以研究Axl暂时功能障碍对博来霉素（BLM）诱导的肺纤维化的影响。使用来自小鼠的原代骨髓来源单核细胞和原代成纤维细胞进行细胞类型特异性研究。从特发性肺纤维化（IPF）患者和健康对照者中收集肺组织和血浆样本，以评估Axl水平。我们发现Axl抑制巨噬细胞的M1极化；急性期抑制Axl会加剧炎症反应及随后的肺纤维化。另一方面，Axl促进成纤维细胞的增殖和侵袭，部分是通过加速粘着斑周转来实现的；在纤维化阶段抑制Axl可显著减轻肺纤维化。一致的是，IPF患者肺样本中纤维化灶处磷酸化Axl水平升高。相比之下，与健康对照者相比，他们血浆中的可溶性Axl（sAxl）水平降低。这些结果表明，Axl可能在急性和纤维化阶段依次并不同地调节巨噬细胞和成纤维细胞，这意味着肺纤维化需要进行阶段特异性治疗。此外，成纤维细胞上激活的Axl可能通过血浆sAxl水平降低反映出来，这可能作为IPF的生物标志物。试验注册：ClinicalTrials.gov标识符：NCT03730337。
