Low density lipoprotein receptor-related protein 1deficiency exacerbates pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by injury and activation of alveolar epithelial cells, (myo)-fibroblast proliferation with formation of fibroblast foci, and excessive deposition of extracellular matrix (ECM) proteins. Low density lipoprotein receptor-related protein 1 (LRP1) was previously found to control cell growth and ECM turnover, however its role in the pathogenesis of IPF has not yet been described. Here, we demonstrate reduction of LRP1 expression in microdissected septae and primary lung fibroblasts isolated from IPF patients. Downregulation of LRP-1 expression was also observed in the lungs of mice subjected to the bleomycin model of pulmonary fibrosis and mice overexpressing Fra-2. The latter spontaneously develop pulmonary fibrosis in older age. LRP1 gene inactivation in AETII cells markedly aggravated bleomycin-induced pulmonary fibrosis as evident by increased mortality, reduced lung compliance, exaggerated deposition of ECM proteins, and aberrant activation of the TGF-β signaling pathway. Surprisingly, loss of LRP1 increased lung collagen I expression even without bleomycin treatment. These findings indicate that LRP1 is critical for maintenance of lung tissue homeostasis and proper regeneration of lung tissue after injury. Thus, reconstitution of LRP1 expression offers a potential therapeutic option for the treatment of pulmonary fibrosis.