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Pharmacodynamic evaluation of azelastine in subjects with asthma.

A broad antiallergic compound called azelastine was studied pharmacodynamically in 34 subjects to correlate bronchodilator effect with blood levels of azelastine and desmethyl azelastine, its major metabolic product in man. Despite azelastine and desmethyl azelastine blood levels that were proportionate to the dosage range, the bronchodilator effect as measured by FEV1 and forced expiratory flow rate between 25% and 75% of FVC was proportionately greater with 4 mg of azelastine during the 8-hour study period than the anticipated bronchodilator response with the 8 and 16 mg doses. Azelastine, already proven effective in allergic rhinitis, has a bronchodilator effect at doses that do not produce intolerable side effects.

Adolescent↗

Prolonged endurance challenge at moderate altitude: effect on serum eosinophil cationic protein, eosinophil dynamics, and lung function.

BACKGROUND: Eosinophils contain granule proteins such as eosinophil cationic protein (ECP) that have proinflammatory effects on airways. ECP may be released on activation of eosinophils into the plasma and is widely used as a marker of bronchial hyperreactivity and allergic inflammation. Environmental factors as well as intense physical exertion may influence eosinophil-related bronchial hyperreactivity. STUDY OBJECTIVES: To investigate the effect of endurance exercise at moderate altitude on levels of circulating eosinophils, serum ECP, serum osmolality (sOS), and dynamic pulmonary function parameters in healthy mountaineers. SETTING: Alpine field study performed in the Alps of Upper Styria in Austria. Type of exercise: Ascent of a mountain at maximal speed. PARTICIPANTS: Thirty healthy male volunteers from a troop of military mountaineers. RESULTS: Mean ECP concentration increased by 66% at the summit checkpoint (H2) and remained at 63% above baseline (base checkpoint [H0]) after descent (H4), while the blood eosinophil count decreased concomitantly from 250/microL at H0 (preexercise) to 118/microL (53%) at H2 and to 22/microL (81%) at H4. The total serum ECP concentration adjusted to sOS correlated negatively with blood eosinophil count (r = - 0.37; p < 0.0001) and PaO(2) (r = - 0.34; p < 0.001), but positively with the peak expiratory flow (PEF) [r = 0.45; p < 0.0001]. Although sOS correlated with serum ECP at H2 (r = 0.47; p = 0.02) and at 12 h after the start of the experiment (H12) [r = 0.57; p = 0.003], the relationship between total ECP and sOS (r = 0.19; p = 0.034) was less pronounced. FEV(1) in percentage of FVC (%FEV(1)/FVC) [the Tiffenau test], forced expiratory flow rate at 25% of vital capacity, and PEF were significantly higher at H2 than at H0 and H4. %FEV(1)/FVC decreased to 88% (p < 0.01) and 83% (p < 0.001) predicted at H12 and 24 h after start of the experiment, respectively. CONCLUSION: Results provide strong evidence for nonspecific activation of blood eosinophils during prolonged intense aerobic exercise at moderate altitude, modifying both eosinophil dynamics and regulation of ECP release in healthy subjects.

Adult↗

[Effects of acupuncture on clinical symptoms and pulmonary function in the patient of bronchial asthma].

OBJECTIVE: To explore the clinical therapeutic effect of acupuncture on bronchial asthma. Methods One hundred and four cases of asthma at persistent period and remission stage were divided into a treatment group and a control group with stratified random method of illness degrees. The treatment group were treated with antiasthma agents plus acupuncture at Quchi (LI 11), Lieque (LU 7), Yuji (LU 10), Neiguan (PC 6), Zusanli (ST 36), Sanyinjiao (SP 6), Taixi (KI 3), once each day, 10 sessions constituting one course, and the control group with anti-asthma agents at the same dose. Changes of clinical symptoms and pulmonary function after treatment were investigated. Results Clinical symptoms significantly improved, the score for asthma symptoms decreased and the wheeze in the lung reduced, severity and grading of the disease significantly improved in the treatment group with significant differences as compared with those in the control group (all P< 0.05). And the first second forced expiratory volume (FEV1), peak of forced expiratory flow rate (PEF), FEF(25%-75%) (% PRED), FEF(75%-85%) (% PRED), FEF50% (%PRED), FEF75% (% PRED) more significantly improved in the treatment group than in the control group (P < 0.05 or P < 0.01 or P < 0.001). Six months later, the incidence rate of asthma acute attack in the treatment group was lower than that in the control group (P < 0.05), and the dose of anti-asthma agents in the 50% of patients in the treatment group was reduced by 1/3-1/4. CONCLUSION: Acupuncture can improve clinical symptoms and pulmonary function and reduce the dose of anti-asthma agents, and has a certain long-term therapeutic effect.

