Effect of phosphodiesterase-4 inhibitor on the inflammation, oxidative damage and apoptosis in a saline lavage-induced model of acute lung injury

Abstract

Introduction: Acute lung injury (ALI) is a disorder characterised by a neutrophil-mediated inflammation, lung edema, and hypoxia. Phosphodiesterase (PDE)-4 is mainly expressed in inflammatory cells, its inhibition reduce action of inflammatory cells. Aim of the study: The study evaluated if systemic administration of PDE-4 inhibitor roflumilast influences inflammation, oxidative stress and apoptosis in ALI. Methods: Rabbits with lavage-induced respiratory failure were divided into: animals with ALI model (A), animals with ALI treated with roflumilast (A+R, 1 mg/kg i.v.):), healthy ventilated controls (C). After 4 hours of ventilation, total and differential counts of cells in bronchoalveolar lavage fluid were measured. Concentrations of thiobarbituric acid-reactive substances (TBARS), 3-nitrotyrosine (3NT), interleukins (IL)-6, -8, and TNF-α in the lung tissue were analysed. Lung edema formation was expressed as wet-dry lung weight ratio. In lung tissue, apoptotic cells were evaluated by TUNEL assay and caspase-3 immunohistochemically. Results: Roflumilast therapy reduced migration of neutrophils into the lungs. PDE4 inhibition decreased the release of pro-inflammatory cytokines (IL-6, -8, TNF-α), markers of oxidative stress (TBARS, 3NT), apoptosis (apoptotic index, caspase-3) in the lung tissue compared to ALI group. Conclusion: Inhibition of PDE4 in the model of ALI mitigated the release of cytokines and chemokines from inflammatory cells and production of reactive oxygen species suggesting potential perspectives of PDE4 inhibitors in the treatment of ALI. Grants: APVV-0435-11, APVV-15-0075, VEGA 1/0356/18, BioMed (ITMS 26220220187).