Partitioning airway and lung tissue resistances in humans: effects of bronchoconstriction

Kaczka, David W., Edward P. Ingenito, Bela Suki, and KennethR. Lutchen. Partitioning airway and lung tissue resistances inhumans: effects of bronchoconstriction. J. Appl.Physiol. 82(5): 1531-1541, 1997.The contributionof airway resistance(Raw) and tissue resistance(Rti) to totallung resistance(RL)during breathing in humans is poorly understood. We have recentlydeveloped a method for separating Rawand Rti from measurements ofRLand lung elastance (EL)alone. In nine healthy, awake subjects, we applied a broad-band optimalventilator waveform (OVW) with energy between 0.156 and 8.1 Hz thatsimultaneously provides tidal ventilation. In four of the subjects,data were acquired before and during a methacholine (MCh)-bronchoconstricted challenge. TheRLandELdata were first analyzed by using a model with a homogeneous airwaycompartment leading to a viscoelastic tissue compartment consisting oftissue damping and elastance parameters. Our OVW-based estimates ofRaw correlated well with estimatesobtained by using standard plethysmography and were responsive toMCh-induced bronchoconstriction. Our data suggest thatRti comprises ~40% of totalRLat typical breathing frequencies, which corresponds to ~60% ofintrathoracic RL. During mildMCh-induced bronchoconstriction, Rawaccounts for most of the increase inRL. At high doses of MCh, therewas a substantial increase in RLat all frequencies and inEL athigher frequencies. Our analysis showed that bothRaw andRti increase, but most of the increaseis due to Raw. The data also suggestthat widespread peripheral constriction causes airway wall shunting toproduce additional frequency dependence inEL.

     

Human respiratory input impedance between 32and 800Hz, measured by interrupter technique and forced oscillations

Frey, Urs, Bela Suki, Richard Kraemer, and Andrew C. Jackson. Human respiratory input impedance between 32 and 800 Hz,measured by interrupter technique and forced oscillations. J. Appl. Physiol. 82(3):1018-1023, 1997.Respiratory input impedance (Zin) over a widerange of frequencies (f) has beenshown to be useful in determining airway resistance (Raw) and tissueresistance in dogs or airway wall properties in human adults. Zinmeasurements are noninvasive and, therefore, potentially useful ininvestigation of airway mechanics in infants. However, accuratemeasurements of Zin at these f valueswith the use of forced oscillatory techniques (FOT) in infants aredifficult because of their relatively high Raw and large compliance ofthe face mask. If pseudorandom noise pressure oscillations generated bya loudspeaker are applied at the airway opening (FOT), the power of theresulting flow decreases inversely withf because of capacitive shunting intothe volume of the gas in the speaker chamber and in the face mask. Westudied whether high-frequency respiratory Zin can be measured by using rapid flow interruption [high-speed interrupter technique(HIT)], in which we expect the flow amplitude in the respiratorysystem to be higher than in the FOT. We compared Zin measured by HIT with Zin measured by FOT in a dried dog lung and in five healthy adultsubjects. The impedance was calculated from two pressure signalsmeasured between the mouth and the HIT valve. The impedance could beassessed from 32 to 800 Hz. Its real part at lowf as well as thef and amplitude of the first andsecond acoustic resonance, measured by FOT and by HIT, were notsignificantly different. The power spectrum of oscillatory flow whenthe HIT was used showed amplitudes that were at least 100 times greaterthan those when FOT was used, increasing atf > 400 Hz. In conclusion,the HIT enables the measurement of high-frequency Zin data ranging from 32 to 800 Hz with particularly high flow amplitudes and, therefore, possibly better signal-to-noise ratio. This is particularly important in systems with high Raw, e.g., in infants, when measurements have tobe performed through a face mask.

     

Respiratory transfer impedance between 8and 384Hz in guinea pigs before and after bronchial challenge

Sobh, Jamil F., Craig M. Lilly, Jeffrey M. Drazen, andAndrew C. Jackson. Respiratory transfer impedance between 8 and384 Hz in guinea pigs before and after bronchial challenge. J. Appl. Physiol. 82(1): 172-181, 1997.We report a forced oscillatory technique for noninvasivelymeasuring respiratory transfer impedance (Ztr) between 8 and 384 Hz inguinea pigs. This technique uses a device consisting of two chambers:one surrounding the animal's head that is used as a plethysmograph tomeasured flow through the airway opening and the other that surroundsthe animal's body and is used to apply pressure oscillations to thebody surface. Ztr was measured in spontaneously breathing awake guineapigs and while the animals were anesthetized in normal andmethacholine-challenged conditions. An eight-element model consistingof an airway compartment separated from a tissue compartment by a shuntgas compression compartment was fit to the data. Anesthesia increasedcentral and peripheral airway resistance and bronchial airway wallcompliance by 13, 31, and 44%, respectively, whereas it decreasedtissue compliance by 37%. Compared with the unanesthetized condition, the methacholine challenge (20 µg/kg) resulted in an increase incentral and peripheral airway resistance (69 and 319%, respectively) and a decrease in bronchial airway wall and tissue compliance (37 and79%, respectively). This technique is capable of measuring Ztr inanesthetized and awake guinea pigs. Analysis of these data with thiseight-element model provides reasonable estimates of airway and tissueparameters.

