title: Inositol-trisphosphate reduces alveolar apoptosis and pulmonary edema in neonatal lung injury.
abstract: D-myo-inositol-1,2,6-trisphosphate (IP3) is an isomer of the naturally occurring second messenger D-myo-inositol-1,4,5-trisphosphate, and exerts anti-inflammatory and antiedematous effects in the lung. Myo-inositol (Inos) is a component of IP3, and is thought to play an important role in the prevention of neonatal pulmonary diseases such as bronchopulmonary dysplasia and neonatal acute lung injury (nALI). Inflammatory lung diseases are characterized by augmented acid sphingomyelinase (aSMase) activity leading to ceramide production, a pathway that promotes increased vascular permeability, apoptosis, and surfactant alterations. A novel, clinically relevant triple-hit model of nALI was developed, consisting of repeated airway lavage, injurious ventilation, and lipopolysaccharide instillation into the airways, every 24 hours. Thirty-five piglets were randomized to one of four treatment protocols: control (no intervention), surfactant alone, surfactant + Inos, and surfactant + IP3. After 72 hours of mechanical ventilation, lungs were excised from the thorax for subsequent analyses. Clinically, oxygenation and ventilation improved, and extravascular lung water decreased significantly with the S + IP3 intervention. In pulmonary tissue, we observed decreased aSMase activity and ceramide concentrations, decreased caspase-8 concentrations, reduced alveolar epithelial apoptosis, the reduced expression of interleukin-6, transforming growth factor-β1, and amphiregulin (an epithelial growth factor), reduced migration of blood-borne cells and particularly of CD14(+)/18(+) cells (macrophages) into the airspaces, and lower surfactant surface tensions in S + IP3-treated but not in S + Inos-treated piglets. We conclude that the admixture of IP3 to surfactant, but not of Inos, improves gas exchange and edema in our nALI model by the suppression of the governing enzyme aSMase, and that this treatment deserves clinical evaluation.
authors.affiliation: Department of Pediatrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Preuss
authors.forename: Sabrina
authors.initials: S
authors.lastname: Stadelmann
authors.forename: Friede D
authors.initials: FD
authors.lastname: Omam
authors.forename: Julia
authors.initials: J
authors.lastname: Scheiermann
authors.forename: Supandi
authors.initials: S
authors.lastname: Winoto-Morbach
authors.forename: Philipp
authors.initials: P
authors.lastname: von Bismarck
authors.forename: Friederike
authors.initials: F
authors.lastname: Knerlich-Lukoschus
authors.forename: Dennis
authors.initials: D
authors.lastname: Lex
authors.forename: Sabine
authors.initials: S
authors.lastname: Adam-Klages
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
authors.forename: Janka
authors.initials: J
authors.lastname: Held-Feindt
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
authors.forename: Martin F
authors.initials: MF
authors.lastname: Krause
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066258:Amphiregulin; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid; D053181:Caspase 8 / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D007295:Inositol Phosphates / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000378:metabolism; D008297:Male; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011663:Pulmonary Surfactants / Q000378:metabolism / Q000494:pharmacology; D012121:Respiration, Artificial / Q000379:methods; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013500:Surface Tension / Q000187:drug effects; D013552:Swine
chemical_list: D066258:Amphiregulin; D002518:Ceramides; D006023:Glycoproteins; D007295:Inositol Phosphates; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; D011663:Pulmonary Surfactants; D013108:Sphingomyelin Phosphodiesterase; D053181:Caspase 8