Mechanical impedance of the lung periphery

Hantos, Z., F. Peták, Á. Adamicza, T. Asztalos, J. Tolnai, and J. J. Fredberg. Mechanical impedance ofthe lung periphery. J. Appl. Physiol.83(5): 1595-1601, 1997.The mechanics of the regional airways andtissues was studied in isolated dog lobes by means of a modifiedwave-tube technique. Small-amplitude pseudorandom forced oscillationsbetween 0.1 and 48 Hz were applied through catheters wedged in2-mm-diameter bronchi in three regions of each lobe at translobarpressures (PL) of 10, 7, 5, 3, 2, and 1 cmH₂O. The measuredregional input impedances were fitted by a model containing theresistance (R₁) and inertance(I) of the regular (segmental) airways, the resistance of thecollateral channels (R₂), andthe damping (G) and elastance (H) of the local tissues. This model gavefar better fits to the data on impedance of the lung periphery thanwhen G and H were replaced by a single tissue compliance, whichexplains why interruption of segmental flow did not lead tomonoexponential pressure decay in previous studies. The interlobar andintralobar variances of the parameters were equally significant, andpoor correlations were found between the airway parametersR₁ andR₂ and between any airway andtissue parameter (e.g., R₁ and H).R₂ was on average ~10 timeshigher than R₁, although theR₂-to-R₁ratios and their dependencies on PL were regionally highlyvariable. However, for the total of 33 regions studied, thePL dependence was the same forR₁ and R₂, which may reflect similarmorphological structures for the regular and collateral airways. Thedependencies of G and H on PLshowed high interregional variations; generally, however, they assumedtheir minima at medium PL values(~5 cmH₂O).

     

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.     

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.     

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.     

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.     

Spatial and spectral dependence of the auditory periphery in the northern leopard frog

We investigated directionalities of eardrum vibration and auditory nerve response in anesthetized northern leopard frogs (Rana pipiens pipiens). Simultaneous measures of eardrum velocities and firing rates from 282 auditory nerve fibers were obtained in response to free-field sounds from eight directions in the horizontal plane. Sound pressure at the external surface of the ipsilateral eardrum was kept constant for each presentation direction (± 0.5 dB). Significant effects of sound direction on eardrum velocity were shown in 90% of the cases. Maximum or minimum eardrum velocity was observed more often when sounds were presented from the lateral and posterior fields, or from the anterior and contralateral fields, respectively. Firing rates of 38% of the fibers were significantly affected by sound direction and maximum or minimum firing rate was observed more frequently when sounds were delivered from the lateral fields, or from the anterior and contralateral fields, respectively. Directionality patterns of eardrum velocity and nerve firing also vary with sound frequency. Statistically significant correlation between eardrum velocity and nerve fiber firing rate was demonstrated in only 45% of the fibers, suggesting that sound transmission to the inner ear through extratympanic pathways plays a non-trivial role in the genesis of directionality of auditory nerve responses.Abbreviations CF characteristic frequency - SVL snout-vent length - TM tympanic membrane     

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)     

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.     

Bronchial blood flow affects recovery from constriction in dog lung periphery

We investigated the effect of eliminating the bronchial circulation on recovery time from intravenous histamine challenge in canine lung periphery. Results from animals with intact bronchial circulations were compared with a second group in which the left lower lobe was isolated in situ. The pulmonary artery to this lobe was perfused and a bronchoscope was wedged in a small airway, which provided an index of resistance to airflow through the collateral system. The lobe was challenged with intravenous histamine, and the time constant of recovery (tau) from bronchoconstriction was measured. With or without pulmonary blood flow, elimination of the bronchial circulation increased tau 44.4 and 48.5%, respectively. This increase was similar to that found by stopping pulmonary blood flow alone (56.5%). Histamine challenges were also performed in sympathectomized or vagotomized animals with intact bronchial circulations. Neither of these conditions increased tau. We conclude that blood flow through the bronchial circulation affects the recovery time from intravenous histamine challenge in the lung periphery to a degree similar to that of the pulmonary circulation.     

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.     

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.     

Structure of slowly adapting pulmonary stretch receptors in the lung periphery.

Pulmonary sensory receptors are the initiating sites for lung reflexes; however, little is known about their structure, especially the relationship between the structure and function of these receptors. Using a novel approach (combining electrophysiological and morphological techniques), we examined the structures of the typical slowly adapting pulmonary stretch receptors (SARs) located in the lung periphery. We recorded SAR activities in the cervical vagus nerve, identified the receptive field, dissected the SARs in blocks, fixed and processed these blocks for immunohistochemical staining using anti-Na+/K+-ATPase, and examined the blocks under a confocal microscope. These SAR structures have multiple endings that have terminal knobs. Some structures that are located in the airway walls have terminal knobs buried in smooth muscle. Others are in the most peripheral part of the lung, and their terminal knobs have no obvious relation to smooth muscle, suggesting that muscle contraction may not be a direct factor for SAR activation.