PubMed:29115860 JSONTXT 2 Projects

Lysyl Oxidase-like 1 Protein Deficiency Protects Mice from AdTGF-β1 Induced Pulmonary Fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterised by excessive deposition of extracellular matrix (ECM) in the lung parenchyma. The abnormal ECM deposition slowly overtakes normal lung tissue disturbing gas-exchange and leading to respiratory failure and death. ECM cross-linking and subsequent stiffening is thought to be a major contributor of disease progression and also promotes the activation of TGF-β1, one of the main pro-fibrotic growth factors. Lysyl oxidase-like1 (LOXL1) belongs to the crosslinking enzyme family and has been shown to be upregulated in active fibrotic regions of bleomycin-treated mice and IPF patients. We demonstrate in this study that LOXL1 deficient mice are protected from experimental lung fibrosis induced by overexpression of TGF-β1-using adenoviral gene transfer (AdTGF-β1). The lack of LOXL1 prevented accumulation of insoluble crosslinked collagen in the lungs and therefore limited lung stiffness after AdTGF-β1. In addition, we applied mechanical stretch to lung slices from LOXL1 +/+ and LOXL1 -/- mice treated with AdTGF-β1. Lung stiffness (Young's modulus) of LOXL1 -/- lung slices was significantly lower compared with LOXL1 +/+ lung slices. Moreover, the release of activated TGF-β1 after mechanical stretch was significantly lower in LOXL1 -/- mice compared to LOXL1 +/+ mice after AdTGF-β1. This data supports the concept that crosslinking enzyme inhibition represents an interesting therapeutic target for drug development in IPF.