Acupuncture Therapy↗

Double-blind, dose-response study of metaproterenol inhalant solution in children with acute asthma.

One hundred children, aged 6 to 12 years, with acute asthma received nebulized therapy with saline, 5, 10, or 15 mg of metaproterenol aerosol solution according to a prerandomized, double-blind protocol. Pulmonary function and cardiac function were assessed for 60 minutes. All patients then received 5 mg of metaproterenol aerosol solution, and observation continued for another 30 minutes. The best response to therapy in terms of rise in FEV1, forced expiratory flow rate between 25% and 75% of FVC, and area under the curve (change in lung function with time) occurred with 5 and 10 mg of metaproterenol. The highest dose, 15 mg, produced significantly less bronchodilation. Although there were no electrocardiographic abnormalities, pulse rate was significantly higher with 10 and 15 mg of metaproterenol than with 5 mg. Five milligrams of metaproterenol aerosol solution is the optimal bronchodilating dose for treating acute asthma in children. Repeating this dose provides some additional bronchodilation and is well tolerated.

Administration, Inhalation↗

Single-dose efficacy and safety of zindotrine, a new oral bronchodilator.

Zindotrine, a new bronchodilator, may be an alternative to theophylline in treating reversible airflow obstruction. Efficacy and cardiovascular effects of a single 300 mg oral dose of zindotrine were compared with placebo in a two-period, double-blind, crossover trial. Twelve subjects with airflow obstruction reversible after isoproterenol and theophylline completed the trial. Improvement in pulmonary function (forced vital capacity [FVC], forced expiratory volume in one second, and forced expiratory flow rate from 25 to 75 percent of FVC) was greater after zindotrine than with placebo. Pulmonary function tests increased 15 percent or more over baseline in 30 minutes after active drug, lasting up to 6 hours. Mild decreases in heart rate and mean blood pressure occurred after both treatments, with changes equal in both treatment groups. Six subjects had mild subjective side effects after zindotrine (headache, dizziness, vertigo, flushing, and heartburn) compared with one report of lightheadedness after placebo. A single dose of zindotrine 300 mg provides effective bronchodilator action with a relatively prolonged response and tolerable side effects.

Adult↗

Azlocillin compared with carbenicillin in the treatment of bronchopulmonary infection due to Pseudomonas aeruginosa in cystic fibrosis.

A randomised controlled open comparison of azlocillin and gentamicin versus carbenicillin and gentamicin was carried out in patients with cystic fibrosis who were chronically infected with Pseudomonas aeruginosa. The clinical response was assessed by measurements of pulmonary function and of the patients' feelings of wellbeing scored on a visual analogue scale. The sputum penetration of the antibiotics used was also studied. The two groups of 10 patients were similar in terms of age, sex, and pulmonary function at entry to the trial. Both regimens produced significant improvement in pulmonary function over 10 days. The mean FEV1 in the azlocillin group increased from 1206 to 1760 ml (p less than 0.001). In the carbenicillin group the mean FEV1 increased from 1116 to 1619 ml (p less than 0.001). Significant improvements in peak expiratory flow rate, forced vital capacity, and score on the visual analogue scale were also seen but there was no significant difference between the antibiotic regimens. Despite high serum concentrations the sputum penetration of the antibiotics was poor.

Adolescent↗

Comparison of Flutter device and chest physical therapy in the treatment of cystic fibrosis pulmonary exacerbation.

