Reduction of Lung Inflammation, Oxidative Stress and Apoptosis by the PDE4 Inhibitor Roflumilast in Experimental Model of Acute Lung Injury

Abstract

Damage of alveolar-capillary barrier, inflammation, oxidative injury, and lung cell apoptosis represent the key features of acute lung injury (ALI). This study evaluated if selective phosphodiesterase (PDE)-4 inhibitor roflumilast can reduce the mentioned changes in lavage-induced model of ALI. Rabbits with ALI were divided into 2 groups: ALI without therapy (A group) and ALI treated with roflumilast i.v. (1 mg/kg; A+R group). One group of healthy animals without ALI served as ventilated controls (C group). All animals were oxygen-ventilated for further 4 h. At the end of experiment, total and differential counts of cells in bronchoalveolar lavage fluid (BALF) and total and differential counts of white blood cells were estimated. Lung edema formation was assessed from determination of protein content in BALF. Pro-inflammatory cytokines (TNFα, IL-6 and IL-8) and markers of oxidation (3-nitrotyrosine, thiobarbituric-acid reactive substances) were detected in the lung tissue and plasma. Apoptosis of lung cells was investigated immunohistochemically. Treatment with roflumilast reduced leak of cells, particularly of neutrophils, into the lung, decreased concentrations of cytokines and oxidative products in the lung and plasma, and reduced lung cell apoptosis and edema formation. Concluding, PDE4 inhibitor roflumilast showed potent anti-inflammatory actions in this model of ALI.

Phosphodiesterase 4 Inhibitors in Allergic Rhinitis/Rhinosinusitis

“…Expression is triggered by epithelial damage, microbial invasion, and allergen sensitization. Its inhibition is a promising target for suppressing inflammatory responses ( Contreras et al., 2017 ) as was demonstrated for roflumilast in an animal model of acute lung injury ( Kosutova et al., 2018 ). PDE4 inhibitors are well-characterized pharmaceutical agents with a broad range of anti-inflammatory activities also in various inflammatory conditions including allergic diseases ( Howell et al., 2018 ).…”

Transplantation of Mesenchymal Stem Cells: A Potential Adjuvant Therapy for COVID-19

“…However, the excessive and inadequate apoptosis can lead to the pathogenesis of diseases. It has been suggested that ALI/ARDS is associated with a dysbalanced lung cell apoptosis ( Kosutova et al, 2018 ; Wu Y. et al, 2020 ). The pulmonary epithelial cells are exposed and susceptible to multiple environmental stress and internal responses, in particular, virus infection is an important stimulus that triggers apoptosis of epithelial cells ( Yeung et al, 2016 ; Khatri et al, 2018 ).…”

Effects of Nitric Oxide Donor on the Lung Functions in a Saline Lavage-Induced Model of ARDS

“…Viability and total number of cells in BALF were determined by cell analyzer Countess (Invitrogen, USA). Total protein in BALF was measured by methods of Bradford (1976), as published by us earlier (Kosutova et al 2018).…”

“…NO reacts with superoxide anions to form a highly potent oxidant peroxynitrite which together with other oxidants damages proteins, lipids, and nucleic acids. The complex action of inflammatory processes and oxidative effects of reactive oxygen and nitrogen species (RONS) finally leads to a disruption of the alveolar-capillary barrier with subsequent formation of interstitial and alveolar edema and progression of lung injury (Lamb et al 1999).…”

“…For instance, inhaled NO attenuated pulmonary hypertension, enhanced gas exchange, and suppressed transendothelial migration of activated neutrophils and synthesis of pro-inflammatory cytokines in a model of septic acute lung injury (ALI) (Miao et al 2002). S-nitroso-N-acetylpenicillamine (SNAP), an NO-releasing compound, has also shown prompt and several hours-lasting bronchodilation (Dupuy et al 1992), pulmonary artery relaxation in hypoxemic conditions (Lakshminrusimha et al 2013), and antiinflammatory effects in in vitro and in vivo lipopolysaccharide exposure (Lee et al 2015). Because of these properties, we have expected that SNAP could be suitable also to alleviate the changes associated with ARDS.…”