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Exposure of the respiratory mucosa to oxygen-enriched air contributes to the generation of the lung damage in both adult respiratory distress syndrome and bronchopulmonary dysplasia. Recent work has identified the nasal submucosal gland as the source of diverse molecules important in mucous membrane host defense. We searched for the presence of antioxidant activity in nasal glandular secretions, the absence of which could possibly predispose to oxygen-induced injury. Employing a low molecular weight preparation of nasal secretions (a pooled concentrate passed over a 10,000-dalton molecular sieve), antioxidant activity capable of inhibiting both horseradish peroxidase and Fenton reagent reactions was discovered. The following lines of evidence suggest that submucosal glands are the source of this activity. (1) Antioxidant activity present in resting, baseline nasal washings is significantly increased after cholinergic stimulation either in response to topical methacholine or induced by a gustatory reflex. (2) Application of atropine reduced the antioxidant activity to baseline levels after either of the cholinergic stimuli. (3) Levels of antioxidant activity correlated very closely with the secretion of lactoferrin, a recognized product secreted solely from the serous cell of the submucosal gland. The antioxidant activity is due to novel, previously unrecognized molecules. This activity is found in nasal secretions containing molecules less than 10,000 daltons, is unaffected by N-ethyl maleimide (which inactivates glutathione, another low molecular weight antioxidant), is not associated with the capacity to reduce cytochrome c (as seen with ascorbic acid), and resides in the water soluble pool of secretions (in contrast to vitamin E, another putative antioxidant).(ABSTRACT TRUNCATED AT 250 WORDS)