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TYLOXAPOL CONFERS DURABLE PROTECTION AGAINST HYPEROXIC LUNG INJURY IN THE RAT
Citation:
Sacks, S., A J. Ghio, AND S. L. Young. TYLOXAPOL CONFERS DURABLE PROTECTION AGAINST HYPEROXIC LUNG INJURY IN THE RAT. EXPERIMENTAL LUNG RESEARCH 25(6):543-559, (1999).
Description:
We tested the hypothesis that the non-lipid components of ExosurfR, tyloxapol (TY) and cetyl alcohol (CA), protect against hyperoxic lung injury by either 1) direct radical scavenging activity or 2) induction of the animals? endogenous anti-oxidant 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 h before (n = 6) and 24 h after
(n = 6) exposure to 100% oxygen, with time to death determined. Rats were also instilled with TY alone at 0 h (n = 6), 48 h (n = 3), 96 h (n = 3), and 186 h (n = 4) prior to exposure to 100% oxygen. Lungs were assayed for superoxide dismutase, glutathione peroxidase, and catalase activity. 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 hr prior to injury. Anti-oxidant enzymes were not induced in protected animals. We conclude that TY provides durable protection against hyperoxic lung injury without induction of anti-oxidant enzymes. It is present in the lung for sufficient duration to invoke a direct mechanism of protection, perhaps 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 ARDS.