Importance of calcium in citric acid-induced airway constriction

In previous studies, a 5-min inhalational challenge with 10% citric acid aerosol (0.52 M) elicited bronchoconstriction in Basenji-Greyhound (BG) dogs with hyperreactive airways but not in mongrel dogs. This response was independent of vagal reflexes because it was not attenuated by atropine. Citric acid might elicit bronchoconstriction because of acidity, calcium chelation, or some other effect of the citrate molecule. To assess these factors, barbiturate-anesthetized BG dogs were challenged (5 min) with aerosols of 10% acetic acid or a citric acid (0.48 M)/Na3citrate (0.04 M) mixture of equivalent pH, 6% Na2-ethylenediaminetetraacetic acid (EDTA), or 6% CaNa2EDTA. Each challenge was delivered in a separate week. The acidity alone was not an adequate stimulus, since pulmonary resistance (RL) was unaltered by 10% acetic acid, although markedly increased by the citric acid-Na3citrate mixture [2.2 +/- 0.4 (SE) cmH2O X l-1 X s prechallenge, 10.0 +/- 2.2 postchallenge]. Aerosols of Na2EDTA provoked a similar increase in RL (2.1 +/- 0.4 cmH2O X l-1 X s prechallenge, 9.0 +/- 1.8 postchallenge). Neither effect was attenuated by intravenous atropine (0.2 mg/kg). CaNa2EDTA caused no changes in RL. We conclude that it is the calcium chelating action of citric acid rather than its acidity that is responsible for bronchoconstriction in BG dogs with hyperreactive airways.     

Partitioning of respiratory mechanics in halothane-anesthetized humans

In five spontaneously breathing anesthetized subjects [halothane approximately 1 minimal alveolar concentration (MAC), 70% N2O, 30% O2], flow, changes in lung volume, and esophageal and airway opening pressure were measured in order to partition the elastance (Ers) and flow resistance (Rrs) of the total respiratory system into the lung and chest wall components. Ers averaged (+/- SD) 23.0 +/- 4.9 cmH2O X l-1, while the corresponding values of pulmonary (EL) and chest wall (EW) elastance were 14.3 +/- 3.2 and 8.7 +/- 3.0 cmH2O X l-1, respectively. Intrinsic Rrs (upper airways excluded) averaged 2.3 +/- 0.2 cmH2O X l-1 X s, the corresponding values for pulmonary (RL) and chest wall (RW) flow resistance amounting to 0.8 +/- 0.4 and 1.5 +/- 0.5 cmH2O X l-1 X s, respectively. Ers increased relative to normal values in awake state, mainly reflecting increased EL. Rw was higher than previous estimates on awake seated subjects (approximately 1.0 cmH2O X l-1 X s). RL was relatively low, reflecting the fact that the subjects had received atropine (0.3-0.6 mg) and were breathing N2O. This is the first study in which both respiratory elastic and flow-resistive properties have been partitioned into lung and chest wall components in anesthetized humans.     

Effect of transpulmonary pressure on airway diameter and responsiveness of immature and mature rabbits.

We previously demonstrated that airway responsiveness is greater in immature than in mature rabbits; however, it is not known whether there are maturational differences in the effect of transpulmonary pressure (Ptp) on airway size and airway responsiveness. The relationship between Ptp and airway diameter was assessed in excised lungs insufflated with tantalum powder. Diameters of comparable intraparenchymal airway segments were measured from radiographs obtained at Ptp between 0 and 20 cmH(2)O. At Ptp > 8 cmH(2)O, the diameters were near maximal in both groups. With diameter normalized to its maximal value, changing Ptp between 8 and 0 cmH(2)O resulted in a greater decline of airway caliber in immature than mature airways. The increases in lung resistance (RL) in vivo at Ptp of 8, 5, and 2 cmH(2)O were measured during challenge with intravenous methacholine (MCh: 0.001-0.5 mg/kg). At Ptp of 8 cmH(2)O, both groups had very small responses to MCh and the maximal fold increases in RL did not differ (1.93 +/- 0.29 vs. 2.23 +/- 0.19). At Ptp of 5 and 2 cmH(2)O, the fold increases in RL were greater for immature than mature animals (13.19 +/- 1.81 vs. 3.89 +/- 0.37) and (17.74 +/- 2.15 vs. 4.6 +/- 0.52), respectively. We conclude that immature rabbits have greater airway distensibility and this difference may contribute to greater airway narrowing in immature compared with mature rabbits.     