Chest physiotherapy (CPT) is recommended for the clearance of bronchial secretions in the management of patients with cystic fibrosis (CF). The Flutter valve (Scandipharm, Birmingham, AL) has been introduced as an alternative method to CPT for airway mucus clearance. The objective of this study was to compare the short-term effects of CPT and the Flutter valve on pulmonary function and exercise tolerance in patients with cystic fibrosis. Twenty-three patients, 5 to 21 years of age, were randomized to receive one of two interventions: CPT or the Flutter valve, upon admission to the hospital for a 2-week treatment of pulmonary exacerbation. Pulmonary function testing (PFTs) and the 6-min walk test were performed on admission, day 7, and day 14 of hospitalization. Data analysis indicated no significant differences between the two groups on admission. Both groups showed improvement in pulmonary function test results, but the Flutter group had a higher mean forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV(1)) compared to the CPT group after 1 week of intervention. Both groups continued to improve during the 2-week intervention, with no significant difference in FVC or FEV(1) between groups by the end of 2 weeks. Mean forced expiratory flow rate between 25-75% of vital capacity (FEF(25-75)), 6-min walk distance, and resting arterial oxyhemoglobin saturation (SaO(2)) showed little change by day 7, but improved significantly (P< 0.05) by day 14 of hospitalization in both groups, with no significant difference between groups. This study demonstrated that patients using the Flutter device had better pulmonary function after 1 week of therapy and similar improvement in pulmonary function and exercise tolerance compared to CPT after 2 weeks of therapy, suggesting that Flutter valve therapy is an acceptable alternative to standard CPT during in-hospital care of patients with CF.

Adolescent↗

Exercise-induced anaphylaxis as a manifestation of cholinergic urticaria.

Two patients presented with a history of exercise-induced hypotension associated with severe pruritus and either generalized urticaria or facial angioedema. Each patient was exercised under controlled conditions with use of bicycle ergometer exerciser (900 KPM/min) for 20 to 30 min at 23 degrees C. Each patients complained of generalized pruritus and then erupted in lesions typical of cholinergic urticaria. In one patient the lesions became confluent about the face and were followed by eyelid edema, lip swelling, and transient hypotension. Plasma histamine levels were elevated in each patient and reached a maximal level between 20 and 25 min. Neither patient had a change in forced expiratory volume in one second during the episode and detailed pulmonary function testing in one patient revealed no change in airway resistance, specific conductance, forced expiratory vital capacity, or forced expiratory flow rates. One patient had a positive methacholine chloride (Mecholyl) skin test with satellite lesions, and the second patient was skin-test negative. The skin test-positive patient, who was not hypotensive when initially challenged, was strenuously exercised for 15 min/day. Progressively less severe reactions were seen associated with diminished histamine release, and the patient is now on a daily exercise program; symptoms in the second patient are controlled with hydroxazine. Our results indicate that some patients with the exercise-induced anaphylactic syndrome are unusual examples of severe cholinergic urticaria. Furthermore, the utility of a regular exercise program as part of the management of some patients with cholinergic urticaria requires further investigation.

Adult↗

The effects of underrecorded forced expirations on spirometric lung function indexes.

A problem with short recorded lengths of expiration, encountered in a large heart attack intervention trial, illustrates the importance of standardization and training in spirometric lung function testing. At baseline, half of the trial's clinical centers had mean FVC values that were between 500 and 1,100 ml below those predicted for these centers. To quantify the effects of underrecorded forced expirations on the FVC, the FEV1/FVC%, the FEF70-80%, the FEF 25-75%, and the FEF45-55%, a study of 80 complete spirograms of good quality was undertaken. The findings were that short lengths of expiration cause underrecording of the FVC, inflating all of the examined FVC-dependent spirometric indexes. The inflation was fairly uniform across all obstructions for the forced expiratory flow rates, but it increased markedly with level of obstruction for the FEV1/FVC%. Virtually no subjects exhibited low values of these spirometric indexes after 3 s of expiration, and the number of subjects with low values was still substantially underestimated after 6 s of expiration. Whereas 18 (23%) of the subjects had FEV1/FVC% greater than or equal to 80% and 21 (26%) had ratios less than or equal to 69% based on complete expiration, 60 (75%) of the subjects had ratios greater than or equal to 80% and only 2 (3%) had ratios less than or equal to 69%, after 3 s of expiration. Even after 6 s, 26 subjects (33%) had ratios greater than or equal to 80%, and only 10 (13%) had ratios less than or equal to 69%. Therefore, completely recorded expirations are essential for accurate measurement of the FVC-dependent spirometric indexes.

