Tyloxapol confers durable protection against hyperoxic lung injury in the rat.
We tested the hypothesis that the nonlipid components of Exosurf, tyloxapol (TY), and cetyl alcohol (CA), protect against hyperoxic lung injury by induction of the animals' endogenous antioxidant defenses. Adult rats were intratracheally instilled with escalating doses of TY and CA (n = 20) or TY alone (n = 32) and immediately exposed to 100% oxygen. Intratracheal instillation of TY alone or in combination with CA protected against lethal hyperoxic injury in the rat in a dose-dependent fashion. To assess the effects of timing, rats were instilled with TY plus CA 24 hours before (n = 6) and 24 hours after (n = 6) exposure to 100% oxygen, with time to death determined. Rats were also instilled with TY alone at 0 hour (n = 6), 48 hours (n = 3), 96 hours (n = 3), and 186 hours (n = 4) prior to exposure to 100% oxygen. Lungs were assayed for superoxide dismutase, glutathione peroxidase, and catalase activities. Finally, the pharmacokinetics of TY in the rat lung were determined by instilling radiolabelled TY intratracheally. TY has a prolonged half-life in the rat lung, and protection against lethal hyperoxic injury was achieved by a single intratracheal dose delivered up to 186 hours prior to injury. Antioxidant enzymes were not induced in protected animals. We conclude that TY provides durable protection against hyperoxic lung injury without induction of antioxidant enzymes. It is present in the lung for sufficient duration to invoke a direct mechanism of protection, possibly as a radical scavenger. These findings raise the prospect of a therapeutic application for TY as prophylaxis in patients at risk for oxygen toxicity and adult respiratory distress syndrome.
Sachs
S
S
Division of Respiratory and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Ghio
A J
AJ
Young
S L
SL
D000818:Animals; D002374:Catalase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005233:Fatty Alcohols / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D006207:Half-Life; D018496:Hyperoxia / Q000150:complications*; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008171:Lung Diseases / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D013482:Superoxide Dismutase / Q000378:metabolism; D013501:Surface-Active Agents / Q000493:pharmacokinetics / Q000494:pharmacology*
D005233:Fatty Alcohols; D013501:Surface-Active Agents; D011092:Polyethylene Glycols; C005031:cetyl alcohol; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C016811:tyloxapol