Targeting Lysine‐specific Demethylase 1 (LSD1) in an Experimental Model of Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic disease that is characterized by abundant deposition of extracellular matrix proteins in the lungs, which ultimately leads to respiratory failure and death. The existing treatment options neither arrest disease progression nor provide significant improvement in lung function. Hence, it is essential that we identify novel targets or develop add‐on pharmacological agents to treat this fatal disease. Epithelial to mesenchymal transition (EMT) plays a key role in the pathogenesis of IPF, wherein alveolar epithelial cells lose part of their characteristics, while gaining mesenchymal markers. Inhibition of the EMT process could be a potential approach to treat lung fibrosis. Accumulating evidence suggests that inhibition of lysine‐specific demethylase 1 (LSD1), a chromatin‐modifying enzyme that regulates gene transcription prevents EMT and fibrogenesis. Here, we hypothesized that inhibition of LSD1 by tranylcypromine protects against bleomycin‐induced lung fibrosis.A single instillation of Bleomycin (Bleo; 2.5mg/Kg) in 8‐weeks old rats was used to induce lung fibrosis. Drug treatment with tranylcypromine was commenced on the same day as Bleo administration using two different doses (1mg/Kg and 2 mg/Kg ip). After two weeks, rats were instrumented to measure right ventricular systolic pressure (RVSP) and cardiac function. Bleo injected animals developed secondary pulmonary hypertension as evidenced by increase in RVSP in comparison with control rats (RVSP; 25.4±0.71 vs 52.7±2.5, mmHg) with a concomitant development of right ventricular hypertrophy (RVH; 0.27±0.01 vs 0.45±0.06). Significant attenuation of RVSP (1mg/kg: 52.7± 2.5 vs 42.3± 3.1; 2mg/kg: 36.2±1.8) and RVH (1 mg/kg: 0.47±0.06 vs 0.4+0.08; 2mg/Kg: 0.34±0.01) was observed with both the doses of tranylcypromine; however, 2mg/Kg dose showed better effects. Bleo‐induced lung fibrosis was also reduced by drug treatment as evaluated by picro‐sirius red staining. Collectively, our findings reveal that inhibition of LSD1 by tranylcypromine protects against bleo‐induced cardiopulmonary damage.