Effects of lung volume on maximal methacholine-induced bronchoconstriction in normal humans

We examined the effects of lung volume on the bronchoconstriction induced by inhaled aerosolized methacholine (MCh) in seven normal subjects. We constructed dose-response curves to MCh, using measurements of inspiratory pulmonary resistance (RL) during tidal breathing at functional residual capacity (FRC) and after a change in end-expiratory lung volume (EEV) to either FRC -0.5 liter (n = 5) or FRC +0.5 liter (n = 2). Aerosols of MCh were generated using a nebulizer with an output of 0.12 ml/min and administered for 2 min in progressively doubling concentrations from 1 to 256 mg/ml. After MCh, RL rose from a base-line value of 2.1 +/- 0.3 cmH2O. 1-1 X s (mean +/- SE; n = 7) to a maximum of 13.9 +/- 1.8. In five of the seven subjects a plateau response to MCh was obtained at FRC. There was no correlation between the concentration of MCh required to double RL and the maximum value of RL. The dose-response relationship to MCh was markedly altered by changing lung volume. The bronchoconstrictor response was enhanced at FRC - 0.5 liter; RL reached a maximum of 39.0 +/- 4.0 cmH2O X 1-1 X s. Conversely, at FRC + 0.5 liter the maximum value of RL was reduced in both subjects from 8.2 and 16.6 to 6.0 and 7.7 cmH2O X 1-1 X s, respectively. We conclude that lung volume is a major determinant of the bronchoconstrictor response to MCh in normal subjects. We suggest that changes in lung volume act to alter the forces of interdependence between airways and parenchyma that oppose airway smooth muscle contraction.     

Significance of thromboxane generation in ozone-induced airway hyperresponsiveness in dogs

To determine whether thromboxane A2 may be involved in ozone (O3)-induced airway hyperresponsiveness, we studied the effect of a thromboxane synthase inhibitor (OKY-046, 100 micrograms X kg-1 X min-1 iv) in five dogs exposed to O3. Airway responsiveness was assessed by determining the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance by 5 cmH2O X l-1 X s. O3 (3 ppm) increased airway responsiveness as demonstrated by a decrease in acetylcholine provocative concentration from 2.42 (geometric SEM = 1.64) to 0.14 mg/ml (geometric SEM = 1.30). OKY-046 significantly inhibited this effect without altering pre-O3 responsiveness or the O3-induced increase in neutrophils and airway epithelial cells in bronchoalveolar lavage fluid. To further examine the role of thromboxane A2, we studied the effect of a thromboxane A2 mimetic, U-46619, on airway responsiveness in five additional dogs. U-46619 in subthreshold doses (i.e., insufficient to increase base-line pulmonary resistance) caused a fourfold increase in airway responsiveness to acetylcholine. Subthreshold doses of histamine had no effect. These results suggest that thromboxane A2 may be an important mediator of O3-induced airway hyperresponsiveness.     

