Respiratory mechanics in adult rats hypoxic in the neonatal period

Newborn rats were exposed to 10% O2 from 24 h to 6 days after birth, then returned to normoxia and examined at 50 days of age, i.e., after reaching sexual maturity. Despite the important impairment in somatic growth during hypoxia, at 50 days body weight and nose-tail length were as in control rats never exposed to hypoxia. Hypoxic rats had a bigger chest, with larger anteroposterior diameter, larger surface area of the muscle component of the diaphragm, and heavier and more expanded lungs. None of these structural changes were observed in a third group of rats, which were exposed for 6 days to hypoxia between 35 and 42 days of age, i.e., at a much more advanced stage of postnatal development. In addition, hypoxic rats had higher compliance of the respiratory system and of the lung and lower total pulmonary resistance than control rats. Frequency dependence of compliance was not different. We conclude that in the rat the structural changes induced by neonatal chronic hypoxia are not resolved by the return to normoxia but persist at least until postpuberty with modifications of the mechanical properties of the respiratory system.     

Respiratory adaptation to chronic hypercapnia in newborn rats

We asked 1) whether newborn rats respond to chronic hypercapnia with a persistent increase in ventilation and 2) whether changes in lung mass were accompanying the respiratory adaptation to chronic hypercapnia, as previously observed during neonatal chronic hypoxia. Five litters of rats were kept in 7% CO2 (with 21% O2) from day 1 to 7 after birth (CO2exp) and compared with six litters of control rats growing in normocapnia-normoxia (C). Body weight was similar between the two groups. Ventilation, measured by flow plethysmography, increased in CO2exp from day 2 and remained steadily elevated, and at day 7 it almost doubled (174%) the C value because of the large increase in tidal volume and mean inspiratory flow (192 and 189%, respectively) with no changes in respiratory frequency. Two days after return to normocapnia, ventilation was still 33% higher than in C; at this time, acute exposure to hypercapnia increased ventilation relatively less in the CO2exp than in C because of a lower increase in tidal volume. Neither the lung weight-to-body weight nor the heart weight-to-body weight ratios increased in CO2exp. We conclude that 1) chronic hypercapnia in newborn rats induces a steady increase in ventilation, which persists at least 2 days after return to normocapnia with a reduction in the acute response to CO2, and 2) hyperventilation per se is not the cause of the increased lung mass observed during chronic neonatal hypoxia.     

Ventilatory effects of impaired glial function in a brain stem chemoreceptor region in the conscious rat.

Glia are thought to regulate ion homeostasis, including extracellular pH; however, their role in modulating central CO2 chemosensitivity is unclear. Using a push-pull cannula in chronically instrumented and conscious rats, we administered a glial toxin, fluorocitrate (FC; 1 mM) into the retrotrapezoid nucleus (RTN), a putative chemosensitive site, during normocapnia and hypercapnia. FC exposure significantly increased expired minute ventilation (VE) to a value 38% above the control level during normocapnia. During hypercapnia, FC also significantly increased both breathing frequency and expired VE. During FC administration, maximal ventilation was achieved at approximately 4% CO2, compared with 8-10% CO2 during control hypercapnic trials. RTN perfusion of control solutions had little effect on any ventilatory measures (VE, tidal volume, or breathing frequency) during normocapnic or hypercapnic conditions. We conclude that unilateral impairment of glial function in the RTN of the conscious rat results in stimulation of respiratory output.     

Oxygen dependency and precision of cytochrome oxidase signal from full spectral NIRS of the piglet brain

Oxidation changes of the copper A (Cu(A)) center of cytochrome oxidase in the brain were measured during brief anoxic swings at both normocapnia and hypercapnia (arterial PCO(2) approximately 55 mmHg). Hypercapnia increased total hemoglobin from 37.5 +/- 9.1 to 50.8 +/- 12.9 micromol/l (means +/- SD; n = 7), increased mean cerebral saturation (Smc(O(2))) from 65 +/- 4 to 77 +/- 3%, and oxidized Cu(A) by 0.43 +/- 0.23 micromol/l. During the onset of anoxia, there were no significant changes in the Cu(A) oxidation state until Smc(O(2)) had fallen to 43 +/- 5 and 21 +/- 6% at normocapnia and hypercapnia, respectively, and the maximum reduction during anoxia was not significantly different at hypercapnia (1.49 +/- 0.40 micromol/l) compared with normocapnia (1.53 +/- 0.44 micromol/l). Residuals of the least squares fitting algorithm used to convert near-infrared spectra to concentrations are presented and shown to be small compared with the component of attenuation attributed to the Cu(A) signal. From these observations, we conclude that there is minimal interference between the hemoglobin and Cu(A) signals in this model, the Cu(A) oxidation state is independent of cerebral oxygenation at normoxia, and the oxidation after hypercapnia is not the result of increased cerebral oxygenation.     

