Additive effects of phosphodiesterase-4 inhibition on effects of rSP-C surfactant.
We have tested the effects of combined treatment with a recombinant surfactant protein C based surfactant (rSP-C surfactant) containing a phosphodiesterase-4 (PDE-4) inhibitor, roflumilast, in a lung lavage model of acute lung injury. The following groups were tested: (1) controls receiving sham exposure; (2) PDE-4 inhibitor (6.0 mg/kg body weight, intratracheally) alone; (3, 4) rSP-C surfactant (25 and 100 mg phospholipids [PL] per kg body weight) alone; and (5, 6 ) treatment with rSP-C surfactant (25 and 100 mg PL per kg body weight) combined with the PDE-4 inhibitor at a dose of 6.0 mg/kg body weight. The different groups were compared with respect to improving oxygenation and histopathologic changes, e.g., hyaline membrane (HM) formation. Both doses of rSP-C surfactant improved oxygenation while even this high dose of the PDE-4 inhibitor alone did not influence oxygenation compared with untreated control animals. Addition of the PDE-4 inhibitor led to improved oxygenation based on both doses of rSP-C surfactant. The PDE-4 inhibitor alone prevented further HM formation and infiltration of neutrophil leukocytes. The rSP-C surfactant was able to prevent further HM formation. Based on both doses of rSP-C surfactant, addition of the PDE-4 inhibitor showed additional effects on oxygenation and inhibition of HM formation. The effects of combined treatment were superior to each treatment alone, leading to the conclusion that a rSP-C surfactant containing a PDE-4 inhibitor may act synergistically in this animal model of acute lung injury. We conclude that combined treatment with rSP-C surfactant and a PDE-4 inhibitor may be an effective treatment for patients with acute lung injury.
Häfner
D
D
Department of Respiratory Pharmacology and Institute of Pathology and Toxicology, Byk Gulden, Konstanz, Germany. dietrich.haefner@byk.de
Germann
P G
PG
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006818:Hyalin; D008168:Lung / Q000473:pathology; D008297:Male; D011510:Proteolipids / Q000008:administration & dosage*; D011659:Pulmonary Gas Exchange; D011663:Pulmonary Surfactants / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D011510:Proteolipids; D011663:Pulmonary Surfactants; D011994:Recombinant Proteins; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4