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.     

Regional and temporal variation in canine peripheral lung responses to dry air

Variation in dry airflow-induced broncho-constriction (AIB) in the canine lung periphery was examined using a wedged bronchoscope technique. Collateral system resistance (Rcs) was measured before and after dry-air challenge. Base-line Rcs was similar throughout the lung periphery, between dogs, and over time. Increasing base-line Rcs was correlated with increasing maximum Rcs 5 min postchallenge (Rcs5), increasing change in Rcs (dRcs5), and decreasing percent change in Rcs above base line (%Rcs5). In contrast to repeated challenge in which base-line Rcs was similar, the magnitude of AIB associated with consecutive challenges with unequal base lines depended on the parameter used to evaluate the response (i.e., Rcs5, dRcs5, or %Rcs5). Peripheral lung resistance then increased to a stimulus specific maximum regardless of base-line Rcs, although data expressed as %Rcs5 or dRcs5 may obscure this observation. Although a change in peripheral lung resistance does not necessarily imply airway narrowing, it is consistent with the idea that changes in Rcs are independent of the collateral system's resting tone.     

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.     

Effects of neutrophils on collateral ventilation and peripheral lung reactivity in dogs

We studied the effects of neutrophil activation on collateral ventilation and peripheral lung reactivity in anesthetized dogs. A fiberoptic bronchoscope was wedged into a segmental airway under direct vision. Ventilation beyond the obstruction thus occurred only through collateral channels. Through one lumen of a double-lumen catheter threaded through the suction port of a bronchoscope, 5% CO2 in air was infused at a known constant rate (V coll). Through the other lumen, pressure at the tip of the bronchoscope was monitored (Pb). For measurements of resistance to flow through the collateral system (Rcs), the ventilation was stopped at functional residual capacity (FRC). Histamine was delivered through the bronchoscope to the obstructed lung segment in the form of an aerosol mist generated by an ultrasonic nebulizer. Measurements of Rcs were used as a parameter of the peripheral lung reactivity to histamine challenge. Within one hour after intravenous infusion of phorbol myristate acetate (PMA), a neutrophil activator, the reactivity to histamine significantly increased. After this, Rcs increased even without histamine challenge. This increase may have been due to an edematous injury of lung caused by PMA. The nature of the injury was confirmed by wet to dry weight ratios. In the other group, the white cell count dropped below 1000 per cu. mm. after intravenous infusion of nitrogen mustard. The same experimental protocols were followed. The Rcs did not increase even with histamine challenge. Our results suggested that substances such as oxygen radicals and arachidonic acid metabolites, which can be released by activated neutrophils, may not not only increase peripheral lung reactivity, but may also induce pulmonary edema.     

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.     

Thromboxane contributes to the immediate antigenic response of canine peripheral airways

The actions of specific humoral mediators in the immediate response of the canine peripheral airways to antigen challenge are not well understood. Using a method which allows localized exposure of the peripheral lung to antigen, we investigated the role of locally released thromboxane A2 (TxA2) in the immediate response of collateral airways to aerosolized antigen. In dogs with native sensitivity to Ascaris suum antigen, resistance to flow through the collateral system (Rcs) was measured using a wedged bronchoscope technique. Local administration of antigen aerosol (25 microliters, 1:10,000 dilution) produced a gradual increase in Rcs which reached a maximum of 365% of base line in 4-8 min. Analysis of bronchoalveolar lavage fluid obtained from the exposed segment at the peak of the response demonstrated significantly more TxB2 compared with control lavage samples (41.8 +/- 7.8 pg/ml vs. 27.9 +/- 8.3; P less than 0.025). After inhibition of thromboxane synthase with UK-37,248 (3 mg/kg iv) or OKY-046 (5 mg/kg iv), the increase in Rcs was significantly reduced at 40 s (P less than 0.001) and 2 min (P less than 0.01) after antigen delivery, and the maximal increase was attenuated by 41% (P less than 0.005). In contrast, the magnitude and time course of the airway response to aerosols of a stable thromboxane analog (U-46619) were not affected by blockade. Despite a similar attenuation (42%) of the maximal increase in Rcs by sodium meclofenamate (3 mg/kg iv), this cyclooxygenase inhibitor had no effect on the time course of the antigenic response.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Calcium channel blockers modulate airway constriction in the canine lung periphery

We studied the effect of two voltage-sensitive calcium channel blockers on Na2EDTA-induced bronchoconstriction in the canine lung periphery. A wedged bronchoscope technique was used to measure collateral system resistance before and after challenges with aerosolized Na2EDTA, hypocapnia, aerosolized acetylcholine, and increased flow of dry air in anesthetized mongrel dogs. Nifedipine, a dihydropyridine calcium channel blocker, reduced hypocapnia-induced bronchoconstriction by 88 +/- 6% (SE) but did not alter Na2EDTA-induced constriction. Verapamil, a phenylalkylamine calcium channel blocker, attenuated hypocapnia- and Na2EDTA-induced bronchoconstriction by 69 +/- 6 and 44 +/- 7%, respectively, but did not significantly alter responses to either acetylcholine or dry air challenge. We conclude that calcium influx through voltage-sensitive calcium channels, perhaps of the T subtype, has a limited role in the initiation of Na2EDTA-induced bronchoconstriction in the canine lung periphery.     