Persistent airway hyperresponsiveness after neonatal viral bronchiolitis in rats.

Viral bronchiolitis in human infants has been associated with permanent changes in small airways and gas exchange and an increased incidence of hyperresponsive airways later in life. Respiratory infection by Sendai virus in neonatal rats also has been reported to cause permanent changes in lung morphology and increased numbers of bronchiolar mast cells and eosinophils. We evaluated pulmonary mechanics, gas exchange, and airway responsiveness in rats at 7 and 13-16 wk after neonatal Sendai virus infection. Rats from the virus group had lower arterial PO2 and increased total lung resistance compared with controls. There were no significant differences between groups for arterial PCO2, dynamic lung compliance, quasi-static respiratory system compliance, or vital capacity. Rats from the infected group were significantly more sensitive to aerosolized methacholine than were controls, although both virus and control groups became less sensitive with age. We conclude that neonatal Sendai virus infection in rats results in persistent alterations in lung function and airway responsiveness. This phenomenon may be valuable for the study of the relationships among airway inflammation, lung morphology, and airway hyperresponsiveness, and it may be relevant to human airway disease.     

Frequency-dependent effects of hypercapnia on respiratory mechanics of cats

The effect of increasing arterial partial pressure of CO2 (PaCO2) on respiratory mechanics was investigated in six anesthetized, paralyzed cats ventilated by constant-flow inflation. Respiratory mechanics were studied after end-inspiratory occlusions. Zero frequency resistance (Rmax), infinite frequency resistance (Rmin), and static elastance (Est) were calculated for the respiratory system, lung, and chest wall. Alveolar ventilation was manipulated by the addition of dead space to achieve a range of PaCO2 values of 29.3-87.3 mmHg. Cats did not become hypoxic during the experiment. Under control conditions marked frequency dependence in Rmax, Rmin, and Est of the respiratory system, lungs, and chest wall was demonstrated. The chest wall contributed 50% of the total resistance of the respiratory system. With increasing PaCO2 the only resistance observed to increase was Rmax of the lung (P less than 0.01). There were also no changes in the static elastic properties of either the lungs or the chest wall. These results suggest that hypercapnia increases resistance by changes in the lung periphery and not in the conducting airways.     

Cyclooxygenase-pathway participates in the regulation of regional cerebral blood flow in response to neuronal activation under normo- and hypercapnia

The present study was designed to investigate whether cyclooxygenase products are involved in the regulation of the regional cerebral blood flow, evoked by somatosensory activation (evoked rCBF) under normo- and hypercapnia. Indomethacin (IMC) was used as cyclooxygenase inhibitor. It was applied intravenously (i.v., 10 mg/kg/h) in two experimental protocols-before hypercapnia (i) and after hypercapnia (ii). Somatosensory activation was induced by electrical hind paw stimulation (5 Hz frequency, 5 s duration, 1.5 mA). The evoked rCBF-response was measured in alpha -chloralose anesthetized rats using laser-Doppler flowmetry. IMC abolished completely the effect of hypercapnia on the baseline level of CBF. The drug reduced significantly evoked rCBF-response also. The inhibitory effect of IMC on evoked rCBF-response is better expressed under normocapnia (approximately 70%) than that under hypercapnia (approximately 40%). After IMC application, the normalized evoked rCBF curves peaked earlier as compared to that before its application (P<0.05), although the rise time of 0.5 s was nearly constant regardless of stimulus frequency. In conclusion, the results suggest a participation of IMC-sensitive and cyclooxygenase-dependent mechanisms in the regulation of evoked rCBF, induced by somatosensory stimulation.     

