The Copper Chelator Tetrathiomolybdate Regressed Bleomycin-Induced Pulmonary Fibrosis in Mice, by Reducing Lysyl Oxidase Expressions

Abstract

Pulmonary fibrosis (PF) is characterized by an increase in the number of fibroblasts and an accumulation of collagen fibers in the extracellular matrix (ECM). The members of the copper-dependent lysyl oxidase (LOX) enzyme family regulate the collagen accumulation in the ECM. Tetrathiomolybdate (TM) is a copper chelator. The present study reported the effect of TM on the expression of LOX proteins (LOX, LOXL1, and LOXL2), collagen digestion enzymes (MMP2 and MMP8), and TIMP1 (a collagenase inhibitor) in PF. The PF in mice was induced by intratracheal bleomycin instillation. Adult mice were divided into four groups: mice dissected after 21 days of the first bleomycin (0.08 mg/kg, single dose) treatment (I) and their controls (II), and mice treated with TM for 1 week (1.2 mg/day/mice for the first 4 days and 0.9 mg/day/mice for the last 3 days) after 14 days of the first bleomycin instillation and dissected in the 21st day of the experiment (III) and their controls (IV). Mice in groups III and IV were fed a low-copper (2 mg/kg) diet during the last 7 days of the experiment. The fibrosis score in the lung was determined under a microscope. The expressions of collagen-I, LOX, MMP, and TIMP1 proteins were analyzed by Western blotting in the lung. Mice lungs with fibrosis were characterized by an overexpression of collagen-I, LOX, MMP, and TIMP1 proteins in addition to an accumulation of collagen fibers. TM treatments significantly regressed the overexpression of these proteins in the fibrotic mice lung. In conclusion, TM treatments can be used for the regression of PF, by decreasing collagen-I protein expression and accumulation.

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

“…Tetrathimolybdate, a copper chelator, has been reported to stop the expression of activated LOX, LOXL1 and LOXL2 in pulmonary fibrosis of mice . Furthermore, digoxin and acriflavine were compounds identified which stopped the expression of LOX proteins and hypoxia induced m RNA of LOX and LOXL4 in MDA‐231 cells and LOXL2 in MDA‐435 cells .…”

The effects of atorvastatin on the kidney injury in mice with pulmonary fibrosis

“…And also, the treatments with BLM are limited because BLM causes the formation of PF. So that, intratracheal BLM administration generally uses to induce PF in experimental animals . BLM is removed from the body by the kidneys.…”

“…Pulmonary fibrosis (PF) is characterized by the fibroblast activation, the increase in number of myofibroblast, the increased synthesis and deposition of extracellular matrix (ECM) components, such as fibronectin, collagen, tenascin-C, hyaluronic acid, heparan sulfate and dermatan sulfate. [1][2][3][4] It can be triggered by the exposure of asbestos, silica and metal powders, the bacterial and viral infections, the autoimmune reactions, the gastro-esophageal reflux, the traumatic injuries of lungs and some drugs used in the treatment of various diseases, such as bleomycin (BLM), amiodarone, propranolol and oxaliplatin. [5][6][7][8][9][10][11] BLM-containing chemotherapy resulted in BLM-induced pneumonitis in 0-46% of cancer patients.…”

Personalized medicine in idiopathic pulmonary fibrosis

“…A therapeutic role for anti-LOXL2 monoclonal antibody, simtuzumab, has been demonstrated in an experimental model of lung fibrosis through reduction of collagen deposition and TGFb1 signaling [75,77,78]. In two independent IPF cohorts, baseline serum LOXL2 levels were upregulated in patients with IPF compared to controls, while a strong association with increased risk of progression and mortality has been also described [51].…”