Effects of elastase-induced emphysema on airway responsiveness to methacholine in rats

We examined the effects of elastase-induced emphysema on lung volumes, pulmonary mechanics, and airway responses to inhaled methacholine (MCh) of nine male Brown Norway rats. Measurements were made before and weekly for 4 wk after elastase in five rats. In four rats measurements were made before and at 3 wk after elastase; in these same animals the effects of changes in end-expiratory lung volume on the airway responses to MCh were evaluated before and after elastase. Airway responses were determined from peak pulmonary resistance (RL) calculated after 30-s aerosolizations of saline and doubling concentrations of MCh from 1 to 64 mg/ml. Porcine pancreatic elastase (1 IU/g) was administered intratracheally. Before elastase RL rose from 0.20 +/- 0.02 cmH2O.ml-1.s (mean +/- SE; n = 9) to 0.57 +/- 0.06 after MCh (64 mg/ml). A plateau was observed in the concentration-response curve. Static compliance and the maximum increase in RL (delta RL64) were significantly correlated (r = 0.799, P less than 0.01). Three weeks after elastase the maximal airway response to MCh was enhanced and no plateau was observed; delta RL64 was 0.78 +/- 0.07 cmH2O.ml-1.s, significantly higher than control delta RL64 (0.36 +/- 0.7, P less than 0.05). Before elastase, increase of end-expiratory lung volume to functional residual capacity + 1.56 ml (+/- 0.08 ml) significantly reduced RL at 64 mg MCh/ml from 0.62 +/- 0.05 cmH2O.ml-1.s to 0.50 +/- 0.03, P less than 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of hypoxia-induced periodic breathing on upper airway obstruction during sleep

We studied the effect of hypoxia-induced unstable and periodic breathing on the incidence of obstructed breaths in nine subjects who varied widely in their increase in total pulmonary resistance (RL) during non-rapid-eye-movement (NREM) sleep. During normoxic NREM sleep, all subjects showed hypoventilation, augmented diaphragmatic electromyogram (EMGdi), and increased RL. This response varied: two subjects doubled their mean RL (range 6-9 cmH2O X l-1 X s); four moderate snorers increased RL four- to eightfold (RL = 16-48 cmH2O X l-1 X s); three heavy snorers showed high RL (31-89 cmH2O X l-1 X s) plus cyclical obstructive hypopnea as their predominant breathing pattern. In seven of nine subjects, hypoxia and coincident hypocapnia initially caused an irregular cyclical breathing pattern with obstructed breaths (RL greater than 50 cmH2O X l-1 X s). The incidence of obstructed breaths induced by unstable breathing was closely correlated with the level of RL experienced in the control condition of normoxic sleep (r = 0.91). The obstructed breaths had relatively high O2 saturation (90-96%) and markedly reduced EMGdi activity and peak flow rate (less than 0.2 l/s) compared with breaths immediately after the obstructed breaths, which showed lower O2 saturation (81-93%) and markedly augmented EMGdi and flow rates. After 3-6 cycles of obstructive hypopnea, periodic breathing occurred in most subjects. During periodic breathing in six of seven subjects, the incidence of obstructed or high-resistance breaths was decreased or eliminated since each central apneic period was followed by breath clusters characterized by very high EMGdi, very low RL, and high flow rates. The remaining subject showed a high incidence of obstructed breaths during all phases of normoxic and hypoxic sleep. These data show that hypoxia-induced instability in breathing pattern can cause obstructed breaths during sleep coincident with reduced motor output to inspiratory muscles. However, this obstruction is only manifested in subjects susceptible to upper airway atonicity and narrowing (such as snorers) and can be prevented in most cases if respiratory drive is permitted to reach sufficiently high levels (as during central apnea).     

Partitioning of airway responses to inhaled methacholine in the rat

We measured the changes in upper and lower airway resistance after inhalation of aerosols of methacholine (MCh) in doubling concentrations (16, 32, 64, and 128 mg/ml) in 11 anesthetized nonintubated spontaneously breathing rats. Upper airway resistance (Ru) increased from a control value of 0.48 +/- 0.04 cmH2O X ml-1 X s (mean +/- SE) to 0.85 +/- 0.15 after 128 mg/ml MCh, whereas lower airway resistance (Rlo) increased from 0.11 +/- 0.03 to 0.21 +/- 0.04. However, there was no correlation between the magnitudes of the changes in Ru and Rlo. In a further seven anesthetized spontaneously breathing rats aerosols of MCh were delivered into the lower airways via a tracheostomy and resulted in increases in Rlo from a control value of 0.20 +/- 0.03 to 0.66 +/- 0.12 after 128 mg/ml MCh. Ru also increased to approximately double its control value. We conclude that inhaled MCh causes narrowing of both Ru and Rlo in the anesthetized rat, the changes in Ru and Rlo are not correlated, and changes in Ru can occur when MCh deposition occurs only in the lower airways.     