Direct measurement of static chest wall compliance in animal and human neonates

The measurement of pulmonary mechanics has been developed extensively for adults, and these techniques have been applied directly to neonates and infants. However, the compliant chest wall of the infant frequently predisposes to chest wall distortion, especially when there is a low dynamic lung compliance (CL,dyn). We describe a technique of directly measuring the static chest wall compliance (Cw,st), developed initially in the newborn lamb and subsequently applied to the premature neonate with chest wall distortion. The mean CL,dyn in seven intubated newborn lambs in normoxia was 2.45 +/- 0.41 ml.cmH2O-1.kg-1, whereas Cw,st was 11.81 +/- 0.25 ml.cmH2O-1.kg-1. These values did not change significantly in seven animals breathing through a tight-fitting face mask or with hypercapnia-induced tachypnea. For the eight premature infants the mean CL,dyn was 1.35 +/- 0.36 ml.cmH2O-1.kg-1, whereas the mean Cw,st was 3.16 +/- 1.01 ml.cmH2O-1.kg-1. This study shows that, under relaxed conditions when measurements of static compliance are performed, the chest wall is more compliant than the lung. The measurement of Cw,st may thus be used to determine the contribution of the respiratory musculature in stabilizing the chest wall.     

Indomethacin does not potentiate renovascular constriction during hypercapnia in unanesthetized rabbits

The role of prostanoids in regulation of the renal circulation during hypercapnia was examined in unanesthetized rabbits. Renal blood flow (RBF) was determined with 15 micron radioactive microspheres during normocapnia (PaCO2 congruent to 30 mmHg) and hypercapnia (PaCO2 congruent to 60 mmHg), before and after intravenous administration of indomethacin (10 mg/kg) or vehicle (n = 6 for each group). Arterial blood pressure was not different among the 4 conditions in each group. RBF was 438 +/- 61 and 326 +/- 69 (P less than 0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before indomethacin, and following administration of indomethacin, RBF was 426 +/- 59 ml/min per 100 g during normocapnia and 295 +/- 60 ml/min per 100 g during hypercapnia (P less than 0.05). In the vehicle group, RBF was 409 +/- 74 and 226 +/- 45 (P less than 0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before vehicle; and following administration of vehicle, RBF was 371 +/- 46 ml/min per 100 g during normocapnia and 219 +/- 50 (P less than 0.05) ml/min per 100 g during hypercapnia. RBF during normocapnia was not affected by administration of indomethacin or vehicle. The successive responses to hypercapnia were not different within the indomethacin and vehicle groups, and the second responses to hypercapnia were not different between the two groups. These findings suggest that prostanoids do not contribute significantly to regulation of the renal circulation during normocapnia and hypercapnia in unanesthetized rabbits.     

Increased ventilation does not impair maximal voluntary contractions of the elbow flexors.

Exercise performance is impaired by increased respiratory work, yet the mechanism for this is unclear. This experiment assessed whether neural drive to an exercising muscle was affected by cortically driven increases in ventilation. On each of 5 days, eight subjects completed a 2-min maximal voluntary contraction (MVC) of the elbow flexor muscles, followed by 4 min of recovery, while transcranial magnetic stimulation tested for suboptimal neural drive to the muscle. On 1 day, subjects breathed without instructions under normocapnia. During the 2-min MVC, ventilation was approximately 3.5 times that at rest. On another day, subjects breathed without instruction under hypercapnia. During the 2-min MVC, ventilation was approximately 1.5 times that on the normocapnic day. On another 2 days under normocapnia, subjects voluntarily matched their breathing to the uninstructed breathing under normocapnia and hypercapnia using target feedback of the rate and inspiratory volume. On a fifth day under normocapnia, the volume feedback was set to each subject's vital capacity. On this day, ventilation during the 2-min MVC was approximately twice that on the uninstructed normocapnic day (or approximately 7 times rest). The experimental manipulations succeeded in producing voluntary and involuntary hyperpnea. However, maximal voluntary force, fatigue and voluntary activation of the elbow flexor muscles were unaffected by cortically or chemically driven increases in ventilation. Results suggest that any effects of increased respiratory work on limb exercise performance are not due to a failure to drive both muscle groups optimally.     

Dopaminergic modulation of ventilation in obese Zucker rats.