     

Airway resistance and tissue elastance from input or transfer impedance in bronchoconstricted monkeys.

Ascaris suum (AS) challenge in nonhuman primates is used as an animal model of human asthma. The primary goal of this study was to determine whether the airways and respiratory tissues in monkeys that are bronchoconstricted by AS inhalation behave similarly to those in asthmatic humans. Airway resistance (Raw) and tissue elastance (Eti) were estimated from respiratory system input (Zin) or transfer (Ztr) impedance. Zin (0.4-20 Hz) and Ztr (2-128 Hz) were measured in anesthetized cynomolgus monkeys (n = 10) under baseline (BL) and post-AS challenge conditions. Our results indicate that AS challenge in monkeys produces 1) predominantly an increase in Raw and not tissue resistance, 2) airway wall shunting at higher AS doses, and 3) heterogeneous airway constriction resulting in a decrease of lung parenchyma effective compliance. We investigated whether the airway and tissue properties estimated from Zin and Ztr were similar and found that Raw estimated from Zin and Ztr were correlated [r(2) = 0.76], not significantly different at BL (13.6 +/- 1.4 and 13.1 +/- 0.9 cmH(2)O. l(-1). s(-1), respectively), but significantly different post-AS (20.5 +/- 4.5 cmH(2)O. l(-1). s(-1) and 18.5 +/- 5.2 cmH(2)O. l(-1). s(-1)). There was no correlation between Eti estimated from Zin and Ztr. The changes in lung mechanical properties in AS-bronchoconstricted monkeys are similar to those recently reported in human asthma, confirming that this is a reasonable model of human asthma.     

Maturational changes in responses of tissue and airway resistance to histamine

Dreshaj, Ismail A., Musa A. Haxhiu, Charles F. Potter, FatonH. Agani, and Richard J. Martin. Maturational changes in responsesof tissue and airway resistance to histamine. J. Appl.Physiol. 81(4): 1785-1791, 1996.We determinedhow postnatal maturation affects the relative contributions of airwaysand lung parenchyma to pulmonary resistance(RL) and whether there are developmental differences in their respective responses to constrictive agents. We studied open-chest ventilated anesthetized piglets of threeages: 2-4 days, 2-3 wk, and 10 wk.RL was partitioned into tissue(Rti) and airway (Raw) resistance by means of alveolar capsules underbaseline conditions and after intravenous histamine. Postnatalmaturation was associated with a progressive decline inRL, Rti, and Raw and with anincrease in the contribution of Rti toRL from 38 ± 8% at 2-4days to 72 ± 2% at both 2-3 and 10 wk. Histamine causedRL to increase at all ages. Whenpartitioned into Rti and Raw, the percent increase in Rti significantlyexceeded that of Raw at both 2-4 days and 2-3 wk. Incontrast, the percent increase in Raw significantly exceeded that ofRti at 10 wk. Administration of atropine before histamine in pigletsaged 10 wk reduced the response of Rti and Raw to histamine.Histamine-induced responses ofRL were blocked by priorH₁-receptor blockade withpyrilamine (2 mg/kg). These results indicate that1) the contribution of Rti and Rawto RL changes during maturationand that 2) contractile responses toexogenous histamine are manifest predominantly in most distal airwaysand lung parenchyma during early postnatal life; with advancingmaturation there is greater contribution of airways to the increase inRL induced by histamine.

     

Lung tissue behavior in the mouse during constriction induced by methacholine and endothelin-1

