18:1/18:1-Dioleoyl-phosphatidylglycerol prevents alveolar epithelial apoptosis and profibrotic stimulus in a neonatal piglet model of acute respiratory distress syndrome

• Published in: Pulmonary pharmacology & therapeutics Vol. 28; no. 1; pp. 25 - 34
• Main Authors: Preuß, Stefanie, Scheiermann, Julia, Stadelmann, Sabrina, Omam, Friede D., Winoto-Morbach, Supandi, Lex, Dennis, von Bismarck, Philipp, Adam-Klages, Sabine, Knerlich-Lukoschus, Friederike, Wesch, Daniela, Held-Feindt, Janka, Uhlig, Stefan, Schütze, Stefan, Krause, Martin F.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2014
• Subjects: (Neonatal) acute respiratory distress syndrome; Airway epithelial cells; Animals; Animals, Newborn; Apoptosis - drug effects; Disease Models, Animal; Epithelial Cells - drug effects; Epithelial Cells - pathology; Epithelial-to-mesenchymal transition; Female; Fibrous lung repair; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - metabolism; Male; Medical Education; Phosphatidylglycerols; Phosphatidylglycerols - pharmacology; Pulmonary Alveoli - cytology; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - pathology; Pulmonary Edema - prevention & control; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - prevention & control; Pulmonary Surfactants - pharmacology; Pulmonary/Respiratory; Respiration, Artificial; Respiratory Distress Syndrome, Newborn - prevention & control; Secretory phospholipase A2; Swine; ITBVI; Secretory phospholipase A2; nARDS; sCrs; PEEP; Phosphatidylglycerols; rBAL; Rrs; TUNEL; Epithelial-to-mesenchymal transition; (Neonatal) acute respiratory distress syndrome; Peak; OI; Fibrous lung repair; PGs; DOPG; BALF; Airway epithelial cells; AECs; EMT; EVLWI; sPLA2; VEI; MAP; SVRI; VT; sC rs; mean airway pressure; V T; extra-vascular lung water index; resistance of the respiratory system; tidal volume; terminal deoxynucleotidyl transferase dUTP nick end labelling; intrathoracic blood volume index; broncho-alveolar lavage fluid; oxygenation index; 18:1/18:1-Dioleoyl-phosphatidylgycerol; positive end-expiratory pressure; repeated bronchoalveolar lavage; R rs; peak inspiratory pressure; systemic vascular resistance index; neonatal acute respiratory distress syndrome; specific (dynamic) compliance; ventilation efficiency index
• ISSN: 1094-5539; 1522-9629; 1522-9629
• DOI: 10.1016/j.pupt.2013.10.002

18:1/18:1-Dioleoyl-phosphatidylgycerol (DOPG) is a surfactant phospholipid that is nearly non-detectable in neonatal surfactant films. When alveolar macrophages are exposed to DOPG in vitro, secretory phospholipase A2 (sPLA2) production is blocked, resulting in suppressed macrophage activity and improved surfactant function. We investigated whether the addition of DOPG to a commercially available surfactant preparation would improve lung function in a neonatal piglet model of acute respiratory distress syndrome. Respiratory failure was achieved by triple-hit lung injury (repeated broncho-alveolar lavage, injurious ventilation, tracheal lipopolysaccharide instillation, each intervention 24 h apart) in twenty-four domestic piglets aged 2–6 days and subject to mechanical ventilation. Following each lung injury protocol the piglets were treated with surfactant alone or with surfactant + DOPG. Within 72 h of mechanical ventilation, we observed significantly improved gas exchange (oxygenation and ventilation), lung mechanics (compliance and resistance of the respiratory system), and pulmonary oedema (extra-vascular lung water index) in the surfactant + DOPG group. This favourable clinical effect could be attributed to improved surfactant function, reduced sPLA2 secretion, inhibition of macrophage migration, reduced alveolar epithelial apoptosis, and suppression of amphiregulin and TGF-β1 expression in pulmonary tissues as a prerequisite for fibrous lung repair. We conclude that surfactant fortified by DOPG preserves lung function, and prevents alveolar epithelial injury and fibrous stimulus by reduction of sPLA2 in a neonatal model of acute respiratory distress syndrome without any relevant discernable side effects. Hence, DOPG supplementation in a neonatal lung exerts important function protecting effects and seems to be justified in cases of overwhelming pulmonary inflammation.