Neonatal capsaicin treatment alters basal pulmonary mechanics and response to methacholine in F344 rats.

Full methacholine dose-response curves were performed on anesthetized tracheostomized Fischer 344 adult rats treated neonatally with capsaicin (50 mg/kg) or with vehicle alone. Capsaicin, the hot extract of pepper, releases substance P (SP) from nonmyelinated sensory nerve endings and causes acute bronchoconstriction and airway microvascular leakiness. Chronic treatment with capsaicin leads to depletion of SP and other tachykinins from afferent C-fibers and can therefore be used as a tool to investigate the contribution of SP innervation to airway responses. The rats (9 controls and 6 treated with capsaicin) were paralyzed with succinylcholine and mechanically ventilated at a constant tidal volume and frequency. Airway resistance (RL) and dynamic compliance (Cdyn) were determined at each dose of methacholine from measurements of volume, flow, and transpulmonary pressure. Capsaicin-treated rats were found to have a significantly reduced baseline RL [0.150 +/- 0.039 (SD) vs. 0.225 +/- 0.050 cmH2O.ml-1.s, P = 0.009] and a correspondingly significantly elevated Cdyn (0.371 +/- 0.084 vs. 0.268 +/- 0.053 ml/cmH2O, P = 0.012). There was no significant difference in sensitivity to methacholine, but the maximal response to methacholine was significantly greater in the capsaicin-treated rats. In terms of RL, the maximal response for capsaicin-treated rats was 6.03 x baseline +/- 0.98 vs. 4.30 x baseline +/- 1.80 (P = 0.05) for controls, and for Cdyn changes the maximal decrease was 5.75 x baseline +/- 1.22 vs. 3.83 +/- 0.69 (P = 0.002). The observed differences in RL and Cdyn coupled with the differences in maximal responses can be attributed to the selective destruction of a subpopulation of pulmonary afferent C-fibers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inspiratory muscle forces and endurance in maximum resistive loading

The ability of the respiratory muscles to sustain ventilation against increasing inspiratory resistive loads was measured in 10 normal subjects. All subjects reached a maximum rating of perceived respiratory effort and at maximum resistance showed signs of respiratory failure (CO2 retention, O2 desaturation, and rib cage and abdominal paradox). The maximum resistance achieved varied widely (range 73-660 cmH2O X l-1 X s). The increase in O2 uptake (delta Vo2) associated with loading was linearly related to the integrated mouth pressure (IMP): delta Vo2 = 0.028 X IMP + 19 ml/min (r = 0.88, P less than 0.001). Maximum delta Vo2 was 142 ml/min +/- SD 68 ml/min. There were significant (P less than 0.05) relationships between the maximum voluntary inspiratory pressure against an occluded airway (MIP) and both maximum IMP (r = 0.80) and maximum delta Vo2 (r = 0.76). In five subjects, three imposed breathing patterns were used to examine the effect of different patterns of respiratory muscle force deployment. Increasing inspiratory duration (TI) from 1.5 to 3.0 and 6.0 s, at the same frequency of breathing (5.5 breaths/min) reduced peak inspiratory pressure and increased the maximum resistance tolerated (190, 269, and 366 cmH2O X l-1 X s, respectively) and maximum IMP (2043, 2473, and 2913 cmH2O X s X min-1, but the effect on maximum delta Vo2 was less consistent (166, 237, and 180 ml/min). The ventilatory endurance capacity and the maximum O2 uptake of the respiratory muscles are related to the strength of the inspiratory muscles, but are also modified through the pattern of force deployment.     

