Hypocapnia does not alter collateral ventilation in sheep.

Hypocapnic constriction has been proposed as a mechanism by which collateral pathways might rapidly alter ventilation to match perfusion. We studied the changes in response to hypocapnia with age in sheep, a species with collateral resistance (Rcoll) similar to those measured in humans. Measurements of Rcoll were made with either 5 or 10% CO2 and with air (hypocapnia) in 29 anesthetized sheep, ages 6 mo to 10 yr, with the wedged bronchoscope technique. Rcoll was 0.42 +/- 0.12, 0.58 +/- 0.18, 0.32 +/- 0.18, and 0.17 +/- 0.04 (SE) cmH2O.ml-1.min in 6-mo- and 1-, 2-, and 10-yr-old animals, respectively. These values were unchanged with hypocapnia. Despite the lack of a change in Rcoll with hypocapnia, administration of histamine aerosol (8 animals) through the bronchoscope increased Rcoll by 151 +/- 35% (P less than 0.05). These data suggest that although collateral pathways exist in sheep and are capable of constriction, they do not respond to hypocapnia. Furthermore, the response to hypocapnia is not influenced by age.

In vivo exposure to ozone causes increased in vitro responses of small airways.

We examined the effects of in vivo exposure to 3 ppm ozone on in vitro reactivity of large and small airways from dogs. No effects in large airways were detected. However, small airways exposed to O3 had larger responses to receptor-mediated stimuli and similar responses to KCl plus phorbol ester. These results suggest that small airways are more vulnerable to O3 inhalation than are large airways and that receptor-mediated pathways reflect that sensitivity. Another possible explanation is that O3 exposure prevents the epithelium from playing its normal dampening role in responses to contractile agonists.

Prolonged increased responsiveness of canine peripheral airways after exposure to O3.

Because it is relatively insoluble, the oxidant gas O3 may penetrate to small peripheral airways when it is inhaled. Increased responsiveness in large airways after O3 breathing has been associated with the presence of inflammatory cells. To determine whether O3 produces prolonged hyperresponsiveness of small airways associated with the presence of inflammatory cells, we exposed the peripheral lungs of anesthetized dogs to 1.0 ppm O3 for 2 h using a wedged bronchoscope technique. A contralateral sublobar segment was simultaneously exposed to air as a control. In the O3-exposed segments, collateral resistance (Rcs) was increased within 15 min and remained elevated approximately 150% throughout the 2-h exposure period. Fifteen hours later, the base-line Rcs of the O3-exposed sublobar segments was significantly elevated, and these segments demonstrated increased responsiveness to aerosolized acetylcholine (100 and 500 micrograms/ml). There were no differences in neutrophils, mononuclear cells, or mast cells (numbers or degree of mast cell degranulation) between O3 and air-exposed airways at 15 h. The small airways of the lung periphery thus are capable of remaining hyperresponsive hours after cessation of localized exposure to O3, but this does not appear to be dependent on the presence of inflammatory cells in the small airway wall.

Aminophylline reduces air-flow-induced constriction in the canine lung periphery.

We examined the effect of aminophylline on air-flow-induced constriction in the canine lung periphery. A wedged bronchoscope technique was used to measure airway wall temperature (Taw) and collateral resistance (Rcs) before and after air flow was increased from a baseline flow of 200 to 500, 1,000, 1,500, or 2,000 ml/min for 2-min periods. When a sublobar segment was challenged with dry air, Taw fell during the challenge (p less than 0.05) and Rcs increased 5 min postchallenge (p less than 0.01). Pretreatment with aminophylline (20 mg/kg) reduced the fall in Taw by 31% and reduced the increase in Rcs by 53%. Aminophylline did not significantly affect either the concentrations of PGD2, TxB2, and histamine or the cell numbers and profiles obtained by bronchoalveolar lavage performed 5 min postchallenge. However, trends were consistent with the decreased physiologic responses observed. Finally, aminophylline proved ineffective in reducing the constrictor response of peripheral lung challenged directly with aerosolized histamine or PGD2. Because preaminophylline and postaminophylline peripheral lung sensitivity (as assessed by the ratio delta Rcs/delta Taw) were not significantly different, we conclude that aminophylline attenuates physiologic responses by reducing the strength of the stimulus. Aminophylline could do this by facilitating the replacement of heat and water removed during dry air challenge by increasing bronchial or pulmonary blood flow, or by reducing heat and water loss via changes in mucosal permeability.