Adult↗

Dose response of inhaled gallopamil (D600), a calcium channel blocker, in attenuating airway reactivity to methacholine and exercise.

To determine if there is a dose-response relationship for calcium channel blockers in preventing experimentally induced bronchoconstriction, we evaluated the effects of inhaled gallopamil (D600), a potent methoxy derivative of verapamil, on airway reactivity to methacholine and exercise in volunteers with mild asthma. Methacholine challenges were completed by 11 subjects 2 hours before and 20 minutes after placebo, and 1, 2, 5, 10, and 20 mg of inhaled gallopamil administered in a single-blind, randomized manner on different days. Gallopamil did not significantly alter FVC, FEV1, or forced expiratory flow rate between 25% and 75% of FVC, but increased the dose of methacholine required to produce a 20% decrease in FEV1 from baseline (p less than 0.0001). The mean +/- SEM fold increase in the dose of methacholine required to produce a 20% decrease in FEV1 from baseline was 1.0 +/- 0.1 after placebo, 2.4 +/- 0.2 after 1 mg, 2.2 +/- 0.2 after 2 mg, 2.5 +/- 0.2 after 5 mg, 2.5 +/- 0.3 after 10 mg, and 2.3 +/- 0.2 after 20 mg. Thirty minutes before a standardized exercise challenge, 10 subjects inhaled 1 and 10 mg of gallopamil or placebo in a randomized, double-blind, crossover manner. The mean +/- SEM maximum decrease in FEV1 after exercise was 25.1 +/- 5% after 10 mg of gallopamil (p less than 0.01), 34.4 +/- 5% after 1 mg (p greater than 0.05), and 39.0 +/- 6% after placebo. We conclude that inhaled gallopamil only modestly alters airway reactivity to methacholine; increasing the dose greater than 1 mg did not provide greater benefit.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Lack of effectiveness of magnesium in chronic stable asthma. A prospective, randomized, double-blind, placebo-controlled, crossover trial in normal subjects and in patients with chronic stable asthma.

BACKGROUND: Magnesium sulfate has been helpful in the treatment of acute exacerbations of asthma. We hypothesized that magnesium would also be an effective bronchodilator in patients with chronic stable asthma. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled, crossover trial in 15 patients with chronic, stable asthma and 10 nonasthmatics. On study day 1, spirometry and albuterol challenge were used to confirm the presence of asthma according to American Thoracic Society criteria. On study day 2, subjects received intravenous magnesium sulfate (2 g) or placebo (saline). On study day 3, subjects were crossed over to receive the other drug. Spirometry was performed before, during, and after drug or placebo administration. Circulating ionized magnesium concentrations were determined before and after intravenous magnesium or placebo administration. RESULTS: Magnesium infusion caused no statistically significant changes in forced expiratory volume in 1 second (mean +/- SEM, 1.92 +/- 0.13 L before, 1.98 +/- 0.12 L during, and 2.01 +/- 0.14 L after magnesium administration), forced vital capacity (mean +/- SEM, 3.44 +/- 0.25 L before, 3.60 +/- 0.26 L during, and 3.59 +/- 0.25 L after magnesium administration), or maximum forced expiratory flow rate (mean +/- SEM, 5.42 +/- 0.44 L/second before, 5.46 +/- 0.46 L/second during, and 5.57 +/- 0.49 L/second after magnesium administration). Placebo caused no changes in these three physiologic variables. CONCLUSION: Magnesium is not effective as a bronchodilator in chronic, stable asthmatics or in normal non-asthmatic adults.

Adult↗

Longitudinal follow-up of lung function from childhood to adolescence in prematurely born patients with neonatal chronic lung disease.