Role of the nose in resistive load detection

Previous resistive load detection (RLD) studies have ignored the nose, the usual route of breathing. Weber's law predicts the delta R50 (the added load detectable on 50% of presentations) to be a fixed percent of the background resistance (R0) and thus the delta R50/R0 ratio (the Weber fraction) is constant. We have noted the nose to be sensitive to added load, we wondered if the nose might play a role in RLD. To determine whether this was true and to characterize the effects of changes in R0 in the range of normal nasal resistance (RN), we determined R0 and delta R50 using standard techniques under the following conditions: nose vs. decongested nose, nose vs. nose with added external R0 (3.0 and 8.0 cmH2O X l-1 X s), nose vs. anesthetized nose, nose vs. mouth, and mouth vs. mouth with added load (3 cmH2O X l-1 X s). We found that decongestant decreased RN [4.3 +/- 0.6 (SE) to 3.1 +/- 0.5 cmH2O X l-1 X s, P less than 0.05] and delta R50 (1.7 +/- 0.5 to 1.1 +/- 0.3 cmH2O X l-1 X s, P less than 0.05). When an external load of 3 cmH2O X l-1 X s was added to the nose, delta R50 did not change significantly (1.4 +/- 0.2 to 1.1 +/- 0.2 cmH2O X l-1 X s), but the Weber fraction decreased (0.28 +/- 0.05 to 0.15 +/- 0.03, P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Deep breath reversal and exponential return of methacholine-induced obstruction in asthmatic and nonasthmatic subjects.

A deep breath (DB) during induced obstruction results in a transient reversal with a return to pre-DB levels in both asthmatic and nonasthmatic subjects. The time course of this transient recovery has been reported to be exponential by one group but linear by another group. In the present study, we estimated airway resistance (Raw) from measurements of respiratory system transfer impedance before and after a DB. Nine healthy subjects and nine asthmatic subjects were studied at their maximum response during a methacholine challenge. In all subjects, the DB resulted in a rapid decrease in Raw, which then returned to pre-DB levels. This recovery was well fit with a monoexponential function in both groups, and the time constant was significantly smaller in the asthmatic than the nonasthmatic subjects (11.6 +/- 5.0 and 35.1 +/- 15.9 s, respectively). Obstruction was completely reversed in the nonasthmatic subjects (pre- and postchallenge mean Raw immediately after the DB were 2.03 +/- 0.66 and 2.06 +/- 0.68 cmH2O.l-1.s, respectively), whereas in the asthmatic subjects complete reversal did not occur (2.29 +/- 0.78 and 4.84 +/- 2.64 cmH2O.l-1.s, respectively). Raw after the DB returned to postchallenge, pre-DB values in the nonasthmatic subjects (3.78 +/- 1.56 and 3.97 +/- 1.63 cmH2O.l-1.s, respectively), whereas in the asthmatic subjects it was higher but not significantly so (9.19 +/- 4.95 and 7.14 +/- 3.56 cmH2O.l-1.s, respectively). The monoexponential recovery suggests a first-order process such as airway wall-parenchymal tissue interdependence or renewed constriction of airway smooth muscle.     

Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia

Neonates and infants presenting with pulmonary hypertension and chronic hypoxia often exhibit airway obstruction. To investigate this association, we utilized a system in which neonatal calves are exposed to chronic hypobaric hypoxia and develop severe pulmonary hypertension. For the present study, one of each pair of six age-matched pairs of neonatal calves was continuously exposed to hypobaric hypoxia at 4,500 m (CH); the other remained at 1,500 m. At 2 wk of age, mean pulmonary arterial pressure (MPAP), dynamic lung compliance (Cdyn), resistance (RL), and static respiratory system compliance (Crs) were measured at 4,500 m in both CH and control calves exposed acutely to hypoxia (C). These measurements were repeated after cumulative administrations of nebulized methacholine (MCh). Tissues were removed for histological examination and assessment of bronchial ring contractility to MCh and KCl. After 2 wk of hypobaric hypoxia, MPAP (C 35 +/- 1.7 vs. CH 120 +/- 7 mmHg, P less than 0.001) and RL (C 2.64 +/- 0.16 vs CH 4.99 +/- 0.47 cmH2O.l-1s, P less than 0.001) increased. Cdyn (C 0.100 +/- 0.01 vs. CH 0.082 +/- 0.007 l/cmH2O) and Crs (CH 0.46 +/- 0.003 vs. C 0.59 +/- 0.009 l/cmH2O) were not significantly different. Compared with airways of C calves, airways of CH animals did not exhibit in vivo or in vitro MCh hyperresponsiveness; however, in vitro contractility to KCl of airways from CH animals was significantly increased. Histologically, airways from the CH calves showed increases in airway fibrous tissue and smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of CO2 rebreathing on pulmonary mechanics in premature infants

The effects of hypercapnia produced by CO2 rebreathing on total pulmonary, supraglottic, and lower airway (larynx and lungs) resistance were determined in eight premature infants [gestational age at birth 32 +/- 3 (SE) wk, weight at study 1,950 +/- 150 g]. Nasal airflow was measured with a mask pneumotachograph, and pressures in the esophagus and oropharynx were measured with a fluid-filled or 5-Fr Millar pressure catheter. Trials of hyperoxic (40% inspired O2 fraction) CO2 rebreathing were performed during quiet sleep. Total pulmonary resistance decreased progressively as end-tidal PCO2 (PETCO2) increased from 63 +/- 23 to 23 +/- 15 cmH2O.l-1.s in inspiration and from 115 +/- 82 to 42 +/- 27 cmH2O.l-1.s in expiration between room air (PETCO2 37 Torr) and PETCO2 of 55 Torr (P less than 0.05). Lower airway resistance (larynx and lungs) also decreased from 52 +/- 22 to 18 +/- 14 cmH2O.l-1.s in inspiration and from 88 +/- 45 to 30 +/- 22 cmH2O.l-1.s in expiration between PETCO2 of 37 and 55 Torr, respectively (P less than 0.05). Resistance of the supraglottic airway also decreased during inspiration from 7.2 +/- 2.5 to 3.6 +/- 2.5 cmH2O.l-1.s and in expiration from 7.6 +/- 3.3 to 5.3 +/- 4.7 cmH2O.l-1.s at PETCO2 of 37 and 55 Torr (P less than 0.05). The decrease in resistance that occurs within the airway in response to inhaled CO2 may permit greater airflow at any level of respiratory drive, thereby improving the infant's response to CO2.     

Nedocromil sodium in allergen-induced bronchial responses and airway hyperresponsiveness in allergic sheep

We examined the effects of nedocromil sodium, a new drug developed for the treatment of reversible obstructive airway disease, on allergen-induced early and late bronchial responses and the development of airway hyperresponsiveness 24 h after challenge in nine allergic sheep. On occasions greater than 2 wk apart the sheep were treated with 1) placebo aerosol (buffered saline) before and 3 h after antigen challenge, 2) an aerosol of nedocromil sodium (1 mg/kg in 3 ml buffered saline) before antigen challenge and placebo 3 h after challenge, and 3) placebo aerosol before and nedocromil sodium aerosol 3 h after challenge. Early and late bronchial responses were determined by measuring specific lung resistance (sRL) before and periodically after challenge. Airway responsiveness was assessed by determining from dose-response curves the carbachol concentration (in % wt/vol) that increased sRL to 5 cmH2O/s. In the placebo trial, antigen challenge resulted in early and late increases in sRL over a base line of 353 +/- 32 and 131 +/- 17% (SE), respectively. Both early and late increases in sRL were blocked (P less than 0.05) when the sheep were pretreated with nedocromil sodium. When nedocromil was given after the early response, the late response was reduced significantly. Eight of nine sheep developed airway hyperresponsiveness 24 h after antigen challenge. In these eight sheep, carbachol concentration before antigen challenge was 2.6 +/- 0.3%, 24 h later carbachol concentration was significantly lower (1.8 +/- 0.3%). Both nedocromil sodium treatments blocked (P less than 0.05) this antigen-induced airway hyperresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharyngeal resistance in normal humans: influence of gender, age, and obesity