Effects of ozone on peripheral lung reactivity

In previous studies, we demonstrated that local exposures to the lung periphery to 0.1 ppm ozone (O3) produce increases in resistance to flow through the collateral system (Rcs) which are prevented by vagotomy, and the local exposures to 1.0 ppm O3 produces increases in Rcs which are only partially mediated by the parasympathetic system. In the present studies, we evaluated the effects of short exposures to O3 on reactions to H2O and histamine in anesthetized male dogs when no residual effects of the O3 exposures could be detected. For this purpose a fiber-optic bronchoscope was wedged in a segmental airway of anesthetized dogs and was used to deliver O3, aerosols of H2O, histamine (1.5 X 10(-4) mg), and atropine (0.1 mg). Measurements of Rcs were used to monitor responses to these agents. Responses to three successive challenges with H2O and with histamine were not different from each other. A 30-min exposure to 0.1 ppm O3 between the first and second challenge did not alter responses to histamine or H2O. However, a 10-min exposure to 1.0 ppm O3 resulted in a significant increase in responses to both H2O and histamine. No correlation was noted between the magnitude of response to O3 and the increase in response to histamine or H2O following O3 exposure. Parasympathetic blockade (atropine or bilateral cervical vagotomy) abolished the increase in response to H2O but not the increase in response to histamine following exposure to 1.0 ppm O3.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium chelators induce bronchoconstriction in the canine lung periphery

We studied the mechanism by which Na2EDTA, a divalent cation chelator, induces bronchoconstriction in the lung periphery of mongrel dogs as a model of nonspecific small airway hyperresponsiveness. Using a wedged bronchoscope technique, we measured collateral system resistance (Rcs) before and after challenges with aerosolized Na2EDTA. An isotonic solution (4% Na2EDTA, 0.28 osmol/kg) increased Rcs 91 +/- 21%. Na2EDTA increased Rcs in a dose-dependent fashion after challenges of increasing concentration (0, 1, 3, and 6%) or duration (15, 30, 60, and 90 s) with 6% Na2EDTA. Atropine (1 mg/kg iv) significantly (P = 0.01) attenuated the response to an aerosol challenge with distilled H2O. Atropine did not significantly (P = 0.35) alter the response to a challenge with 4% Na2EDTA. Challenge with 6% Na2EDTA (0.42 osmol/kg) increased Rcs to a significantly greater (P less than 0.01) extent than did challenge with 6% CaNa2EDTA (0.37 osmol/kg, 250 +/- 55 vs. 29 +/- 11%, respectively). We conclude that Na2EDTA induces bronchoconstriction in the canine lung periphery in a dose-dependent fashion. As suggested by the Na2EDTA-CaNa2EDTA comparison, hyperosmolality of the solution alone cannot explain this phenomenon. The mechanism does not depend on muscarinic activity and appears to involve chelation of calcium.     

Central role of cyclooxygenase in the response of canine peripheral airways to antigen

We studied the effects of antigen aerosol challenge on the airways of the canine peripheral lung and examined the roles of cyclooxygenase products, histamine, and cholinergic activity in the responses. One-minute deliveries of 1:10,000 or 1:100,000 concentrations of Ascaris suum antigen aerosol through a wedged bronchoscope resulted in mean maximal increases in collateral system resistance (Rcs) of 415 and 177%, respectively, after 4-8 min. Repeated antigen challenge (1:100,000) resulted in significantly decreased responsiveness to antigen after the initial exposure (P less than 0.005). Bronchoalveolar lavage fluid obtained from the isolated, challenged segment had a significant increase in mean (+/- SE) prostaglandin D2 (PGD2) concentration vs. control (222.0 +/- 65.3 vs. 72.7 +/- 19.5 pg/ml; P less than 0.05); histamine concentrations were variable and not significantly different (4.1 +/- 2.6 vs. 1.2 +/- 0.2 ng/ml; P greater than 0.05). In nine experiments, cyclooxygenase inhibition significantly attenuated the antigen-induced increase in Rcs by 53.4% (P less than 0.001), and the concentration of PGD2 in lavage fluid was reduced by 96.0% (P less than 0.01). Blockade of histamine H1-receptors (n = 8) or cholinergic receptors (n = 7) did not significantly affect the airway response (P greater than 0.05). These data indicate that the canine peripheral lung responds in a dose-dependent manner to antigen aerosol challenge and exhibits characteristics of antigen tachyphylaxis. Results also suggest that cyclooxygenase products play a central role in the acute bronchoconstrictive response of the lung periphery.     