We investigated whether early lung function abnormalities in prematurely born children with a history of chronic lung disease improve in late childhood and adolescence. We performed a prospective, longitudinal evaluations of pulmonary function over an 8 year period. In seventeen patients from the age (mean +/- SD) of 8.2 +/- 1.2 years to the age of 15.1 +/- 1.6 years. They had been born at 29.1 +/- 1.9 weeks of gestation, with a birthweight of 1120 +/- 190 g, and they had received supplemental oxygen, with or without mechanical ventilation, for 40.4 +/- 23.8 days during the neonatal period. They all had radiographic evidence of chronic lung disease at 4 weeks of age. Annual measurements of lung volumes using the helium dilution technique, and of airway function with spirometry and maximal expiratory flow-volume curves over a 5 to 8 year period, were obtained. The results indicated that total lung capacity (TLC) and vital capacity (VC) were within the predicted normal range in all patients and increased over time. In contrast, the initially abnormal residual volume (RV) and RV/TLC ratio decreased over time, suggesting gradual resolution of air-trapping. The peak expiratory flow rate (PEFR), forced expiratory volume in 1 second (FEV1), and the ratio FEV1/FVC remained at or above the predicted normal range in all patients. FEF25-75, FEF50, and FEF75 were within normal limits in eight patients and abnormally low (more than 2 SD below the predicted normal value) in the remaining nine patients, indicating small airway obstruction. Eight of the nine patients with lower airway obstruction showed significant response to inhaled bronchodilator, and four responded to a histamine challenge. None of the eight patients with normal airway function responded to histamine, but four responded to bronchodilators. The perinatal history, family history of asthma, and exposure to smoking were similar in patients with and without airway obstruction. The height and weight were and remained within the normal range. We conclude that gradual normalization of air-trapping continues well into adolescence in virtually all patients with a history of prematurity and chronic lung disease. in contrast, airflow obstruction may persist but does not get worse later in life. Although chronic airflow obstruction probably is the consequence of injury to the small airways during the neonatal period, it is present in only some of the children, and it does not appear to be directly related to the perinatal history. Finally, there is evidence that airway hyperresponsiveness may be a contributing factor to the development and/or persistence of airflow obstruction in chronic lung disease of prematurity.

Bronchopulmonary Dysplasia↗

Laparoscopic mobilization of the stomach for oesophageal replacement.

Nine patients of mean(s.d.) age 61(8) years underwent oesophagogastrectomy with laparoscopic gastric mobilization and abdominal lymphadenectomy for oesophageal cancer. Moderate to severe airway obstruction was present in all patients, in whom the mean(s.d.) value of forced expiratory flow rate at 1 s was 65(17) (range 35-85) per cent of the predicted value. Six patients had an abdominal laparoscopic approach combined with a right open thoracotomy; the other three had a laparoscopic abdominal and transhiatal approach combined with a left cervicotomy. No patient required conversion to open laparotomy. All had an uneventful postoperative course with extubation occurring at the end of the surgical procedure (n = 2) or on day 1 after operation (n = 7). Mean(s.d.) duration of hospitalization was 10.3(3.1) (range 8-18) days. The laparoscopic approach for gastric mobilization and abdominal lymphadenectomy is safe and can be used in patients with impaired pulmonary function.

Aged↗

Can schoolchildren provide valid answers about their respiratory health experiences in questionnaires? Implications for epidemiological studies.

To evaluate the relative validity of information on children's respiratory experience given by different informants, we examined and compared the relationship between low ventilatory function (defined as more than 1 standard deviation below the corresponding mean) and schoolchildren's respiratory symptoms or illnesses reported separately by the children and their parents, using a standard respiratory questionnaire. A total of 1,963 children aged 8-12 years from 12 primary schools in three districts of Hong Kong provided parent-completed and self-completed questionnaires, as well as acceptable spirometric measurements. Prevalence of low forced expiratory volume ratio (FEV1/FVC) and low forced expiratory flow rate between 25-75% of FVC (FEF25-75) were higher among those with either parent or child-reported symptoms/illnesses. Child-reported cough and phlegm performed better than the corresponding parent-reported symptoms in predicting low FEV1/FVC. The contrary was true for wheezing and bronchitis. For low FEF25-75, parent-reported wheezing, asthma, and bronchitis performed better, while the opposite was true for cough. Subgroup analysis by age showed that for older children (age 10 or above), child-reported symptoms/illnesses performed better in general in the prediction of low FEV1/FVC. On the other hand, parent-reported symptoms/illnesses seemed to have an advantage over child-reported ones in predicting low FEF25-75. Subgroup analysis by sex did not reveal any clear pattern. Overall, there was little difference between respiratory illness experiences reported by schoolchildren and their parents in terms of their associations with low ventilatory function. In a population-based study in which schoolchildren are subjects, it would be appropriate for respiratory questionnaires to be administered to the children themselves, especially if they have reached age 10. By doing so, higher response rates, and perhaps also better yields of correct information, may be obtained.