Nagase, Takahide, Hirotoshi Matsui, Tomoko Aoki, YasuyoshiOuchi, and Yoshinosuke Fukuchi. Lung tissue behavior in the mouseduring constriction induced by methacholine and endothelin-1. J. Appl. Physiol. 81(6):2373-2378, 1996.Recently, mice have been extensively used toinvestigate the pathogenesis of pulmonary disease because appropriatemurine models, including transgenic mice, are being increasinglydeveloped. However, little information about the lung mechanics of miceis currently available. We questioned whether lung tissue behavior andthe coupling between dissipative and elastic processes, hysteresivity(), in mice would be different from those in the other species. Toaddress this question, we investigated whether tissue resistance (Rti)and  in mice would be affected by varying lung volume, constrictioninduced by methacholine (MCh) and endothelin-1 (ET-1), andhigh-lung-volume challenge during induced constriction. From measuredtracheal flow and tracheal and alveolar pressures in open-chest ICRmice during mechanical ventilation [tidal volume = 8 ml/kg,frequency (f) = 2.5 Hz], we calculated lung resistance(RL), Rti, airway resistance(Raw), lung elastance (EL),and  (=2fRti/EL). Underbaseline conditions, increasing levels of end-expiratory transpulmonarypressure decreased Raw and increased Rti. The administration ofaerosolized MCh and intravenous ET-1 increasedRL, Rti, Raw, andEL in a dose-dependent manner.Rti increased from 0.207 ± 0.010 to 0.570 ± 0.058 cmH₂O ^· ml^{1 ·} safter 10⁷ mol/kg ET-1(P < 0.01). After inducedconstriction, increasing end-expiratory transpulmonary pressuredecreased Raw. However,  was not affected by changing lung volume,constriction induced by MCh and ET-1, or high-lung-volume challengeduring induced constriction. These observations suggest that1)  is stable in mice regardlessof various conditions, 2) Rti is animportant fraction of RL andincreases after induced constriction, and3) mechanical interdependence mayaffect airway smooth muscle shortening in this species. In mammalianspecies, including mice, analysis of  may indicate that both Rti andEL essentially respond to asimilar degree.

     

Confidence intervals of respiratory mechanical properties derived from transfer impedance

Short-term intraindividual variability of the parameters derived from respiratory transfer impedance (Ztr) measured from 4 to 32 Hz was studied in 10 healthy subjects. The corresponding 95% confidence intervals (CIo) were compared with those computed from a single set of data (CIL) according to Lutchen and Jackson (J. Appl. Physiol. 62: 403-413, 1987). Ztr was analyzed with the six-coefficient model of DuBois et al. (J. Appl. Physiol. 8: 587-594, 1956), which includes airway resistance (Raw) and inertance (Iaw), tissue resistance (Rti), inertance (Iti), and compliance (Cti), and alveolar gas compressibility (Cg). The lowest variability was seen for Iaw (CIo = 11.1%), closely followed by Raw (14.3%) and Cti (14.8%), and the largest for Rti and Iti (24.6 and 93.6%, respectively). Using a simpler model, where Iti was excluded, significantly decreased the variability of Iaw (P less than 0.01) and Rti (P less than 0.05) but was responsible for a systematic decrease of Raw and Iaw and increase of Rti. Except for Raw with both models and Iaw with the simpler model, CIL was greater than CIo. Whatever the model, a high correlation between both sets of confidence intervals was found for Rti and Iaw, whereas no correlation was seen for Raw. This suggests that the variability of the former coefficients mainly reflects experimental noise, whereas that of the latter is largely due to biological variability.     

Respiratory tissue properties derived from flow transfer function in healthy humans

Tomalak, W., R. Peslin, and C. Duvivier. Respiratorytissue properties derived from flow transfer function in healthy humans. J. Appl. Physiol. 82(4):1098-1106, 1997.Assuming homogeneity of alveolar pressure, therelationship between airway flow and flow at the chest during forcedoscillation at the airway opening [flow transfer function(FTF)] is related to lung and chest wall tissue impedance (Zti):FTF = 1 + Zti/Zg, where Zg is alveolar gas impedance, which isinversely proportional to thoracic gas volume. By using a flow-typebody plethysmograph to obtain flow rate at body surface, FTF has beenmeasured at oscillation frequencies (f_os) of 10, 20, 30 and 40 Hz in eight healthy subjects during both quiet and deepbreathing. The data were corrected for the flow shunted through upperairway walls and analyzed in terms of tissue resistance (Rti) andeffective elastance (Eti,eff) by using plethysmographically measuredthoracic gas volume values. In most subjects, Rti was seen to decreasewith increasingf_os and Eti,effto vary curvilinearly withf_os²,which is suggestive of mechanical inhomogeneity. Rti presented a weakvolume dependence during breathing, variable in sign according tof_os and amongsubjects. In contrast, Eti,eff usually exhibited a U-shaped patternwith a minimum located a little above or below functional residualcapacity and a steep increase with decreasing or increasing volume(30-80 hPa/l²) on eitherside. These variations are in excess of those expected from the sigmoidshape of the static pressure-volume curve and may reflect the effect ofrespiratory muscle activity. We conclude that FTF measurement is aninteresting tool to study Rti and Eti,eff and that these parametershave probably different physiological determinants.

