Effects of phosphodiesterase inhibitors on the lung functions in a saline lavage-induced model of acute lung injury

Introduction: Acute lung injury (ALI) is characterized by inflammation, excessive transepithelial migration of inflammatory cells. Cyclic AMP is a key intracellular second messenger which at higher levels has anti-inflammatory effect. Its concentration is determined by activity of the phosphodiesterase (PDE) enzymes. Aim of the study: The study evaluated if intravenous administration of selective (PDE3, PDE5) and non-selective PDE inhibitors enhances lung functions in a model of ALI. Methods: ALI was induced in rabbits by repetitive saline lung lavage (30 ml/kg, 6-12 times) until PaO2 reached values <26.7 kPa in oxygen ventilation. Animals were divided into 4 groups: animals with ALI which were untreated (A) or treated with PDE inhibitors (1 mg/kg i.v.): non-selective inhibitor aminophylline (A+A), PDE3 inhibitor olprinone (A+O), or PDE5 inhibitor sildenafil (A+S). Animals were ventilated for additional 4 h, and ventilatory pressures, blood gases, total and differential counts of cells in bronchoalveolar lavage fluid (BALF) were measured. Lung edema formation was expressed as wet-dry lung weight ratio. Results: Therapy (Th) with PDE inhibitors decreased total cell count in the BALF and decreased percentage of neutrophils. Significant improvement in lung functions during experiment was observed in all treated groups.. Formation of lung edema significantly decreased in A+A and A+S groups. Conclusion: Therapy with different types of PDE inhibitors positively affected the lung functions and gas exchange, and alleviated inflammation. Grant support: APVV-0435-11, APVV-15-0075, VEGA 1/0305/14, BioMed (ITMS 26220220187), UK/82/2017.