To investigate the hypothesis that the impaired respiratory drive noted in morbid obesity was attributable to altered dopaminergic mechanisms acting on peripheral and/or central chemoreflex sensitivity, seven obese and seven lean Zucker rats were studied at 11 wk of age. Ventilation (VE) was measured by the barometric technique during hyperoxic (100% O(2)), normoxic (21% O(2)), hypoxic (10% O(2)), and hypercapnic (7% CO(2)) exposures after the administration of vehicle (control), haloperidol [Hal, 1 mg/kg, a central and peripheral dopamine (Da) receptor antagonist], or domperidone (Dom, 0.5 mg/kg, a peripheral Da receptor antagonist). In both lean and obese rats, Hal increased tidal volume and decreased respiratory frequency during hyperoxia or normoxia, resulting in an unchanged VE. In contrast, Dom did not affect tidal volume, frequency, or VE during hyperoxia or normoxia. During hypoxia, however, VE significantly increased from 1,132 +/- 136 to 1,348 +/- 98 ml. kg(-1). min(-1) (P < 0.01) after the administration of Dom in obese rats, whereas no change was observed in lean rats. Hal significantly decreased VE during hypoxia compared with control in lean but not obese rats. In both lean and obese rats, Hal decreased VE in response to hypercapnia, whereas Dom had no effect. Our major findings suggest that peripheral chemosensitivity to hypoxia in obese Zucker rats is reduced as a result of an increased dopaminergic receptor modulation in the carotid body.     

Role of the carotid bodies in chemosensory ventilatory responses in the anesthetized mouse.

We examined the effects of carotid body denervation on ventilatory responses to normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90 and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements were made with a whole body, single-chamber plethysmograph before and after cutting both carotid sinus nerves. Baseline measurements in air showed that carotid body denervation was accompanied by lower minute ventilation with a reduction in respiratory frequency. On the basis of measurements with an open-circuit system, no significant differences in O2 consumption or CO2 production before and after chemodenervation were found. During both levels of hypoxia, animals with intact sinus nerves had increased respiratory frequency, tidal volume, and minute ventilation; however, after chemodenervation, animals experienced a drop in respiratory frequency and ventilatory depression. Tidal volume responses during 15% hypoxia were similar before and after carotid body denervation; during 10% hypoxia in chemodenervated animals, there was a sudden increase in tidal volume with an increase in the rate of inspiration, suggesting that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were lower with a smaller tidal volume after chemodenervation than before. We conclude that the carotid bodies are essential for maintaining ventilation during eupnea, hypoxia, and hypercapnia in the anesthetized mouse.     

Effect of carbon dioxide on neonatal mouse lung: a genomic approach.

Despite the deleterious effects associated with elevated carbon dioxide (CO(2)) or hypercapnia, it has been hypothesized that CO(2) can protect the lung from injury. However, the effects of chronic hypercapnia on the neonatal lung are unknown. Hence, we investigated the effect of chronic hypercapnia on neonatal mouse lung to identify genes that could potentially contribute to hypercapnia-mediated lung protection. Newborn mouse litters were exposed to 8% CO(2), 12% CO(2), or room air for 2 wk. Lungs were excised and analyzed for morphometric alterations. The alveolar walls of CO(2)-exposed mice appeared thinner than those of controls. Analyses of gene expression differences by microarrays revealed that genes from a variety of functional categories were differentially expressed following hypercapnia treatment, including those encoding growth factors, chemokines, cytokines, and endopeptidases. In particular and of major interest, the expression level of genes encoding surfactant proteins A and D, as well as chloride channel calcium-activated 3, were significantly increased, but the expression of WNT1-inducible signaling pathway protein 2 was significantly decreased. The significant changes in gene expression occurred mostly at 8% CO(2), but only a few at 12% CO(2). Our results lead us to conclude that 1) there are a number of gene families that may contribute to hypercapnia-mediated lung protection; 2) the upregulation of surfactant proteins A and D may play a role as anti-inflammatory or antioxidant agents; and 3) the effects of CO(2) seem to depend on the level to which the lung is exposed.     

