Relationship among mediators, inflammation, and volume history with antigen versus hyperpnea challenge in guinea pigs.

Paralyzed mechanically ventilated guinea pigs constricted to a similar degree by either isocapnic hyperpnea or antigen challenge display significantly different lung resistance (RL) volume history responses to a deep breath. We compared bronchoalveolar lavage (BAL) mediator profiles, BAL total protein concentrations, and tissue histopathology of antigen-constricted (AC), hyperpnea-constricted (HC), and control guinea pigs to determine whether patterns of volume history near peak constriction could be related to specific patterns of lung mediators, indices of microvascular leakage, or severity of tissue inflammation assessed pathologically. Methacholine constricted (MC) animals served as a second control group for assessing the effects of direct smooth-muscle contraction on indices of inflammation and volume history responses. Our results show that despite similar baseline and postchallenge RL, HC and MC animals displayed significant constriction reversal after a deep lung inflation, whereas AC animals did not. BAL concentrations of prostaglandin D2(PGD2), thromboxane B2 (TxB2), and leukotriene C4/D4/E4 (slow reacting substance of anaphylaxis, SRSA) were significantly elevated in both AC and HC animals compared with control and MC animals, with AC and HC BAL differing only with respect to PGD2 values (AC 2.4-fold higher). BAL total protein in AC animals was significantly greater than in HC, MC, and control animals. Histopathology showed significant peribronchial and interstitial cellular inflammation in AC animal specimens, whereas specimens from HC animals had little or no inflammation. Differences in volume history responses observed between equally constricted AC, HC, and MC animals may be due to differences in airway and/or parenchymal microvascular leak and cellular inflammation.

Bronchoalveolar lavage cell and mediator responses to hyperpnea-induced bronchoconstriction in the guinea pig.

We studied the association between bronchoconstriction and bronchoalveolar lavage (BAL) cell and mediator profiles in unsensitized guinea pigs (GP) after hyperpnea to determine whether eicosanoids or histamine are released during hyperpnea-induced bronchoconstriction (HIB). Twelve animals were challenged with warm, moist (WM) air (T = 35 degrees C, relative humidity = 91 to 94%), 14 with room dry (RD) air (T = 25 degrees C, relative humidity less than 2.1%), and 18 with cold, dry (CD) air (T = 7 degrees C, relative humidity less than 2.1%). Lung resistance (RL) and elastance (EL) were recorded at baseline and at 2-min intervals after hyperventilation. Challenges were terminated either when a greater than or equal to 100% increase in RL was observed postchallenge or after completion of a 135 breaths/min challenge if RL did not increase. BAL was performed, and samples were analyzed for total cells, white cell and epithelial cell differentials, total protein concentration, and mediator content.(ABSTRACT TRUNCATED AT 250 WORDS)

Breathing pattern affects respiratory heat loss but not bronchoconstrictor response in asthma.

To determine whether changes in breathing pattern alone affect respiratory heat loss (RHL) and the constrictor response to cold dry gas hyperpnea in asthmatic subjects, we performed the following 2 part study: first we measured RHL in 8 asthmatic and 8 normal subjects during controlled eucapnic hyperpnea while they breathed at inspiratory to expiratory ratios (I/E) of 1:3, 3:1, and 2:2, and we recorded postchallenge forced expiratory volume in 1 sec (FEV1) in the asthmatic group; we then performed the same measurements in 8 asthmatic and 8 normal subjects at fixed target minute ventilation (VE) for tidal volumes of 0.2 X Forced vital capacity (FVC), 0.4 X FVC, and 0.6 X FVC by varying the target respiratory rate appropriately. Our results show that (1) increasing I/E ratio or tidal volume-frequency ratio (VT/f) at fixed VE produced small but statistically significant increases (p less than 0.05) in overall heat loss per unit volume of respired gas (RHL/VE) in both asthmatic and nonasthmatic subjects of 1-4 cal/L; (2) changes in breathing pattern alone did not affect bronchoconstrictor response as assessed by lack of change in slopes and intercepts of % delta FEV1 vs. RHL dose-response curves; and (3) the increase in RHL per unit volume of respired gas resulting from increasing VT/f ratios during cold gas hyperpnea was significantly greater in asthmatic than in nonasthmatic subjects. We conclude that changes in breathing pattern may affect overall RHL measured at the mouth, although the maximum effect of such changes in both asthmatic and nonasthmatic subjects is small (10-15%); that such changes do not significantly alter airway constrictor response in asthmatic persons; and (3) that the effects of changing breathing pattern on RHL may be more pronounced in asthmatic than nonasthmatic subjects, which suggests that the asthmatic group may be less able to adapt to factors that alter the magnitude and site of RHL.