Child↗

Ozone-induced pulmonary functional, pathological, and biochemical changes in normal and vitamin C-deficient guinea pigs.

Since Vitamin C (ascorbate, AH2) is an important airway antioxidant and is an essential component of tissue repair, and since acute (4 hr) O3 toxicity is enhanced by AH2 deficiency, we hypothesized that longer-term O3 effects might also be increased. Female Hartley guinea pigs (260-330 g) were fed either an AH2-sufficient or an AH2-deficient diet 1 week prior to exposure, and were maintained on their respective diets during 1 week of continuous exposure to O3 (0, 0.2, 0.4, and 0.8 ppm, 23 hr/day), and during 1 week postexposure recovery in clean air. The AH2-deficient diet caused lung AH2 to drop to about 30% of control in 1 week, and to below 10% by the end of exposure and recovery. Body weight gains during exposure were decreased in the 0.8 ppm O3 group, while the AH2 deficiency began to affect body weights only during recovery. O3 caused a concentration-dependent decrease in total lung capacity, vital capacity, carbon monoxide diffusing capacity, nitrogen washout, and static compliance, while increasing forced expiratory flow rates and residual or end-expiratory volume (suggestive of pulmonary gas-trapping). The lung/body weight ratio and fixed lung displacement volume were also increased in O3-exposed animals. Lung pathology consisted of mononuclear cell and neutrophil infiltration, airway as well as alveolar epithelial cell hyperplasia, and general decrease in epithelial cell cytoplasm. Thickening of the interstitium and an apparent increase in collagen staining were seen at the terminal bronchiolar regions. Some of these effects were marginally exacerbated in AH2-deficient guinea pigs. One week postexposure to air reversed all O3-induced abnormalities, irrespective of AH2 deficiency. Whole lung hydroxyproline and desmosine were not changed at any time by either O3 or AH2 deficiency. Measurement of lung prolyl hydroxylase activity suggested that AH2 deficiency as well as O3 exposure may have increased the tissue levels of this enzyme. The lack of a significant increase in toxicity with the longer-term exposure scenario suggests that AH2 has minimal influence on other compensatory mechanisms developed over time.

Animals↗

Phenyl isocyanate-induced asthma in rats following a 2-week exposure period.

This study was conducted to assess the toxic effects of repeated inhalation exposures to phenyl isocyanate vapor in male Wistar rats. Rats were exposed to design concentrations of 0, 1, 4, 7, or 10 mg/m3 phenyl isocyanate air for 2 weeks (6 hr/day, 5 days/week). The rats were assessed for normal toxicologic parameters, and pulmonary function tests, blood gas measurements, and analysis of bronchoalveolar lavage fluid (BALF) parameters were utilized shortly after exposures as well as 2 months postexposure. The results indicated that rats exposed to 7 and 10 mg/m3 experienced decreased body weights, hypoactivity, hypothermia, signs of respiratory tract irritation, delayed onset of mortality, and changes in organ weights. In addition, pulmonary function tests demonstrated decreased forced expiratory flow rates and quasistatic lung compliance. Arterial blood gases showed an arterial hypoxemia and changes consistent with a pronounced venous-admixture-like perfusion, suggesting severe mismatch of the ventilation/perfusion relationship. Delayed onset of mortality appeared to be associated with respiratory acidosis and hypoxemia. Biochemical and cellular components in BALF complemented the results of the functional alterations. Remarkable changes were indicated by increased activities of the BALF parameters, gamma-GPT, protein, and sialic acid. Histopathological findings provided evidence of increased secretory cell activity and a concentration-dependent increase in goblet cell hyperplasia at concentrations of 4 mg/m3 and above. In rats exposed to 7 mg/m3 further findings consisted of intraluminal inflammation of airways, hypertrophia of bronchial smooth muscle, epithelial desquamation, and eosinophilia of the airways. A complete regression of morphological lesions was not found in the animals exposed to 4 mg/m3 and above at the 2-month postexposure time period. In conclusion, the damage to the airways comprise most of the features characteristic of chronic airway inflammation or asthma.

