Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
College of Arts and Science, Vanderbilt University, Nashville, TN, USA.
Nat Commun. 2022 Nov 19;13(1):7114. doi: 10.1038/s41467-022-34870-w.
Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays a central role in the progression of pulmonary fibrosis. Here we show that platelet endothelial aggregation receptor 1 (PEAR1) in fibroblasts may serve as a target for pulmonary fibrosis therapy. Pear1 deficiency in aged mice spontaneously causes alveolar collagens accumulation. Mesenchyme-specific Pear1 deficiency aggravates bleomycin-induced pulmonary fibrosis, confirming that PEAR1 potentially modulates pulmonary fibrosis progression via regulation of mesenchymal cell function. Moreover, single cell and bulk tissue RNA-seq analysis of pulmonary fibroblast reveals the expansion of Activated-fibroblast cluster and enrichment of marker genes in extracellular matrix development in Pear1 fibrotic lungs. We further show that PEAR1 associates with Protein Phosphatase 1 to suppress fibrotic factors-induced intracellular signalling and fibroblast activation. Intratracheal aerosolization of monoclonal antibodies activating PEAR1 greatly ameliorates pulmonary fibrosis in both WT and Pear1-humanized mice, significantly improving their survival rate.
肺纤维化是一种慢性间质性肺疾病，可导致不可逆转和进行性的肺瘢痕和呼吸衰竭。成纤维细胞的激活在肺纤维化的进展中起着核心作用。在这里，我们表明成纤维细胞中的血小板内皮细胞聚集受体 1 (PEAR1) 可作为肺纤维化治疗的靶点。老年小鼠中 Pear1 的缺失会自发引起肺泡胶原的积累。间充质特异性 Pear1 缺失加剧博来霉素诱导的肺纤维化，证实 PEAR1 通过调节间充质细胞功能潜在地调节肺纤维化的进展。此外，对肺成纤维细胞的单细胞和批量组织 RNA-seq 分析表明，在 Pear1 纤维化肺中，活化的成纤维细胞簇扩大，并富集细胞外基质发育的标记基因。我们进一步表明，PEAR1 与蛋白磷酸酶 1 结合，抑制纤维化因子诱导的细胞内信号和成纤维细胞激活。PEAR1 激活的单克隆抗体经气管内雾化吸入可显著改善 WT 和 Pear1 人源化小鼠的肺纤维化，显著提高其存活率。
