The role of the low density lipoprotein (LDL) receptor-related protein-1 (LRP-1) in pulmonary fibrosis

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This proposal aims to explore the pathogenic role of the multifunctional scavenger and signaling receptor LRP-1 in lung fibrosis, and to apply new therapeutic strategies based on these investigations. In the first funding period, we gained important insight in the expression of LRP-1 and its impact on lung fibroblast activities under fibrotic conditions. We found strong down-regulation of LRP-1 expression in isolated lung fibroblasts from Idiopathic Pulmonary Fibrosis (IPF) patients and in a respective animal model. LRP-1 deficiency markedly impacted fibroblast functions evidenced by altered adhesive and migratory properties, enhanced proliferation, increased production and altered composition of extracellular matrix (ECM) proteins, as well as diminished endocytosis of ECM proteins and haemostatic factors. Based on these findings the objectives of the proposal for the next funding period are (a) To causally link LRP-1 deficiency and the development of lung fibrosis in vivo by investigating newly generated conditional cell-specific LRP-1 knockout mice. (b) To identify factors, including microRNA(s), responsible for down-regulation of LRP-1 expression in fibrotic lungs. (c) To evaluate the consequences of LRP-1 deficiency for TGF-beta1-driven human lung fibroblast cellular activities (proliferation, ECM production, myofibroblast differentiation). (d) To identify the molecular mechanisms mediating LRP-1-regulated adhesive and migratory properties of lung fibroblasts. (e) To apply different approaches in order to prevent and/or reverse the remodelling process in animal models of lung fibrosis by systemic/local application of molecules modulating LRP-1 expression.