Ventilatory chemosensitivity of the 1-day-old chicken hatchling after embryonic hypoxia

We investigated the effects of sustained embryonic hypoxia on the neonatal ventilatory chemosensitivity. White Leghorn chicken eggs were incubated at 38 degrees C either in 21% O(2) throughout incubation (normoxia, Nx) or in 15% O(2) from embryonic day 5 (hypoxia, Hx), hatching time included. Hx embryos hatched approximately 11 h later than Nx, with similar body weights. Measurements of gaseous metabolism (oxygen consumption, Vo(2)) and pulmonary ventilation (Ve) were conducted either within the first 8 h (early) or later hours (late) of the first posthatching day. In resting conditions, Hx had similar Vo(2) and body temperature (Tb) and slightly higher Ve and ventilatory equivalent (Ve/Vo(2)) than Nx. Ventilatory chemosensitivity was evaluated from the degree of hyperpnea (increase in Ve) and of hyperventilation (increase in Ve/Vo(2)) during acute hypoxia (15 and 10% O(2), 20 min each) and acute hypercapnia (2 and 4% CO(2), 20 min each). The chemosensitivity differed between the early and late hours, and at either time the responses to hypoxia and hypercapnia were less in Hx than in Nx because of a lower increase in Ve and a lower hypoxic hypometabolism. In a second group of Nx and Hx hatchlings, the Ve response to 10% O(2) was tested in the same hatchlings at the early and late hours. The results confirmed the lower hypoxic chemosensitivity of Hx. We conclude that hypoxic incubation affected the development of respiratory control, resulting in a blunted ventilatory chemosensitivity.     

Compliances of the liquid-filled lungs and chest wall during development in fetal sheep.

Our aim was to measure the compliance of the liquid-filled lungs (CL), and the compliance of the chest wall (CW) in fetal sheep in utero. CL and CW were measured in 6 fetuses. The compliance of the lungs and chest wall combined (respiratory system, Crs) was measured in 9 fetuses. Pressure differences across the lungs (PL), chest wall (PW) and respiratory system (Prs) were measured while the lungs were deflated and inflated with liquid from their resting lung liquid volume (V1). V1 was measured using an indicator dilution technique. Specific compliance values were obtained by normalizing the values of CL, CW and Crs with respect to values of V1. From values obtained during stepwise inflation from V1, specific compliances (ml/cm H2O/ml of lung liquid) were: lungs, 0.22 +/- 0.02; chest wall, 0.41 +/- 0.07; respiratory system, 0.13 +/- 0.01. Specific compliances of the lungs, chest wall and respiratory system did not change significantly with advancing gestational age from 120 to 143 days. Our baseline data will be valuable in assessing the in utero progress of the structural development of the lungs following manipulations known to cause altered lung growth.     

Thermal and respiratory control in young rats exposed to cold during postnatal development

We questioned to what extent sustained increases in metabolic rate during the neonatal period may influence the development of thermal and respiratory control. Male rats were exposed to cold (14 degrees C) for the first 3 weeks, which increased metabolic rate with small effects on body growth. Measurements were performed at 1 month of age, when the body weight of the Cold group averaged approximately 88% of Controls. In Cold rats, the concentration of the uncoupling protein of the brown adipose tissue was increased. Acute exposures to different ambient temperatures (5, 15, 25 and 35 degrees C) provoked changes in body temperature similar in Cold and in Control rats. At these temperatures, small differences in the absolute values of oxygen consumption (Vdot;(O(2))) between the two groups could be explained by the differences in body weight. Hematocrit and lung weight of Cold rats were as in Controls, but the lung protein-DNA ratio was increased because of a drop in lung cellularity. The resting ventilation-oxygen consumption ratio (Vdot;(E)/Vdot;(O(2))) was similar between Cold and Controls. Also the changes in Vdot;(O(2)) and Vdot;(E) during acute hypoxia (10% O(2)) or hypercapnia (5% CO(2)), and the corresponding hyperventilatory responses (increases in Vdot;(E)/Vdot;(O(2))) did not significantly differ between the two groups. In conclusion, in the rat, the increased metabolic requirements caused by cold exposure during the early postnatal phases improved the thermogenic capacity, while having negligible impact on the development of respiratory control.     

Respiratory function in lambs after in utero treatment of lung hypoplasia by tracheal obstruction.

Tracheal obstruction (TO) stimulates growth of hypoplastic lungs in the fetus, but there is little knowledge of subsequent postnatal respiratory function. We have determined the effectiveness of TO in fetal sheep with existing lung hypoplasia in restoring postnatal respiratory function. Lung hypoplasia was induced by lung liquid drainage from 112 days of gestation to term ( approximately 148 days). We used an untreated group (ULH), a treated group (TLH) in which the trachea was obstructed for 10 days, and a control group. ULH lambs died within 4 h of birth. TLH lambs were hypoxic for the first week and were hypercapic at 2 days. Pulmonary diffusing capacity, gas volumes, and respiratory compliances were not different between control and TLH lambs. Minute ventilation was not different between the two groups; however, tidal volumes were lower and respiratory frequencies were higher in TLH lambs than in controls for 2 wk after birth. We conclude that 10 days of TO in the presence of initial lung hypoplasia prevents death at birth and returns most aspects of pulmonary function to normal by 1-2 wk after birth.     