Airflow-induced bronchospasm. Imbalance between airway cooling and airway drying?

We used an animal model of airflow-induced bronchospasm (AIB) to examine the role of airway cooling in responses to dry air challenge. A bronchoscope was wedged in situ into perfused lower lobes of anesthetized dogs. Through the bronchoscope, dry air was delivered, resistance to collateral flow (Rcs) was measured, and airway wall temperature (Taw) was monitored. A dry-air challenge through the bronchoscope produced a fall in Taw and a rise in Rcs, presumably related to evaporative heat loss (EHL) and/or an increase in osmolarity. By changing the temperature of blood perfusing the lobe it was possible to lower Taw without affecting either EHL or osmolarity. Four series of experiments were performed. In the first series, Taw was lowered in 2 ways: by increasing dry air flow and by cooling the pulmonary perfusate. After a 2-min challenge with dry air, Rcs rose. After lowering Taw with cooled blood for 2 min, Rcs did not rise. In the second series of studies, Taw was lowered for 15-min periods by reducing the temperature of blood. Neither cooling per se nor rewarming after the 15 min of cooling initiated increases in lung tone. In the third series of experiments, a 2-min dry air challenge was performed while the lobe was perfused with cool blood. Despite greater reductions in Taw during the dry-air challenge, responses after the challenge were virtually abolished. In a final series of experiments in which pulmonary perfusion was stopped during challenge, airway cooling was enhanced, and responses were again significantly attenuated. Thus, cooling actually depressed increases in Rcs produced by dry-air challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypocapnia-induced constriction of the canine peripheral airways exhibits tachyphylaxis.

Hypocapnia-induced constriction of peripheral airways may be important in regulating the distribution of ventilation in pathological conditions. We studied the response of the peripheral lung to hypocapnia in anesthetized, paralyzed, mechanically ventilated dogs using the wedged bronchoscope technique to measure resistance of the collateral system (Rcs). A 5-min hypocapnic challenge produced a 161 +/- 19% (mean +/- SE) increase in Rcs. The magnitude of this response was not diminished with repeated challenge or by atropine sulfate (1 mg base/kg iv), chlorpheniramine maleate (5 mg base/kg iv), or indomethacin (5 mg/kg iv). The response was reduced by 75% by isoproterenol (5 micrograms/kg iv) (P less than 0.01) and reduced by 80% by nifedipine (20 micrograms/kg iv) (P less than 0.05). During 30-min exposure to hypocapnia the maximum constrictor response occurred at 4-5 min, after which the response attenuated to approximately 50% of the maximum response (mean = 53%, range 34-69%). Further 30-min challenges with hypocapnia resulted in significantly decreased peak responses, the third response being 50% of the first (P less than 0.001). The inability of indomethacin or propranolol to affect the tachyphylaxis or attenuation of the response suggests that neither cyclooxygenase products nor beta-adrenergic activity was involved. Hence, hypocapnia caused a prompt and marked constrictor response in the peripheral lung not associated with cholinergic mechanisms or those involving histamine H1-receptors or prostaglandins. With prolonged exposure to hypocapnia there was gradual attentuation of the constrictor response with continued exposure and tachyphylaxis to repeated exposure both of which would tend to diminish any compensatory effect of hypocapnic airway constriction on the distribution of ventilation.

Dry air-induced constriction: effects of pharmacological intervention and temperature.

We studied airway wall temperature (Taw) during dry air challenge of the canine lung periphery. We measured collateral resistance (Rcs) before and after periods of elevated airflow using a wedged bronchoscope technique. As flow rate increased, Taw dropped and postchallenge Rcs rose. A significant negative correlation was found between Taw recorded during challenge and Rcs observed 5 min after challenge. Repetitive dry air challenge produced similar changes in Rcs and Taw. However, responses to warm moist air were significantly lower than consecutive responses to dry air. Taw was significantly lower during dry air challenge than during moist air challenge. Indomethacin (5 mg/kg) and atropine (1 mg/kg) reduced responses to dry airflow challenge. Indomethacin did not affect Taw during the challenge, whereas atropine reduced the fall in Taw. We conclude that temperature correlates negatively with peripheral lung tone 5 min after dry air challenge. This correlation holds under conditions where airflow is increased, air is humidified, or atropine is administered. The dissociation between Taw and physiological response after indomethacin likely reflects a decrease in mediators released during challenge.

Effects of maturation and aging on collateral ventilation in sheep.