Localization of the site of the bronchoconstrictor effects of leukotriene C4 compared with that of histamine in asthmatic subjects.

Although the sulfidopeptide leukotrienes are known to be potent bronchoconstrictors, the relative aerodynamic site of response to these compounds is controversial. We determined the decrease in maximal expiratory flow rates (Vmax) from partial and maximal flow-volume curves in seven asthmatic subjects after inhalation of aerosols of histamine or leukotriene C4 (LTC4) while breathing air or a mixture of 80% helium and 20% oxygen (He/O2). Density dependence (DD) of maximal expiratory flow was determined from partial expiratory flow volume curves by an isovolumic comparison of maximal expiratory flows with subjects breathing He/O2 with those obtained while breathing air. Measurements were made before and after inhalation of aerosols generated from graded concentrations of each constrictor agent. An aerodynamic site of response to LTC4 more central than for histamine was indicated by a significant (p less than 0.02) increase in DD with the former but not with the latter agonist. The ratio of Vmax at 30% vital capacity determined from maximal and partial maneuvers (M/P) was routinely higher at baseline while breathing He/O2 compared to the corresponding values with air, suggesting a degree of peripheral obstruction that was reversed by a deep inhalation. Obstruction induced by LTC4 inhalation resulted in a greater increase in M/P compared with baseline when air was the test gas (p less than 0.02). This was not observed when He/O2 was the test gas. Similar effects on M/P were not induced by histamine aerosol inhalation, consistent with a central airway response to LTC4 that was not affected by volume history.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory mechanics in acute quadriplegia. Lung and chest wall compliance and dimensional changes during respiratory maneuvers.

We measured lung and chest wall compliance as well as rib cage and abdominal dimensions in the supine position in five acute C4-7 quadriplegics. Studies were performed serially from 1 to 12 months after injury. Results were compared with those of control groups of chronic (greater than 1 yr after injury) quadriplegics and normal volunteers. We found that lung compliance was lower in acute and chronic quadriplegics (0.129 +/- 0.023 and 0.176 +/- 0.043 L/mm Hg, respectively) than in normal subjects (0.278 +/- 0.086 L/mm Hg) and that these changes apparently occurred within 1 month of injury. Specific lung compliance appeared to be reduced to a lesser degree, suggesting that the changes in lung compliance were partly due to reduced lung volumes and partly to altered mechanical properties of the lung. During respiratory maneuvers, abdomen and rib cage dimensional changes demonstrated rib cage distortion. This distortion was less severe in chronic than in acute quadriplegics. The improvement in chest wall stability was likely due to increased strength of cervical accessory muscles of respiration and improved coupling of the various rib cage elements in chronic quadriplegics.

Effects of airway tone and volume history on maximal expiratory flow in asthma.

We assessed the difference between isovolumic maximal expiratory flows (Vmax) using maneuvers begun at mid-lung volumes, so-called partial expiratory flow-volume curves (P), vs. those begun at full inflation, so-called maximal expiratory flow-volume curves (M), in 10 asthmatic subjects before and following obstruction induced by isocapnic hyperpnea with cold air and before and after bronchodilation with a beta-agonist or antimuscarinic agent. Volume history effects were quantitated as an M-to-P ratio of Vmax at 30% vital capacity (M/P V30). Although M/P V30 was variable among patients at base line, there was a uniform increase in M/P V30 during constriction and a consistent decrease below base line after dilation. Blunting of induced obstruction with beta-agonists also diminished the increase in M/P V30. Antimuscarinics, despite equivalent bronchodilation, failed to alter the degree of obstruction induced by cold air or the increase in M/P V30 seen during obstruction. The level of airway tone, as indicated by specific resistance, related directly to the M/P V30. We conclude that the response of the asthmatic lung to a deep inhalation is relatively predictable when acute changes in airway tone are produced.

Finite difference analysis of respiratory heat transfer.

A numerical computer model of heat and water transfer within the tracheobronchial tree of humans was developed based on an integral formulation of the first law of thermodynamics. Simulation results were compared with directly measured intraluminal airway temperature profiles previously obtained in normal human subjects, and a good correlation was demonstrated. The model was used to study aspects of regional pulmonary heat transfer and to predict the outcomes of experiments not yet performed. The results of these simulations show that a decrease in inspired air temperature and water content at fixed minute ventilation produces a proportionately larger increase in heat loss from extrathoracic airways relative to intrathoracic, whereas an increase in minute ventilation at fixed inspired air conditions produces the opposite pattern, with cold dry air penetrating further into the lung, and that changes in breathing pattern (tidal volume and frequency) at fixed minute ventilation and fixed inspiratory-to-expiratory (I/E) ratio do not affect local air temperature profiles and heat loss, whereas changes in I/E ratio at fixed minute ventilation do cause a significant change.

