Nitric-Oxide-Releasing Dexamethasone Derivative NCX-1005 Improves Lung Function and Attenuates Inflammation in Experimental Lavage-Induced ARDS.

Petra Kosutova,Pavol Mikolka,Andrea Calkovska,Maros Kolomaznik,Daniela Mokra

doi:10.3390/pharmaceutics13122092

Petra Kosutova, Pavol Mikolka + Show 3 more

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https://doi.org/10.3390/pharmaceutics13122092

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Journal: Pharmaceutics	Publication Date: Dec 5, 2021
Citations: 4	License type: CC BY 4.0

Affiliation: Comenius University Bratislava

Abstract

Acute respiratory distress syndrome (ARDS) is a common complication of critical illness and remains a major source of morbidity and mortality in the intensive care unit (ICU). ARDS is characterised by diffuse lung inflammation, epithelial and endothelial deterioration, alveolar–capillary leak and oedema formation, and worsening respiratory failure. The present study aimed to investigate the anti-inflammatory activity of nitric-oxide-releasing dexamethasone derivative NCX-1005 as a potential novel drug for ARDS. Adult rabbits with lavage-induced ARDS were treated with dexamethasone i.v. (0.5 mg/kg; DEX) and nitro-dexamethasone i.v. (0.5 mg/kg, NCX-1005) or were untreated (ARDS). Controls represented healthy ventilated animals. The animals were subsequently oxygen-ventilated for an additional 4 h and respiratory parameters were recorded. Lung oedema, inflammatory cell profile in blood and bronchoalveolar lavage, levels of the cytokines (IL-1β, IL-6, IL-8, TNF-α), and oxidative damage (TBARS, 3NT) in the plasma and lung were evaluated. Nitric oxide-releasing dexamethasone derivative NCX-1005 improved lung function, reduced levels of cytokines, oxidative modifications, and lung oedema formation to similar degrees as dexamethasone. Only NCX-1005 prevented the migration of neutrophils into the lungs compared to dexamethasone. In conclusion, the nitric oxide-releasing dexamethasone derivative NCX-1005 has the potential to be effective drug with anti-inflammatory effect in experimental ARDS.

Highlights

Acute respiratory distress syndrome (ARDS) is defined as an acute-onset syndrome, with bilateral diffuse infiltrates on chest radiography and non-cardiogenic respiratory failure [1]
Repetitive lung lavage caused a severe deterioration in all observed lung function parameters; the ratio of arterial oxygen partial pressure to fraction of inspired oxygen (P/F), oxygenation index (OI), alveolar–arterial gradient (AaG), ventilation efficiency index (VEI), dynamic compliance (Cdyn ), static compliance (Cstat ), mean airway pressure (MAP), and airway resistance (Raw) were significantly altered at timepoint “Model” in the time graphs (P/F ratio
There were no significant differences across all animals in the baseline values (BVs) of the respiratory parameters, and no differences in the same parameters across both injured groups (ARDS vs. NCX-1005) at the timepoint Model

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is defined as an acute-onset syndrome, with bilateral diffuse infiltrates on chest radiography and non-cardiogenic respiratory failure [1]. ARDS is associated with diffuse alveolar damage and lung capillary endothelial injury leading to respiratory failure and oxygenation impairment. The early phase of ARDS is characterized by a neutrophil-mediated inflammation, and lung cell injury and apoptosis, with the subsequent influx of protein-rich fluid into the alveoli and oedema formation. The mentioned overwhelming phenomena could lead to ARDS, initially with either direct (mainly pneumonia, aspiration of gastric contents) or indirect (mainly sepsis, multiple trauma) insults to the lung. Supportive therapy and mechanical ventilation are used for ARDS to prevent further ventilator-induced damage, reduce pulmonary oedema, and reduce hypoxaemia [3].

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