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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.

The study aimed to prove the hypothesis that exogenous surfactant and an antibiotic polymyxin B (PxB) can more effectively reduce lipopolysaccharide (LPS)-induced acute lung injury (ALI) than surfactant treatment alone, and to evaluate the effect of this treatment on the gene expression of surfactant proteins (SPs). Anesthetized rats were intratracheally instilled with different doses of LPS to induce ALI. Animals with LPS 500 μg/kg have been treated with exogenous surfactant (poractant alfa, Curosurf ® , 50 mg PL/kg b.w.) or surfactant with PxB 1% w.w. (PSUR + PxB) and mechanically ventilated for 5 hrs. LPS at 500 μg/kg increased lung edema, oxidative stress, and the levels of proinflammatory mediators in lung tissue and bronchoalveolar lavage fluid (BALF). PSUR reduced lung edema and oxidative stress in the lungs and IL-6 in BALF. This effect was further potentiated by PxB added to PSUR. Exogenous surfactant enhanced the gene expression of SP-A, SP-B, and SP-C, however, gene expression for all SPs was reduced after treatment with PSUR + PxB. In mechanically ventilated rats with LPS-induced ALI, the positive effect of exogenous surfactant on inflammation and oxidative stress was potentiated with PxB. Due to the tendency for reduced SPs gene expression after surfactant/PxB treatment topical use of PxB should be considered with caution.

This study aimed to evaluate the molecular background of N -acetylcysteine (NAC) and recombinant human superoxide dismutase (rhSOD) antioxidant action when combined with exogenous surfactant in the treatment of meconium aspiration syndrome (MAS), considering redox signalling a principal part of cell response to meconium. Young New Zealand rabbits were instilled with meconium suspension (Mec) and treated by surfactant alone (Surf) or surfactant in combination with i.v. NAC (Surf + NAC) or i.t. rhSOD (Surf + SOD), and oxygen-ventilated for 5 h. Dynamic lung-thorax compliance, mean airway pressure, PaO₂/FiO₂ and ventilation efficiency index were evaluated every hour; post mortem, inflammatory and oxidative markers (advanced oxidation protein products, total antioxidant capacity, hydroxynonenal (HNE), p38 mitogen activated protein kinase, caspase 3, thromboxane, endothelin-1 and secretory phospholipase A₂) were assessed in pulmonary tissue homogenates. rhSOD addition to surfactant improved significantly, but transiently, gas exchange and reduced levels of inflammatory and oxidative molecules with higher impact; Surf + NAC had stronger effect only on HNE formation, and duration of treatment efficacy in respiratory parameters. In both antioxidants, it seems that targeting reactive oxygen species may be strong supporting factor in surfactant treatment of MAS due to redox sensitivity of many intracellular pathways triggered by meconium.

After inhalation, lipopolysaccharide (LPS) molecules interfere with a pulmonary surfactant, a unique mixture of phospholipids (PLs) and specific proteins that decreases surface tension at the air⁻liquid interphase. We evaluated the behaviour of a clinically used modified porcine pulmonary surfactant (PSUR) in the presence of LPS in a dynamic system mimicking the respiratory cycle. Polymyxin B (PxB), a cyclic amphipathic antibiotic, is able to bind to LPS and to PSUR membranes. We investigated the effect of PxB on the surface properties of the PSUR/LPS system. Particular attention was paid to mechanisms underlying the structural changes in surface-reducing features. The function and structure of the porcine surfactant mixed with LPS and PxB were tested with a pulsating bubble surfactometer, optical microscopy, and small- and wide-angle X-ray scattering (SAXS/WAXS). Only 1% LPS ( w / w to surfactant PLs) prevented the PSUR from reaching the necessary low surface tension during area compression. LPS bound to the lipid bilayer of PSUR and disturbed its lamellar structure by swelling. The structural changes were attributed to the surface charge unbalance of the lipid bilayers due to LPS insertion. PxB acts as an inhibitor of structural disarrangement induced by LPS and restores original lamellar packing, as detected by polarised light microscopy and SAXS.