Targeting Lysyl oxidase-like 2 in Idiopathic Pulmonary Fibrosis

Abstract

The composition of extracellular matrix (ECM) is altered during pathologic scarring in damaged organs including the lung. One major change in the ECM involves the crosslinking of collagen, which promotes fibroblast to myofibroblast differentiation. Objective:We examined the role of lysyl oxidase (LOX)-like 2 in lung fibroblasts cultured from normal or IPF lung samples and in a humanized mouse model of IPF using a monoclonal antibody (Simtuzumab). Research Design and Methods: Primary lung fibroblasts from normal donor lungs and IPF lung explants were examined for expression of LOXL2. Targeting LOXL2 with Simtuzumab on normal and IPF fibroblasts was examined both in vitro and in vivo for synthetic, functional, and profibrotic properties. Results: LOXL2 was increased at transcript and protein level in IPF compared with normal lung samples. In a dose-dependent manner, Simtuzumab enhanced differentiation of fibroblasts into myofibroblasts. Inhibition of LOXL2 also enhanced fibroblast invasion and accelerated the outgrowth of fibroblasts from dissociated human lung cell preparations. Finally, preventative or delayed delivery of Simtuzumab enhanced lung fibrosis in a humanized mouse model of pulmonary fibrosis. Conclusion: Consistent with its failure in a Phase 2 clinical trial, Simtuzumab exhibited no therapeutic efficacy in translational in vitro and in vivo assays.

Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases

“…LOX family proteins are involved in several biological processes including tumour suppression, cell motility, cell transduction and cell adhesion. Dysregulation of LOX activity has been linked to pathological conditions such as cancer and fibrosis in lungs and liver [89][90][91][92][93]. TG is an enzyme responsible for cross-linking proteins such as collagen and fibronectin between glutamine and lysine residues or a primary amino group in a calcium-dependent manner.…”

Mechanotherapeutics for the Treatment of Idiopathic Pulmonary Fibrosis

“…Two major families of matrix crosslinking enzymes, LOX and TG, have been shown to be upregulated in patients with IPF 36,37 . Members of the LOX family comprise LOX, and LOX-like LOXL1, LOXL2, LOXL3 and LOXL4.…”