ET-1 induced bronchoconstriction in the early phase but not late phase of anesthetized dogs is inhibited by indomethacin and ICI 198615.

Intratracheally injected or aerosolized ET-1 induced quick and long-lasting bronchoconstriction of anesthetized mongrel dogs, thus increasing respiratory resistance(Rrs) with concomitantly decreasing dynamic compliance(Cdyn). As collateral resistance(Rcs) was measured postexposure to aerosolized ET-1 using wedged bronchoscope technique, ET-1 increased Rcs in a dose and time dependent manner. The increase attained maximal in 2 min and then, gradually declined. When the dogs were pretreated with the intravenous injection of 0.1 micrograms/kg ICI 198615, an inhibitor of lipoxygenase, the constrictive response was slowed down. Essentially similar results were also observed with the intravenous injection of 5 mg/kg indomethacin. Our observations suggest that the early phase of the ET-1 induced bronchoconstriction is mediated by eicosanoid metabolites.     

Reduced hyperpnea-induced bronchospasm following repeated cold air challenge

This study assessed reduction in expiratory function in 12 asthmatic subjects both after 5 min of cold air provocation (CAP) with dry air conditioned to approximately 0 degrees C and after exercise (to 85% of predicted maximum heart rate) while breathing ambient room air (approximately 21 degrees C and 40% relative humidity). These assessments were done both before and after the following training protocol. Three 5-min periods of isocapnic cold air hyperpnea separated by 5-min rest periods were performed breathing 0 degrees to -10 degrees C air, for 36 sessions over 12 wk. As expected, pretraining expiratory function was significantly reduced (P less than 0.001) after both CAP and exercise. The posttraining reduction in expiratory function after CAP and exercise, however, was significantly less pronounced (largest P less than 0.05). These data support our hypothesis that repeated bouts of cold air challenge result in airway acclimatization to cold air and consequent decrease in exercise-induced bronchospasm. Acclimatization may result directly either by habituation of the airways or by vasodilation leading to increased bronchial blood flow and consequent reduced airway cooling. An unanticipated finding, though, is that repeated cold air challenge may also cause long-term inflammatory changes in the airways. A significant percentage of subjects experienced reduced base-line pulmonary function and overall exacerbation of asthma symptoms during the training period.     

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.     

Hyperosmotic-induced bronchoconstriction in the canine lung periphery

Hypertonic aerosol- and dry airflow-induced bronchoconstriction were examined in the canine lung periphery by the use of a wedged bronchoscope technique. Collateral resistance was measured in anesthetized dogs before and after exposure to isotonic and hypertonic aerosols and dry airflow. Hypertonic aerosols produced significantly greater responses than isotonic aerosols, and resistance increased in an exposure-dependent manner. Atropine attenuated responses to these challenges, indicating that aerosol-induced peripheral lung constriction was, in part, muscarinic in origin. Paired hypertonic- and dry airflow-induced constriction exhibited marked differences in magnitude and time course: responses to hypertonic aerosol peaked immediately; dry air-induced responses rose slowly to a maximum 5-min postchallenge. These differences may reflect differences in stimulus strength or differences in the regulatory pathways activated by each challenge. Despite this, a significant correlation exists between aerosol- and dry air-induced responses in the canine lung periphery and suggests that changes in airway fluid osmolality have an important role in the initiation of airflow-induced bronchoconstriction.     

Effect of magnesium sulfate on bronchoconstriction in the lung periphery

Magnesium sulfate has been shown to be effective clinically as a bronchodilator, but its mechanism of action is unknown. We used a wedged bronchoscope technique to study the ability of MgSO4 at clinically relevant concentrations to attenuate hypocapnia-, acetylcholine- (ACh), and dry air-induced bronchoconstriction in the canine lung periphery. Control experiments demonstrated that consecutive challenges of either hypocapnia or ACh resulted in greater collateral system resistance (Rcs) after the second challenge compared with the first. Intravenous infusion of MgSO4 diminished the maximum response to a second hypocapnic challenge (Rcs = 1.59 +/- 0.29 cmH2O.ml-1.s prechallenge vs. 1.12 +/- 0.20 postchallenge) but had no effect on either ACh- or dry air-induced bronchoconstriction. Serum magnesium levels before MgSO4 administration were 1.59 +/- 0.04 meq/l and rose to 6.20 +/- 0.13 during the infusion. Previous studies demonstrated that nifedipine, like MgSO4 in this study, attenuates hypocapnia-induced bronchoconstriction in the canine lung periphery but has no effect on ACh- or dry air-induced bronchoconstriction. We conclude that these results are consistent with the idea that, like nifedipine, magnesium acts in the airway as a voltage-sensitive calcium channel blocker.     