Endogenous adrenergic modification of exercise-induced asthma.

To determine if endogenous adrenergic activity could modify the obstructive response to exercise in subjects with asthma, we had 10 subjects undergo two bouts of cycle ergometry under controlled inspired air conditions while peak expiratory flow rates and plasma catecholamines were serially recorded. The second challenge of each pair was timed to coincide with the height of the bronchospasm induced by the first. A similar protocol was undertaken with isocapnic hyperventilation to serve as a control. The initial exercise produced bronchodilatation followed by bronchoconstriction when exercise ceased. During the second challenge, the obstruction resolved totally, only to recur once more when the subjects stopped work. Plasma concentrations of norepinephrine exactly mirrored the fluctuations in pulmonary mechanics, rising with bronchodilatation and falling with bronchoconstriction. The pattern with hyperventilation differed from exercise in that there was no significant increase in norepinephrine during the challenges. To determine if norepinephrine could abolish the bronchial narrowing produced by exercise, and, as a result, possibly account for the changes in mechanics that we observed, we performed a second study in which eight subjects were administered an aerosol of this compound to inhale during an episode of exercise-induced asthma. As with the endogenous elevation, exogenously administered norepinephrine also totally abolished the attack. These data demonstrate that the sympathoadrenal activity that occurs with repetitive exercise in subjects with asthma can materially influence the severity of exercise-induced asthma.

Changes in lung volume and rib cage configuration with abdominal binding in quadriplegia.

Previous studies suggest that abdominal binding may affect the interaction of the rib cage and the diaphragm over the tidal range of breathing in quadriplegia. To determine whether abdominal binding influences rib cage motion over the entire range of inspiratory capacity, we used spirometry and the helium-dilution technique to measure functional residual capacity (FRC), inspiratory capacity, and total lung capacity (TLC) in eight quadriplegic and five normal subjects in supine, tilted (37 degrees), and seated positions. Combined data in all three positions indicated that, with abdominal binding, FRC and TLC decreased in normal subjects [delta FRC = -0.33 + 0.151 (SD) P less than 0.01); delta TLC = -0.16 + 0.121, P less than 0.05]. In quadriplegia there was also a reduction in FRC with binding (delta FRC = -0.32 + 0.101, P less than 0.001). However, TLC increased in quadriplegia (delta TLC = 0.07 + 0.061, P less than 0.025). In an additional six quadriplegic and five normal subjects, we used magnetometers to define the influences of abdominal binding on rib cage dimensions and TLC. In quadriplegia, rib cage dimensions were increased at TLC with abdominal binding, whereas there was no change in normals. Our data suggest that this inspiratory effect of abdominal binding on augmenting rib cage volume in quadriplegia is greater than the effect of impeding diaphragm descent, and thus abdominal binding produces a net increase in TLC in quadriplegia.

Breathing pattern affects airway wall temperature during cold air hyperpnea in humans.

We studied the influence of flow rate on respiratory heat exchange in 9 healthy adult subjects using a new noninvasive technique, the single-breath temperature washout (SBTW) curve. The SBTW curve is a plot of exhaled gas temperature versus exhaled volume during a standard exhalation and consists of an initial rise (within the first 200 ml) to a plateau temperature that persists through the remainder of exhalation. We found that exhaled gas temperatures within the initial expirate were colder at every airway locus than corresponding intra-airway gas temperatures at end-inspiration, suggesting that heat exchange occurs between lumenal gas and the relatively cooler airway walls during exhalation. The SBTW plateau temperatures were: (1) lower after preconditioning the airways with rapid (80 L/min) isocapnic hyperpnea of frigid air than after less rapid (40 L/min) cold-air hyperpnea or after quiet breathing; (2) lower when, after identical airway preconditioning regimens, the SBTW exhalation was performed with a slower (0.5 versus 2.5 L/s) expiratory flow; and (3) lower when SBTW curves were obtained after airway preconditioning using respiratory patterns with larger inspiration-expiration duration (I:E) ratios (5:1 versus 1:5) at fixed minute ventilation and respiratory rate. Our results indicate that the global respiratory gas-wall heat transfer coefficient increases with velocity to the 0.9 power, a finding similar to that in previous studies of turbulent flow in rigid pipes.

Intraairway thermal profiles during exercise and hyperventilation in normal man.