CO2 relaxes parenchyma in the liquid-filled rat lung.

CO(2) regulation of lung compliance is currently explained by pH- and CO(2)-dependent changes in alveolar surface forces and bronchomotor tone. We hypothesized that in addition to, but independently of, those mechanisms, the parenchyma tissue responds to hypercapnia and hypocapnia by relaxing and contracting, respectively, thereby improving local matching of ventilation (Va) to perfusion (Q). Twenty adult rats were slowly ventilated with modified Krebs solution (rate = 3 min(-1), 37 degrees C, open chest) to produce unperfused living lung preparations free of intra-airway surface forces. The solution was gassed with 21% O(2), balance N(2), and CO(2) varied to produce alveolar hypocapnia (Pco(2) = 26.1 +/- 2.4 mmHg, pH = 7.56 +/- 0.04) or hypercapnia (Pco(2) = 55.0 +/- 2.3 mmHg, pH = 7.23 +/- 0.02). The results show that lung recoil, as indicated from airway pressure measured during a breathhold following a large volume inspiration, is reduced approximately 30% when exposed to hypercapnia vs. hypocapnia (P < 0.0001, paired t-test), but stress relaxation and flow-dependent airway resistance were unaltered. Increasing CO(2) from hypo- to hypercapnic levels caused a substantial, significant decrease in the quasi-static pressure-volume relationship, as measured after inspiration and expiration of several tidal volumes, but hysteresis was unaltered. Furthermore, addition of the glycolytic inhibitor NaF abolished CO(2) effects on lung recoil. The results suggest that lung parenchyma tissue relaxation, arising from active elements in response to increasing alveolar CO(2), is independent of (and apparently in parallel with) passive tissue elements and may actively contribute to Va/Q matching.     

Sigmoidal equation for lung and chest wall volume-pressure curves in acute respiratory failure.

To assess incidence and magnitude of the "lower inflection point" of the chest wall, the sigmoidal equation was used in 36 consecutive patients intubated and mechanically ventilated with acute lung injury (ALI). They were 21 primary and 5 secondary ALI, 6 unilateral pneumonia, and 4 cardiogenic pulmonary edema. The lower inflection point was estimated as the point of maximal compliance increase. The low constant flow inflation method and esophageal pressure were used to partition the volume-pressure curves into their chest wall and lung components on zero end-expiratory pressure. The sigmoidal equation had an excellent fit with coefficients of determination >0.90 in all instances. The point of maximal compliance increase of the chest wall ranged from 0 to 8.3 cmH2O (median 1 cmH2O) with no difference between ALI groups. The chest wall significantly contributed to the lower inflection point of the respiratory system in eight patients only. The occurrence of a significant contribution of the chest wall to the lower inflection point of the respiratory system is lower than anticipated. The sigmoidal equation is able to determine precisely the point of the maximal compliance increase of lung and chest wall.     

Acid aspiration increases sensitivity to increased ambient oxygen concentrations

Previously we have demonstrated that prolonged exposure to 100% ambient oxygen leads to a marked loss in functional lung volume and lung compliance, hypoxemia, and surfactant system abnormalities similar to acute respiratory distress syndrome (ARDS). However, 50% oxygen administration is believed to be safe in most clinical settings. In the present study, we have evaluated the effects of a 24-h exposure to 50% oxygen in rabbits immediately following experimental gastric acid aspiration. Mild hypoxemia, but no changes in mortality, lung volume, lung compliance, surfactant metabolism, or edema formation occurred after 24 h of normoxia postacid aspiration. Conversely, a relatively short (24-h) exposure to 50% oxygen after acid aspiration results in increased pulmonary edema, physical signs of respiratory distress, and mortality, as well as decreased arterial oxygenation, lung volume, lung compliance, and type II alveolar cell surfactant synthesis. These results suggest that acid aspiration alters the "set point" for oxygen toxicity, possibly by "priming" cells through activation of inflammatory pathways. This pathogenic mechanism may contribute to the progression of aspiration pneumonia to ARDS.