In the lung, ECM components constitute the interstitial connective tissue matrix, which has its major function in scaffolding tissue but also serves as a local reservoir for growth factors like FGF, WNT ligands and most importantly for tissue fibrosis, TGF-ОІ 4. Mechanical stress caused by increased crosslinking and stiffening of ECM is now regarded as a crucial factor for the self-perpetuating nature of IPF and other fibrotic disorders 3. In recent years, the post-transcriptional modification of ECM components has become a major focus of fibrosis research. Thus far, treatment options for IPF are limited as therapies which restore tissue homeostasis do not yet exist. Although the origin of IPF is still unclear, uncontrolled wound repair caused by repetitive micro-injuries of the lung epithelium and resulting aberrant epithelial cell - fibroblast crosstalk is thought to be a main cause of IPF 1, 2. Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM), finally leading to disrupted lung architecture and severely impaired lung function. In summary, our study provides a comprehensive analysis of the LOX/L family in fibrotic lung disease and indicates prominent roles for LOXL2/3 in fibroblast activation and LOX/LOXL2 in IPF. As FMT could only be reconstituted with an enzymatically active LOXL2 variant, we conclude that LOXL2 enzymatic function is crucial for fibroblast transdifferentiation. Using siRNA experiments we observed that LOXL2 and LOXе…ѓ were crucial for fibroblast-to-myofibroblast transition (FMT). Immunohistochemical analysis of lung tissue from 14 IPF patients and healthy donors revealed strong induction of LOX and LOXL2 in bronchial and alveolar epithelium as well as fibroblastic foci. Various pro-fibrotic stimuli broadly induced LOX/L expression in fibroblasts, whereas specific induction of LOXL2 and partially LOX was observed in epithelial cells. Basal expression of all LOX/L family members was detected in epithelial cells and at higher levels in fibroblasts. Here, we systematically investigated LOX/L expression in primary fibroblasts and epithelial cells under fibrotic conditions, Bleomycin (BLM) induced lung fibrosis and in human IPF tissue. Lysyl oxidase (LOX) and LOX-like (LOXL) proteins play crucial roles in ECM remodeling due to their collagen crosslinking and intracellular functions. Potential inhibitors were also identified for LOX-like-protein-3 (LOXе…ѓ) and LOX-like-protein-4 (LOXL4), that are considered as emerging drug targets in the therapy of melanoma and gastric cancer.Extracellular matrix (ECM) composition and stiffness are major driving forces for the development and persistence of fibrotic diseases.

Ten hits (10.4% hit rate) were identified, and the compounds showed distinct activity profiles.

We measured the LOX inhibitory profile of a small targeted library generated by 2D ligand-based chemoinformatics methods. We confirmed that MCP-1, thiram, disulfiram are in fact pan-inhibitors, while BAPN inhibits only LOX-like enzymes (preferably LOX-like-protein-2, LOXL2) in contrast to the previous reports. During assay validation, previously reported non-selective small inhibitor molecules (BAPN, MCP-1, thiram, disulfiram) were investigated on all of the major LOX enzymes. In order to measure the inhibitory activity of small molecules on the LOX enzyme family members a fluorometric activity screening method was developed. Lysyl oxidase (LOX) enzymes as potential drug targets maintain constant attention in the therapy of fibrosis, cancer and metastasis.

The lox the family