We studied collateral ventilation as a function of age by measuring the resistance (Rcoll) and time constant (Tcoll) of collateral airflow in young (2-10 mo), mature (16-24 mo), and old sheep (6-13 yr). Rcoll was 0.50 +/- 0.11 cmH2O X ml-1 X min (SE) in young sheep and decreased significantly to 0.05 +/- 0.02 and 0.02 +/- 0.01 cmH2O X ml-1 X min in mature and old sheep, respectively. Tcoll was 34.4 +/- 7.9 (SE) s in young sheep and decreased to 5.7 +/- 0.9 and 10.2 +/- 3.1 s in mature and old sheep, respectively. We conclude that a marked decrease in Rcoll and Tcoll occurs between birth and maturity but changes little with further aging. In the young an increased resistance and time constant of collateral airflow may accentuate ventilation perfusion imbalance and impair the removal of secretions in disease states.

Airflow-induced bronchoconstriction: role of epithelium and eicosanoid mediators.

We examined the role of cyclooxygenase-derived metabolites and epithelial cells in airflow-induced bronchospasm. Male dogs were anesthetized and collateral system resistance (Rcs) was measured with the wedged-bronchoscope technique. A 2-min high flow challenge with dry air in nine animals produced a mean increase in Rcs of 69 +/- 13% (SE). After treatment with indomethacin (5 mg/kg), the response was significantly attenuated; Rcs increased only 40 +/- 8%. Bronchoalveolar lavage performed 5 min after a dry air challenge yielded fluid with greater concentrations of prostaglandin D2 (PGD2) and thromboxane B2 than samples from unchallenged segments. Challenge with humidified air produced a smaller physiological response than did challenge with dry air. Lavage samples obtained after dry challenge had greater concentrations of PGD2 than samples taken after challenge with humidified air. After dry air challenge, epithelial cells in lavage fluid were increased by 454 and 515% when compared with control and humidified air challenge, respectively. Significant correlations were found between epithelial cell number and PGD2 recovered in lavage fluid after dry air challenges. We conclude that both epithelial cells and prostaglandins play an important role in peripheral lung responses to dry air.

Lithium dampens neurotransmitter response in smooth muscle: relevance to action in affective illness.

Lithium, by inhibiting inositol phosphate metabolism, interferes with the phosphatidylinositol ("phosphoinositide") cycle, which is stimulated by numerous hormones and neurotransmitters. To examine the relevance of this action to neurotransmission, we evaluated effects of lithium treatment on smooth muscle responses to transmitters. In lithium-pretreated tracheal muscle, the relaxation following carbachol or histamine contractions is retarded. Lithium does not affect relaxation following contractions elicited by treatment with KCl and phorbol 12,13-diacetate in combination, which bypasses receptor stimulation of the phosphatidylinositol cycle. Half-maximal effects of lithium occur at 1 mM, corresponding to therapeutic concentrations. Dampening of neurotransmitter responses by lithium treatment may explain the unique ability of lithium to relieve and prevent both mania and depression.

Perfusion of lung periphery: effects of local exposures to ozone and pressure.

Following ozone (O3) exposure, airways reactivity increases. We investigated the possibility that exposure to O3 causes a decrease in pulmonary perfusion, and that this decrease is associated with the increase in reactivity. Perfusion was measured with radiolabeled microspheres. A wedged bronchoscope was used to isolate sublobar segments in the middle and lower lobes of anesthetized dogs. Isolated segments were exposed to either O3 or an elevated alveolar pressure. Although increased alveolar pressure decreased microsphere density, exposure to 1 ppm O3 did not. Collateral system resistance rose significantly following exposure to O3 and to high pressure. These studies do not support the hypothesis that pulmonary perfusion is decreased following O3 exposure and is associated with subsequent increases in reactivity.

Pulmonary blood flow affects recovery from constriction in dog lung periphery.