When large volumes of air are inhaled at rapid rates of ventilation, substantial segments of the tracheobronchial tree become involved in the conditioning process and the inspirate does not reach body conditions of temperature and humidity until it passes well into the peripheral bronchi. To determine if the manner in which ventilation is elevated is an important factor in producing this response, we measured the temperature of the airstream at six points in the tracheobronchial tree from the pharynx to the subsegmental bronchi during 5 min of exercise and voluntary hyperventilation in seven normal subjects while they inhaled frigid air. Minute ventilation and respiratory frequency were recorded at minute intervals and intrathoracic temperatures were measured continuously. With both forms of hyperpnea, airway temperature fell dramatically, and there were no significant differences between exercise and hyperventilation. These results demonstrate that the thermal events that occur within the lung during short, moderately intense degrees of exercise can be readily simulated by voluntary hyperventilation when ventilation and inspired air conditions are matched. Our data also indicate that this form of exercise does not result in an increase in airstream temperature and raise the possibility that the bronchial blood supply may be determined by the local thermal needs of the airways to recover heat and water independent of, at least moderate, increases in cardiac output.

Thermal mapping of the airways in humans.

To characterize the intrathoracic thermal events that occur during breathing in humans, we developed a flexible probe (OD 1.4 mm) containing multiple thermistors evenly spaced over 30.2 cm, that could be inserted into the tracheobronchial tree with a fiberoptic bronchoscope. With this device we simultaneously recorded the airstream temperature at six points from the trachea to beyond the subsegmental bronchi in six normal subjects while they breathed ambient and frigid air at multiple levels of ventilation (VE). During quiet breathing of room air the average temperature ranged from 32.0 +/- 0.05 degrees C in the upper trachea to 35.5 +/- 0.3 degrees C in the subsegmental bronchi. As ventilation was increased, the temperature along the airways progressively decreased, and at a VE of 100+ 1/min the temperature at the above two sites fell to 29.2 +/- 0.5 and 33.9 +/- 0.8 degrees C, respectively. Interval points were intermediate between these extremes. With cold air, the changes were considerably more profound. During quiet breathing, local temperatures approximated those recorded in the maximum VE room-air trial, and at maximum VE, the temperatures in the proximal and distal airways were 20.5 +/- 0.6 and 31.6 +/- 1.2 degrees C, respectively. During expiration, the temperature along the airways progressively decreased as the air flowed from the periphery of the lung to the mouth: the more the cooling during inspiration, the lower the temperature during expiration. These data demonstrate that in the course of conditioning inspired air the intrathoracic and intrapulmonic airways undergo profound thermal changes that extend well into the periphery of the lung.

Influence of cromolyn sodium on airway temperature in normal subjects.

It is well established that cromolyn sodium attenuates the bronchoconstriction induced by airway cooling in both normal and asthmatic subjects. To determine whether this protection derives from a modification of the thermal events that transpire during the conditioning of inspired air, we first recorded the effect of cromolyn on the bronchoconstrictor response to hyperventilation with frigid air in 7 normal subjects. On a separate occasion, we imposed the same thermal burden and measured the temperature at multiple sites within the airways before and after pretreatment with cromolyn. The first cold air challenge produced a significant decrease in forced expiratory volume in one second (FEV1) of 5.5 +/- 0.9% (SEM) and these changes were significantly reduced by cromolyn (FEV1 = 2.8 +/- 0.9%; p less than 0.05). In concert with the improvement in mechanics, the temperatures (T) within the trachea (tr) and the anterior segment of the right lower lobe (AS-RLL) were significantly higher after cromolyn (Ttr = 1.3 +/- 0.2 degrees C; p less than 0.01; TAS-RLL = 1.0 +/- 0.4 degrees C; p = 0.05), and there was a direct positive relationship between the mechanical protection offered by the drug and the increase in airway temperature (Spearman's rank correlation coefficient = 0.83; p = 0.05). These data suggest that cromolyn modifies respiratory heat exchange in such a fashion as to limit airway cooling. The mechanism of this action is not presently known but may reflect a direct or indirect influence on the bronchial vasculature.

The role of infection in asthma: implications for antibiotic therapy.

Respiratory infection, most prominently bronchiolitis, contracted in infancy is frequently associated with recurrent wheezing episodes and asthma in later life. Atopic individuals and those with a family history of allergy or asthma in first-degree relatives are especially susceptible to the development of chronic airway dysfunction and should be identified early. It is also noteworthy that parenteral cigarette smoking may serve as an additional marker of the high-risk patient. Respiratory infection affecting older children and adults is more commonly due to rhinovirus and influenza A and may cause a transient hyperreactivity to bronchoconstrictor agonists, but does not cause persistent dysfunction. The mechanism(s) by which antecedent respiratory infection is related to recurrent wheezing and asthma remain speculative, and at present a direct causal relationship cannot be established with certainty. Infectious respiratory disorders are also a cause of exacerbations of asthma in adults but more commonly in children, and these also are primarily viral in origin. Consequently, in the absence of clear evidence of bacterial infection, routine antibiotic use in this setting is unwarranted.