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.     

Hypertonic aerosol inhalation does not alter central airway blood flow in dogs

Tracheobronchial blood flow in dogs increases with cold or dry air hyperventilation, possibly as a result of airway drying leading to increased osmolarity of airway surface fluid. This study was designed to examine whether administration of aerosols of various tonicity to alter airway surface fluid osmolarity would induce similar blood flow changes. Tracheobronchial blood flow was measured by the radioactive microsphere technique in six anesthetized dogs ventilated with warm humid air (100% relative humidity) for 15 min (period 1), air containing ultrasonically nebulized saline aerosol (1,711 mosmol/kg) for 3 min (period 2) and 12 min (period 3), and the same aerosol at a higher nebulizer output for a further 3 min (period 4). Between periods 3 and 4, the dogs were ventilated with warm humid air for 30 min to reestablish base-line conditions. In another five dogs, measurements were made after 30 min of ventilation with 1) warm humid air, 2) isotonic saline aerosol, 3) warm humid air, 4) distilled water aerosol (3 dogs), and hypertonic saline aerosol (2 dogs). After the last measurement was made, each dog was killed, the trachea and major bronchi were excised, and blood flow was calculated. No change in blood flow was found during any period of aerosol inhalation. The osmolar load imposed on the airways was estimated and was similar to that occurring during cold or dry air hyperventilation. These data suggest that increasing osmolarity of airway surface fluid does not explain the blood flow changes seen during hyperventilation of cold or dry air.     

Functional antagonism of airway constriction in the canine lung periphery.

We studied the ability of a beta-adrenergic agonist (albuterol) to attenuate calcium chelator- and acetylcholine-induced airway constriction in the lung periphery of anesthetized mongrel and Basenji-Greyhound (BG) dogs. A wedged bronchoscope technique was used to measure collateral system resistance before and after challenges with aerosolized Na2EDTA and acetylcholine. Time course of the response to Na2EDTA differed significantly between mongrel and BG dogs. Peak response to challenge with 4% Na2EDTA occurred within 2 min for mongrel dogs and at 5 min for BG dogs. Albuterol (1 microgram/kg iv) significantly attenuated Na2EDTA-induced bronchoconstriction in both groups of animals (P less than 0.01, each group). Albuterol (1 microgram/kg iv) significantly attenuated acetylcholine-induced bronchoconstriction in mongrel (P less than 0.01) but not in BG dogs. We conclude that a qualitative difference exists in the mechanism of Na2EDTA-induced constriction in the lung periphery of BG compared with mongrel dogs. In addition, the lung periphery of BG dogs demonstrates reduced beta-adrenergic sensitivity with respect to a cholinergic challenge compared with mongrels, suggesting enhanced cholinergic inhibition of the beta-adrenergic system.     

Oscillation mechanics of the human lung periphery in asthma.

To more precisely measure the mechanical properties of the lung periphery in asthma, we have developed a forced oscillation technique that applies a broad-band flow signal through a wedged bronchoscope. We interpreted the data from four healthy and eight mildly asthmatic subjects in terms of an anatomically accurate computer model of the wedged segment. There was substantial overlap in impedance between the two groups, with resistance (R) showing minimal frequency dependence and elastance (E) showing positive and negative frequency dependence across subjects. After direct instillation of methacholine, R rose in both groups, but compared with healthy subjects, the asthmatic subjects displayed upward, parallel shifts in their dose-response curves. The baseline frequency-response patterns of E were enhanced after methacholine. Frequency dependencies of R and E were well reproduced in two normal subjects by a computational model that employed rigid airways connected to constant-phase tissue units but were better reproduced in the other two normal and three asthmatic subjects when the model employed heterogeneous, peripheral airway narrowing and compliant airways. To capture the frequency dependencies of R and E in the remaining five asthmatic subjects, the model was modified by increasing airway wall stiffness. These results indicate that the lung periphery of mildly asthmatic subjects is not well distinguished from that of healthy subjects by measurement of mechanical impedance at baseline, but group differences are seen after challenge with methacholine. Modeling of the response suggests that variable contributions of airway narrowing and wall compliance are operative in determining overall mechanical impedance of the lung periphery in humans with asthma, likely reflecting the functional consequences of airway inflammation and remodeling.