The influence of blood flow through the pulmonary circulation on the time course of recovery of the lung periphery from challenge with three bronchoconstrictive agents was studied in dogs. The rate of perfusion of the left lower lobe was varied between 0 and 300 ml/min. A fiber-optic bronchoscope (OD = 5.5 mm) was wedged in a small airway in the same lobe, and resistance to airflow through the collateral system was continuously monitored. The lung was challenged with histamine aerosol for 1 min, or with intravenous boluses of histamine, acetylcholine, or methacholine. The time constant (tau) of recovery from each of the challenges was measured under the various pulmonary blood flow conditions. The mean tau of the recoveries from histamine was inversely related to the rate of blood flow. However, pulmonary blood flow had no effect on recovery from challenge with acetylcholine or methacholine, two agents metabolized by cholinesterase in lung tissue. From this study we conclude that recovery of the lung periphery from histamine is perfusion dependent, whereas recovery from acetylcholine or methacholine is perfusion independent. This suggests that the rate of blood flow through the pulmonary circulation could play an important role in recovery of the peripheral airways from certain mediators of bronchoconstriction.

Dry air-induced constriction in lung periphery: a canine model of exercise-induced asthma.

We studied the effects of the flow of dry air on collateral tone in the lung periphery. A bronchoscope was wedged in sublobar segments of anesthetized dogs, and measurements of collateral resistance (Rcs) were recorded before and after flow was increased from 200 to 2,000 ml/min for a 5-min period. Five minutes after exposure was completed, Rcs increased by an average of 117 +/- 25.2% (SE) over control. Maximum Rcs occurred 5 min after the challenge was concluded and required 48 +/- 10.5 min to return to base line. When flow rate was held constant and exposure period varied, Rcs increased with increased stimulus duration. With exposure times held constant, the response of the collateral system was positively associated with changes in stimulus strength (flow rate). No refractory period was observed with repetitive challenges. Finally, when dry air (delivered at 22 degrees C) and conditioned air (i.e., delivered at 28 degrees C; relative humidity = 80%) challenges were alternated in the same wedged segment, dry air produced a mean increase in Rcs of 93.2%, whereas challenge with warm moist air increased Rcs only 33.5%. Regardless of which challenge was presented first, dry air consistently produced a greater constrictor response. This response is similar to that observed in cold air- and exercise-induced asthma and indicates that the lung periphery in dogs, like larger airways in asthmatic subjects, has the potential to increase tone when exposed to dry air. Peripheral airways in dogs thus constitute a model that can be used for the investigation of exercise-induced asthma.

Tonic beta-sympathetic activity in the lung periphery in anesthetized dogs.

The present study was undertaken to determine whether beta-adrenoceptors could be physiologically detected in the lung periphery and whether they were under tonic stimulation in the resting state in anesthetized dogs. A fiberoptic bronchoscope was wedged in a sublobar segment of lung in anesthetized male mongrel dogs for measurement of resistance through the collateral system (Rcs). beta-Agents were delivered locally as aerosols through the bronchoscope, and the response was evaluated by changes in Rcs. Distilled water alone produced a mean increase of 8.5 +/- 2.43% (SE) in Rcs at 2 min in six dogs, whereas dl-isoproterenol produced a mean decrease of 8.9 +/- 2.10% (P less than 0.03), thus demonstrating the presence of submaximally stimulated beta-receptors. To test whether the beta-receptors were under tonic stimulation, we compared the effect of aerosolized d- and dl-propranolol in 5 dogs. d-Propranolol that lacks significant beta-blocking activity and dl-propranolol both produced large transient increases in Rcs. However, with d-propranolol, Rcs had returned to base line at 15 min, whereas with dl-propranolol Rcs remained elevated at a mean of 20% above base line for greater than 2 h (P less than 0.01). Local timolol aerosol also produced a sustained increase in Rcs. After pretreatment with reserpine or after bilateral adrenalectomy, both d- and dl-propranolol still produced large transient increases in Rcs, but dl-propranolol no longer produced a sustained increase. Neither isoproterenol nor atropine affected Rcs in the presence of dl-propranolol, nor did pretreatment with atropine affect the response of Rcs to dl-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrogen washout and mortality.

We studied the association between different tests of pulmonary function and subsequent mortality. Subjects were drawn from an epidemiology study of chronic obstructive pulmonary disease. Between 1971 and 1976, 2,539 nonpatient adults had tests of forced expiration, diffusing capacity, and single-breath nitrogen washout. By 1981, 115 of those subjects had died, including 3 from known lung disease. In assessing the relationship between lung function and mortality, the following tests of pulmonary function were examined: forced expiratory volume in one second as a percentage of forced vital capacity, forced expiratory volume divided by height cubed, slope of phase III from the single-breath nitrogen test, closing capacity, diffusing capacity for CO, and the ratio of maximal flow at 75% to that at 25% vital capacity. When adjustments for age and smoking were made, slope of phase III was strongly associated with mortality, even more so than tests of forced expiration. There are two possible explanations for this striking relationship between these observed abnormalities of lung function and subsequent overall mortality (which is largely from nonpulmonary disease): the lungs may serve to protect other systems of the body and therefore poor pulmonary function may contribute to a number of diseases leading to death, or lung function may merely reflect existing disorders in other systems of the body, and the observed association between mortality and pulmonary function is a byproduct of nonpulmonary diseases.

