Abstract
Background
Pulmonary fibrosis is a chronic progressive lung disease characterized by extensive fibrosis and poor prognosis, highlighting the urgent need for novel therapeutic strategies. This study aims to elucidate the role of the small proteoglycan proline/arginine-rich end leucine-rich repeat protein (PRELP), evaluate the protective potential of recombinant PRELP protein, and investigate its underlying molecular mechanisms.Methods
RNA in situ hybridization was performed on lung sections prepared from control subjects and patients with idiopathic pulmonary fibrosis (IPF). In mouse experiments, we established a bleomycin (BLM)-induced lung fibrosis model using PRELP knockout mice and assessed the extent of fibrosis. Furthermore, we administered recombinant PRELP protein via the airway in wild-type mice with BLM-induced fibrosis to evaluate its effects. In vitro experiments were conducted to investigate the role of PRELP in alveolar epithelial cells and fibroblasts.Results
In human lungs, PRELP expression was mainly detected in stromal regions and partly in type 2 alveolar epithelial cells. Furthermore, PRELP was broadly expressed in alveolar areas of controls but was markedly reduced in the alveolar region and localized to vessel walls in IPF patients. In mouse experiments, fibrosis was more severe in PRELP knockout mice after BLM intratracheal administration than in wild-type mice. Notably, prophylactic trans-airway administration of recombinant PRELP suppressed BLM-induced fibrosis in wild-type mice in vivo. In vitro experiments revealed that PRELP suppresses the acquisition of mesenchymal traits and enhances the maintenance of epithelial cell function in epithelial cells, while inhibiting the migratory ability of fibroblast cells. Mechanistically, PRELP suppressed fibrotic changes in epithelial cells not only through the transforming growth factor-beta (TGF-β) pathway but also via Receptor for advanced glycation end products (RAGE)/ Diaphanous 1 (DIAPH1)/ Yes-associated protein (YAP) signaling axis.Conclusions
The small proteoglycan PRELP plays a pivotal role in a mouse model of pulmonary fibrosis by suppressing the upregulation of mesenchymal markers, reinforcing epithelial cell function, and inhibiting fibroblast migration. Notably, prophylactic trans-airway administration of recombinant PRELP protected against pulmonary fibrosis, indicating that PRELP may be a promising novel protective agent for this disease.