Investigation into the etiology of obstructive sleep apnea is beginning to focus increasing attention on upper airway anatomy and physiology (patency and resistance). Before conclusions concerning upper airway resistance in these patients can be made, the normal range of supraglottic and, more specifically, pharyngeal resistance needs to be better defined. We measured supraglottic and pharyngeal resistances during nasal breathing in a normal population of 35 men and women. Our technique measured epiglottic pressure with a balloon-tipped catheter, choanal pressure using anterior rhinometry, and flow with a sealed face mask and pneumotachograph. Resistance was measured at a flow rate of 300 ml/s during inspiration. Men had a mean pharyngeal resistance (choanae to epiglottis) of 4.6 +/- 0.8 (SE) cmH2O X l-1 X s, whereas women demonstrated a significantly (P less than 0.01) lower value, 2.3 +/- 0.3 cmH2O X l-1 X s. Supraglottic resistance was also higher in men (P = 0.01). Age (r = 0.73, P less than 0.01) correlated closely with pharyngeal resistance in men, but no such correlations could be found in women. These results may have implications in the epidemiology of obstructive sleep apnea.     

Effects of ozone on cyclooxygenase metabolites in the baboon tracheobronchial tree

Short-term exposure to 0.5 parts per million (ppm) ozone has been shown to cause an increase in respiratory resistance in primates that can be diminished by 50% with pretreatment with cromolyn sodium. Because of the known membrane-stabilizing effects of cromolyn and the resultant inhibition of mediator production, we hypothesized a role for the products of arachidonic acid (AA) metabolism in these events. We exposed five adult male baboons to 0.5 ppm ozone on two occasions, once with cromolyn pretreatment and once without. Pulmonary resistance (RL) was monitored and bronchoalveolar lavage (BAL) was performed before and after each exposure. The BAL was analyzed for a stable hydrolysis product of prostacyclin, 6-keto-prostaglandin (PG) F1 alpha, PGE2, a stable hydrolysis product of thromboxane (Tx) A2, TxB2, and PGF2 alpha. RL increased after ozone exposure (1.62 +/- 0.23 to 3.77 +/- 0.51 cmH2O.l-1.s, difference 2.15; P less than 0.02), and this effect was partially blocked by cromolyn (1.93 +/- 0.09 to 3.18 +/- 0.40 cmH2O.l-1.s, difference 1.25; P less than 0.02). The base-line levels of the metabolites of AA in the BAL were as follows (in pg/ml): 6-keto-PGF1 alpha 72.78 +/- 12.6, PGE2 145.92 +/- 30.52, TxB2 52.52 +/- 9.56, and PGF2 alpha 22.28 +/- 5.42. Ozone exposure had no effect on the level of any of these prostanoids (P = NS). These studies quantify the magnitude of cyclooxygenase products of AA metabolism in BAL from baboon lungs and demonstrate that changes in the levels of these mediators in BAL are not prerequisites for ozone-induced increases in respiratory resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Canine bronchoconstriction, gas trapping, and hypoxia with methacholine