Risk factors associated with longitudinal change in pulmonary function.

In a longitudinal study of pulmonary function, we investigated the relationship between loss of forced expiration over time and a series of potential risk factors, as well as 4 other measures of pulmonary function at initial visit. Data on 1,912 adults tested twice, with an average of 4.7 yr between visits, were used. Of the potential risk factors examined, only age and smoking were consistently associated with increased loss of forced expiratory function in both men and women. Statistically significant differences among ABO blood types and among Pi types were also seen in women, although the direction of these differences was unexpected in that non-Z Pi variant phenotypes showed less decline in pulmonary function than did the most common Pi M phenotypes. Similar patterns of differences were seen in men, although these were not statistically significant. Of 4 initial-visit pulmonary function measures examined, only closing capacity at initial visit was consistently associated with subsequent loss of forced expiratory volume in one second (delta FEV1) in both men and women. The final predictive model for delta FEV1 accounted for a modest proportion of the total variation seen in this sample, however, limiting its potential use for predicting decline in pulmonary function over a 5-yr span in individual subjects.

Risk factors, pulmonary function, and mortality.

In a genetic-epidemiologic study of obstructive airway disease (OAD), cross sectional and longitudinal data (4.7 year follow-up) were collected to investigate relationships among risk factors, pulmonary function, and mortality. In the cross sectional evaluation of 2539 non-patient adults, 11 potential risk factors were found to be significantly associated with airways obstruction. Most important among these were age and smoking. Others included: demographic variables (gender, SES, education); the intake of coffee and diet soda; genetic markers (protease inhibitor "Pi" type, ABO type, ABH secretor status); and familial pulmonary disease. Examination of combinations of risk factors in cross sectional data indicated that some of these factors were important risk factors in cigarette smokers but less evident in never smokers. For example, ABO type, familial component, coffee drinking and diet soda intake were related to marked differences in lung function in cigarette smokers, but had little impact in never smokers. Thus, interactions of factors must be considered when assessing risk of pulmonary dysfunction. In the longitudinal evaluation, 11 factors found to be significant on cross sectional study plus 4 tests of lung function (closing capacity, diffusing capacity, slope of Phase III, and flow volume curves) were examined for correlations with loss of forced expiratory volume. Consistently greater declines of lung function were noted in males, older subjects, smokers, whites, and individuals carrying the type A blood group allele. Increased initial visit closing capacity was also associated with increased deterioration. Together, however, these factors accounted for only a modest amount of observed variation in decline in lung function (17% in females and 12% in males). Initial visit characteristics were not only associated with deterioration of lung function in survivors, as described above, but with survivorship per se. Age, sex, race and cigarette smoking were associated with differences in mortality. In addition to these, pulmonary dysfunction itself at initial visit was an independent risk factor for increased mortality. For example, the mortality of unobstructed males in the 5th decade of life was 16 per thousand compared to 25 per thousand in obstructed males. For females, the mortality in the 5th decade of life was 7 per thousand if unobstructed and 12 per thousand if obstructed. We conclude: 1) In cross sectional evaluation, multiple factors are associated with airways obstruction. Of these, smoking appears to interact strongly with other factors.(ABSTRACT TRUNCATED AT 400 WORDS)

Impaired pulmonary function as a risk factor for mortality.

Prospective follow-up information obtained between 1976 and 1981 on mortality among 2539 individuals showed that pulmonary function impairment is a risk factor for short-term mortality, even when risk factors such as age, sex, and smoking are considered. Predicted risk curves for impaired individuals (those with forced expiratory volume in one second less than 68% of forced vital capacity) are consistently higher among all race-sex categories over all ages. Survival analysis using the proportional hazards model shows a steeper decline in estimated survival among individuals with poor pulmonary function compared to those with good pulmonary function, adjusted for age, race, and smoking effects. These observations are consistent with the concept that impairment of pulmonary function is a risk factor for morbidity and mortality from several nonrespiratory as well as respiratory diseases and that it acts by contributing to various pathogenic mechanisms in different organ systems.