Abstract
Bleomycin (BLM) is an effective curative option in the management of several malignancies including pleural effusions; but pulmonary toxicity, comprising of pneumonitis and fibrosis, poses challenge in its use as a front-line chemotherapeutic. Although Amifostine has been found to protect lungs from the toxic effects of radiation and BLM, its application is limited due to associated toxicity and unfavorable route of administration. Therefore, there is a need for selective, potent, and safe anti-fibrotic drugs. The current study was undertaken to assess the protective effects of DRDE-30, an analog of Amifostine, on BLM-induced lung injury in C57BL/6 mice. Whole body micro- computed tomography (CT) was used to non-invasively observe tissue damage, while broncheo-alveolar lavage fluid (BALF) and lung tissues were assessed for oxidative damage, inflammation and fibrosis. Changes in the lung density revealed by micro-CT suggested protection against BLM-induced lung injury by DRDE-30, which correlated well with changes in lung morphology and histopathology. DRDE-30 significantly blunted BLM-induced oxidative stress, inflammation and fibrosis in the lungs evidenced by reduced oxidative damage, endothelial barrier dysfunction, Myeloperoxidase (MPO) activity, pro-inflammatory cytokine release and protection of tissue architecture, that could be linked to enhanced anti-oxidant defense system and suppression of redox-sensitive pro-inflammatory signaling cascades. DRDE-30 decreased the BLM-induced augmentation in BALF TGF-β and lung hydroxyproline levels, as well as reduced the expression of the mesenchymal marker α-smooth muscle actin (α-SMA), suggesting the suppression of epithelial to mesenchymal transition (EMT) as one of its anti-fibrotic effects. The results demonstrate that the Amifostine analog, DRDE-30, ameliorates the oxidative injury and lung fibrosis induced by BLM and strengthen its potential use as an adjuvant in alleviating the side effects of BLM.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating interstitial lung disease (ILD), which is characterized by gradual scarring of normal lung tissue, causing respiratory distress
The present study was undertaken to evaluate the protective effects of Defence Research and Development Establishment (DRDE)-30 in an animal model of pulmonary fibrosis induced by intra-tracheal instillation of bleomycin
This model has contributed tremendously in elucidating the important roles played by cytokines, growth factors and signaling pathways in pulmonary fibrosis (Kalayarasan et al, 2008; Matsuoka et al, 2002), besides identifying TGF-β as one of the key pro-fibrogenic factors (Willis and Borok, 2007) The choice of using female C57BL/6 mice as the model system was based on their reported higher susceptibility to bleomycin-induced fibrosis compared to other strains like BALB/c mice, which are relatively fibrosisresistant, attributable to the differential expression of various cytokines and proteases/anti-proteases (Schrier et al, 1983; Phan and Kunkel, 1992)
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating interstitial lung disease (ILD), which is characterized by gradual scarring of normal lung tissue, causing respiratory distress. It causes considerable morbidity and mortality in humans, with the median survival time between 2–5 years following diagnosis (Hutchinson et al, 2015). After large multicentre clinical trials, two oral treatment options: nintedanib (Ofev, inhibitor of PDGF/VEGF/FGF receptor tyrosine kinases) and pirfenidone (Esbriet, anti- inflammatory and anti-fibrotic agent) have recently been approved for treating mild to moderate cases of IPF, both causing only a partial reduction in the disease progression (reduce the decline in lung function, measured as Forced Vital Capacity) but no cure or regression of the disease (King et al, 2014; Richeldi et al, 2014). The identification of novel compounds and their preclinical evaluation in animal models of lung fibrosis presents an urgent need
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