Cyclooxygenase-inhibition enhances the effects of rSP-C surfactant therapy in a rat lavage model of acute respiratory distress syndrome (ARDS).
The effects of additional i.v. therapy with a cyclooxygenase-inhibitor Eltenac to a recombinant surfactant protein C (rSP-C) based surfactant were investigated in a rat lung lavage model of acute lung injury. Treatment was done at 60 min after the induction of acute lung injury by lavage. The influence of the different treatments were tested with regard to improving oxygenation, histopathological changes (hyaline membrane formation and alveolar influx of neutrophil leukocytes). These effects were further compared to a fixed combination of Eltenac with rSP-C surfactant which was administered intratracheally (i.tr.), 60 min after lavage. To prove that fibrinogen is involved in the formation of hyaline membranes in this animal model confocal microscopy was applied. Furthermore, for selected cases the influence of Eltenac or rSP-C surfactant on fibrinogen leakage was investigated by using confocal microscopy. Results of additional i.v. therapy exhibited an improved oxygenation with rSP-C surfactant, while a high dose of Eltenacalone did not influence oxygenation as compared to untreated controls. Addition of Eltenac lead to improved oxygenation using the low dose of rSP-C surfactant. The rSP-C surfactant prevented further hyaline membrane formation. Furthemore, addition of Eltenac to the low dose of rSP-C surfactant lead to improved hyaline membrane formation at a dose of 100 micromol/kg b.w. Results of combined i.tr. therapy confirmed the results of the additional therapy. Again, rSP-C surfactant improved oxygenation and further hyaline membrane formation, while even the high dose of i.tr. administered Eltenacalone only prevented further hyaline membrane formation. Using the low dose of rSP-C surfactant, combined treatment with Eltenac showed additional effects on oxygenation and inhibition of hyaline membrane formation. The maximum therapeutic effect of combined treatment was achieved at 0.3 mg Eltenac per kg b.w. which is equivalent to approximately 1 micromol. The inflammatory cell infiltration into the lung was not influenced by any of the therapeutic approaches. Confocal microscopy gave evidence that fibrinogen is involved in hyaline membrane formation in this animal model. Furthermore, as was shown by the explorative investigations with confocal microscopy, addition of the cyclooxygenase-inhibitor decreases the diffuse interstitial leakage of fibrinogen into the lung while surfactant monotherapy did not exhibit any influence on the fibrinogen influx into the alveoli.


CONCLUSIONS
Confocal microscopy may be an effective method to investigate the connection between fibrinogen leakage and hyaline membrane formation. Effects of additional or combined treatment were superior when compared to each treatment alone leading to the conclusion that a rSP-C surfactant containing a cyclooxygenase-inhibitor, acts synergistically in this animal model of acute lung injury. Lower doses of Eltenac could be used to reach similar effects on oxygenation and prevention of hyaline membrane after combined i.tr. treatment than after additional i.v. treatment together with surfactant. This leads to the conclusion that a fixed combination of rSP-C surfactant and a cyclooxygenase-inhibitor may be an effective treatment. Further testing may be warranted to prove whether this is a promising treatment for patients with acute lung injury.
Häfner
Dietrich
D
Department of Respiratory Pharmacology, Byk Gulden, Konstanz, Germany.
Ibrahim
Merdol
M
Wollin
Lutz
L
Germann
Paul-Georg
PG
D000208:Acute Disease; D000814:Aniline Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001784:Blood Gas Analysis; D018893:Bronchoalveolar Lavage / Q000379:methods; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005340:Fibrinogen / Q000378:metabolism; D007275:Injections, Intravenous; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D011663:Pulmonary Surfactants / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000188:drug therapy*; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*
D000814:Aniline Compounds; D016861:Cyclooxygenase Inhibitors; D011663:Pulmonary Surfactants; D011994:Recombinant Proteins; D013876:Thiophenes; D005340:Fibrinogen; C071200:eltenac