The effects of an intravenous methacholine infusion on cardiovascular-pulmonary function were measured in seven mongrel dogs (22.0 +/- 2.8 kg), anesthetized with chloralose and urethan and beta-adrenergically blocked with propranolol. In a volume-displacement plethysmograph, physiological measurements were made at base line and 25 min after establishing a methacholine infusion (0.1-1.0 mg X kg-1 X h-1). Methacholine significantly (P less than 0.05) increased airways resistance (1.9 +/- 0.8 to 8.2 +/- 2.9 cmH2O X l-1 X s), decreased static lung compliance (84.7 +/- 18.5 to 48.2 +/- 9.4 ml/cmH2O), depressed arterial PO2 (81 +/- 17 to 56 +/- 10 Torr), and lowered blood pressure (132 +/- 10 to 69 +/- 18 Torr) and cardiac output (5.7 +/- 1.9 to 4.1 +/- 1.2 l/min). These effects persisted during a further 80 min of methacholine infusion conducted in five of the animals. During the initial 25-min period of methacholine, the end-expired volume (volume-displacement Krogh spirometer) rose in all animals, indicating an increase in functional residual capacity from 997 +/- 115 to 1,623 +/- 259 ml (P less than 0.0005). Analysis of pulmonary pressure-volume curves revealed no change in total lung capacity but an increase in residual volume from 489 +/- 168 to 1,106 +/- 216 ml (P less than 0.001). Thus methacholine caused 617 ml of gas trapping, which was not detected by the Boyle's law principle, presumably because gas was trapped at high transpulmonary pressure. We suggest that intravenous methacholine-induced canine bronchoconstriction, which causes gas trapping and hypoxia, may be a useful animal model of clinical status asthmaticus.     

Effects of vasomotor- and mediator-induced hypotension on bronchomotor tone in swine

We studied the sympathetic neural response on airways to hypotensive stimuli in 19 swine in vivo. The effects of pharmacologically induced hypotension with nitroprusside (NTP) and hypotension elicited by intravenous compound 48/80 (48/80), a mast cell degranulating agent, were compared after equivalent reductions in mean arterial blood pressure (MAP). Reduction of the MAP to 60% of base line with NTP in six swine caused an increase in plasma epinephrine (E) from 60 +/- 28 to 705 +/- 276 pg/ml (P = 0.032) and plasma norepinephrine (NE) from 270 +/- 46 to 796 +/- 131 pg/ml (P = 0.032). Comparable reduction in MAP elicited with 48/80 in six other swine caused a substantially greater increase in both plasma E (9,581 +/- 4,147 pg/ml; P = 0.012 vs. NTP group) and plasma NE (2,239 +/- 637 pg/ml; P = 0.041 vs. NTP group). Catecholamine secretion attenuated mediator-induced changes in lung resistance (RL). In animals receiving 48/80, RL increased from 2.97 +/- 0.31 to 7.44 +/- 0.56 cmH2O.l-1.s. In animals having ganglionic blockade with 7.5 mg/kg iv hexamethonium and beta-adrenergic blockade with propranolol (4.0 mg/kg iv followed by 40 micrograms/kg-1.min-1), comparable doses of 48/80 caused an increase in RL to 18.6 +/- 4.55 cmH2O.l-1.s (P less than 0.04 vs. swine receiving neither hexamethonium nor propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)     

Airway hyperresponsiveness induced by cationic proteins in vivo: site of action

Major basic protein and other native cationic proteins increase airway hyperresponsiveness when administered to the luminal surface of the airways in vitro. To determine whether the same applies in vivo, we assessed airway responsiveness in rats challenged with both aerosolized and intravenously infused methacholine. We partitioned total lung resistance into its airway and tissue components using the alveolar capsule technique. Neither poly-l-lysine nor major basic protein altered baseline mechanics or its dependence on positive end-expiratory pressures ranging from 1 to 13 cmH(2)O. When methacholine was administered to the lungs as an aerosol, both cationic proteins increased responsiveness as measured by airway resistance, tissue resistance, and tissue elastance. However, responsiveness of all three parameters was unchanged when the methacholine was infused. Together, these findings suggest that cationic proteins alter airway responsiveness in vivo by an effect that is apparently limited to the bronchial epithelium.