Administration, Inhalation↗

Adaptation to ozone in rats and its association with ascorbic acid in the lung.

Ozone (O3) adaptation is a well-known, but poorly understood phenomenon that has been demonstrated in humans and laboratory animals. This study examined pulmonary function and bronchoalveolar lavage fluid (BALF) parameters in O3-adapted F-344 rats to explore possible mechanisms of adaptation. Of particular interest was ascorbic acid (AA), an antioxidant reported to be protective against O3 injury and found to be increased in O3-adapted rats. Adaptation was induced by exposure to 0.25 ppm O3, 12 hr/day for 6 or 14 weeks and evaluated with a challenge test, one that reexposed rats to 1.0 ppm O3 and measured attenuation in the O3 effect on frequency of breathing. Pulmonary function was assessed 1 day postexposure and adaptation and BALF were evaluated 1, 3, and 7 days postexposure. Results showed that forced vital capacity increased over time but decreased due to exposure and that the 14-week, O3-exposed rats had an increase in forced expiratory flow rate. All of the O3-exposed rats that were tested demonstrated adaptation on Postexposure Days 1, 3, and 7, but it was diminished on Day 7. Adaptation was also more pronounced in rats exposed for 14 weeks. Except for AA, BALF levels of total protein, potassium, lysozyme, uric acid, and alpha-tocopherol were unaffected by O3 exposure. Lactic acid dehydrogenase, alkaline phosphatase, glucose-6-phosphate dehydrogenase, and total glutathione were also assayed but were always below detectable limits. Ascorbic acid concentrations were elevated on Days 1, 3, and 7, showing postexposure patterns similar to those found for adaptation. Significant correlation was found between AA concentration and the magnitude of adaptation (r = 0.91, p < 0.002). We conclude that AA may play an important role in mechanisms associated with O3 adaptation in rats.

Adaptation, Physiological↗

Altered lung function in rats after subacute exposure to n-butyl isocyanate.

The objectives of this study were to use pulmonary function tests, blood gas measurements and bronchoalveolar lung lavage (BAL) to characterize lesions in the respiratory tract of young adult male Wistar rats as a result of a 5-day exposure (6 h/day) to 0, 1.1, 6.2, 15 or 26 mg n-butyl isocyanate (n-BIC)/m3 air. Further objectives were to probe the diagnostic sensitivities of these procedures in comparison with more traditional evaluations (clinical observation, lung weight, histopathology). Measurements were performed during post-exposure weeks 2 and 5. Most rats exposed to 26 mg/m3 died or were sacrificed in a moribund state during post-exposure week 2. All other rats survived the exposure regimen. In rats exposed to 15 and 26 mg/m3 a significant decrease in body weight, laboured breathing, hypoactivity, nasal discharge, cyanosis, and hypothermia were observed. Pulmonary function measurements revealed increased total lung capacity (TLC) and residual volume (RV), decreased forced expiratory flow rates and quasi-static compliance in rats exposed to 26 mg/m3. At the end of the observation period rats exposed to 6.2 and 15 mg/m3 air were hyperresponsive to an acetylcholine bronchoprovocation aerosol. Arterial blood gas measurements revealed an arterial hypoxia and an increase in venous admixture, suggesting a severe mismatch of the ventilation-perfusion relationship. Biochemical and cellular components in BAL fluid (BALF) indicated a concentration dependent and protracted increase of polymorphonuclear leucocytes and further inflammatory parameters. In the 1.1 mg/m3 group BALF parameters were not significantly elevated. The major histopathological lesions of the lung were thickening of septa, emphysema, and intra-alveolar oedema in rats exposed to 26 mg/m3.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