The increase in airway responsiveness induced by O3 exposure in dogs is associated with airway epithelial inflammation, as evidenced by an increase in the number of neutrophils (polymorphonuclear leukocytes) found in epithelial biopsies and in bronchoalveolar lavage fluid. We investigated in 10 healthy, human subjects whether O3-induced hyperresponsiveness was similarly associated with airway inflammation by examining changes in the types of cells recovered in bronchoalveolar lavage fluid obtained after exposure to air or to O3 (0.4 or 0.6 ppm). We also measured the concentrations of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in lavage fluid. We measured airway responsiveness to inhaled methacholine aerosol before and after each exposure and performed bronchoalveolar lavage 3 h later. We found more neutrophils in the lavage fluid from O3-exposed subjects, especially in those in whom O3 exposure produced an increase in airway responsiveness. We also found significant increases in the concentrations of prostaglandins E2, F2 alpha, and thromboxane B2 in lavage fluid from O3-exposed subjects. These results show that in human subjects O3-induced hyperresponsiveness to methacholine is associated with an influx of neutrophils into the airways and with changes in the levels of some cyclooxygenase metabolites of arachidonic acid.

We have examined the effects of indomethacin (I) on tolerance to the bronchomotor effects of repetitive challenge with exercise (EX) and eucapnic hyperpnea (EH) in 7 asthmatic subjects. Each subject was studied on 4 separate days. EH was performed for 4 min at a minute ventilation found previously to increase specific airway resistance (SRaw) by 8 units (cm H2O/L/s). All exercise challenges were performed on a cycle ergometer for 5 min at a constant work load. Subjects breathed room temperature, dry air for both stimuli. SRaw was serially measured before and after each stimulus. Tolerance was examined by giving up to 3 repetitions of EH or EX, allowing a return of SRaw to within 1 unit of baseline between repetitions. Placebo (P) or I (25 mg four times a day for 7 doses) was administered in a single-blind manner. The timing between stimulus repetitions on the P day was matched to that of the I day. After P, the initial rise in SRaw was similar for both EX and EH, with a significant and progressive decrease in this rise after each stimulus repetition (p = 0.032 for EX, p = 0.006 for EH). After I, tolerance was still demonstrated to EH (p = 0.002), but not to EX (p = 0.231). This finding indicates that EH and EX are not identical stimuli, since there is an I-sensitive mechanism (possibly a bronchodilating prostaglandin) associated with the development of tolerance to EX but not to EH. Our data also suggest a possible additional bronchoconstricting mechanism associated with EX and not with EH.

We have previously reported that bedtime ethanol (2.0 ml/kg of 100 proof vodka) increases upper airway closing pressure in males who habitually snored but were otherwise healthy. We also observed that some of these snorers developed obstructive apneas. To explore this phenomenon in more detail, we measured the inspiratory resistance (R 1 ) and respiratory drive after bedtime ethanol in 10 nonobese men (ages 23 to 33) with no history of snoring. Subjects went to bed wearing a tightly fitting valved mask over the nose and mouth that allowed measurement of inspiratory and expiratory flow, pressure in the mask, and endtidal CO 2 . We measured R 1 by calculating the pressure difference between the mouth and a balloon positioned in the midesophagus. Respiratory drive was quantified by the inspiratory occlusion pressure (P 0.1 ), the ventilatory response to hyperoxic hypercapnia (ΔV̇E/ΔP ET CO 2 ), and the ventilatory response to isocapnic hypoxia (ΔV̇E/ΔS a O 2 ). Measurements were made during waking and during stage 2 NREM sleep on two nights: (1) when the subjects drank 1.5 ml/kg of 100 proof vodka in orange juice over a 30-min period 15-45 min before lights out and (2) when the orange juice contained less than 0.1 ml of vodka floating on the top. Eight of the nine men in whom we had technically adequate measurements showed a rise in R 1 during NREM sleep above the waking level on both control and ethanol nights and the sleeping R 1 was greater on the ethanol than on the control night. There was a tendency for P 0.1 to be higher during sleep and greater on the ethanol night, suggesting that the neural output to the respiratory muscles was not depressed and may have been stimulated by the inspiratory "loading" secondary to the increased R 1 . The hypercapnic response was significantly depressed during sleep. Whereas the response tended to be less on the ethanol than on the control night, the difference was not significant. The hypoxic response showed little change from waking to sleeping and no significant change with ethanol. We speculate that inspiratory loading due to increased upper airway resistance tends to stimulate respiratory drive and thereby partially offsets the depressant effect of ethanol on the central respiratory chemoreceptors. Keywords Ethanol; Respiratory Drive; Sleep; Upper Airway ResistanceThe depressant effect of ethanol on respiratory drive has been recognized for many years. 1-4 More recently, we and others have shown that moderate doses of ethanol taken at bedtime can have another deleterious effect on respiration by increasing the upper airway resistance. Ethanol increases snoring in men who snore and worsens the severity of apneic episodes in patients with obstructive sleep apnea. 1,5-9 However, there are no data examining the effects of ethanol on inspiratory resistance in nonsnorers whose upper airway remains relatively patent during sleep. This study was done to characterize and analyze the magnitude of changes in inspiratory resistance and respiratory drive after a group of norm...