Abstract
Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial–endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.
Highlights
An acute lung damage originating from a variety of direct or indirect reasons is characterized by an acute development of respiratory distress and hypoxemia resulting from diffuse damage of an alveolar–capillary barrier, dysfunction of a pulmonary surfactant, massive generation of a lung edema, and ventilation-perfusion mismatch, followed by neutrophil-mediated inflammation
PDE2 serves as a regulator for the crosstalk between cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) pathways, which may couple adverse augmented cAMP signaling with cardioprotective cGMP signaling, and thereby PDE2 may serve as a therapeutic target in several cardiovascular diseases [105]
PDE4 inhibitors might be of benefit in situations, such as persistent pulmonary hypertension of the newborn (PPHN) or in abnormally constricted pulmonary vasculature in sepsis, respiratory distress syndrome (RDS), meconium aspiration syndrome etc., as well as in acute respiratory distress syndrome (ARDS)-induced pulmonary vasoconstriction and pulmonary hypertension, the PDE5 and PDE3 inhibitors are of a major importance in influencing of these changes [164]
Summary
An acute lung damage originating from a variety of direct (pulmonary) or indirect (extrapulmonary) reasons is characterized by an acute development of respiratory distress and hypoxemia resulting from diffuse damage of an alveolar–capillary barrier, dysfunction of a pulmonary surfactant, massive generation of a lung edema, and ventilation-perfusion mismatch, followed by neutrophil-mediated inflammation. The so-called Berlin definition of ARDS in 2012 defined “ARDS” as an acute form of diffuse lung injury occurring in patients with a predisposing risk factor, meeting the following criteria: (1) an onset within 1 week of a known clinical insult or new/worsening respiratory symptoms; (2) presence of bilateral opacities on the chest X-ray, not fully explained by effusion, lobar/lung collapse, or nodules; (3) diagnosis of respiratory failure not fully explained by cardiac failure or fluid overload; (4) presence of hypoxemia, as defined by a specific threshold of the PaO2/FiO2 ratio measured with a minimum requirement of positive end-expiratory pressure (PEEP) ≥5 cm H2O; identifying three categories of ARDS based on a severity of hypoxemia: mild (PaO2/FiO2 200–300 mm Hg), moderate (PaO2/FiO2 100–200 mm Hg), and severe ARDS (PaO2/FiO2 ≤100 mm Hg) [2]. The term “acute lung injury” has remained as a general term expressing acute damage of the lung, as well as for experimental studies, where the lung damage is induced artificially, and other signs from the definition, except of hypoxemia, cannot be measured
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