     

Density dependence of respiratory input and transfer impedances in humans

Total respiratory input (Zin) and transfer (Ztr) impedances were obtained from 4 to 30 Hz in 10 healthy subjects breathing air and He-O2. Zin was measured by applying pressure oscillations around the head to minimize the upper airway shunt and Ztr by applying pressure oscillations around the chest. Ztr was analyzed with a six-coefficient model featuring airways resistance (Raw) and inertance (Iaw), alveolar gas compressibility, and tissue resistance, inertance, and compliance. Breathing He-O2 significantly decreased Raw (1.35 +/- 0.32 vs. 1.74 +/- 0.49 cmH2O.l-1.s in air, P less than 0.01) and Iaw (0.59 +/- 0.33 vs. 1.90 +/- 0.44 x 10(-2) cmH2O.l-1.s2), but, as expected, it did not change the tissue coefficients significantly. Airways impedance was also separately computed by combining Zin and Ztr data. This approach demonstrated similar variations in Raw and Iaw with the lighter gas mixture. With both analyses, however, the changes in Iaw were more than what was expected from the change in density. This indicates that factors other than gas inertance are included in Iaw and reveals the short-comings of the six-coefficient model to interpret impedance data.     

Greater airway narrowing in immature than in mature rabbits during methacholine challenge

Shen, X., V. Bhargava, G. R. Wodicka, C. M. Doerschuk, S. J. Gunst, and R. S. Tepper. Greater airway narrowing in immature thanin mature rabbits during methacholine challenge. J. Appl. Physiol. 81(6): 2637-2643, 1996.It hasbeen demonstrated that methacholine (MCh) challenge produces a greaterincrease in lung resistance in immature than in mature rabbits (R. S. Tepper, X. Shen, E. Bakan, and S. J. Gunst.J. Appl. Physiol. 79: 1190-1198, 1995). To determine whether this maturational difference in the response to MCh was primarily related to changes in airway resistance (Raw) or changes in tissue resistance, we assessed airway narrowing in1-, 2-, and 6-mo-old rabbits during intravenous MCh challenge (0.01-5.0 mg/kg). Airway narrowing was determined frommeasurements of Raw in vivo and from morphometric measurements on lungsections obtained after rapidly freezing the lung after the MChchallenge. The fold increase in Raw was significantly greater for 1- and 2-mo-old animals than for 6-mo-old animals. Similarly, the degree of airway narrowing assessed morphometrically was significantly greaterfor 1- and 2-mo-old animals than for 6-mo-old animals. The foldincrease in Raw was highly correlated with the degree of airwaynarrowing assessed morphometrically(r² = 0.82, P < 0.001). We conclude that thematurational difference in the effect of MCh on lung resistance isprimarily caused by greater airway narrowing in the immature rabbits.

     

Effect of tidal volume and frequency on airway responsiveness in mechanically ventilated rabbits

Shen, X., S. J. Gunst, and R. S. Tepper. Effect oftidal volume and frequency on airway responsiveness in mechanically ventilated rabbits. J. Appl. Physiol.83(4): 1202-1208, 1997.We evaluated the effects of the rate andvolume of tidal ventilation on airway resistance (Raw) duringintravenous methacholine (MCh) challenge in mechanically ventilatedrabbits. Five rabbits were challenged at tidal volumes of 5, 10, and 20 ml/kg at a frequency of 15 breaths/min and also under static conditions(0 ml/kg tidal volume). Four rabbits were subjected to MCh challenge atfrequencies of 6 and 30 breaths/min with a tidal volume of 10 ml/kg andalso under static conditions. In both groups, the increase in Raw with MCh challenge was significantly greater under static conditions thanduring tidal ventilation at any frequency or volume. Increases in thevolume or frequency of tidal ventilation resulted in significant decreases in Raw in response to MCh. We conclude that tidal breathing suppresses airway responsiveness in rabbits in vivo. The suppression ofnarrowing in response to MCh increases as the magnitude of the volumeor the frequency of the tidal oscillations is increased. Our findingssuggest that the effect of lung volume changes on airway responsivenessin vivo is primarily related to the stretch of airway smooth muscle.

     

Reliability of parameter estimates from models applied to respiratory impedance data

Many previous studies have fit lumped parameter models to respiratory input (Zin) and transfer (Ztr) impedance data. For frequency ranges higher than 4-32 Hz, a six-element model may be required in which an airway branch (with a resistance and inertance) is separated from a tissue branch (with a resistance, inertance, and compliance) by a shunt compliance. A sensitivity analysis is applied to predict the effects of frequency range on the accuracy of parameter estimates in this model obtained from Zin or Ztr data. Using a parameter set estimated from experimental data between 4 and 64 Hz in dogs, both Zin and Ztr were simulated from 4 to 200 Hz. Impedance sensitivity to each parameter was also calculated over this frequency range. The simulation predicted that for Zin a second resonance occurs near 80 Hz and that the impedance is considerably more sensitive to several of the parameters at frequencies surrounding this resonance than at any other frequencies. Also, unless data is obtained at very high frequencies (where the model is suspect), Zin data provides more accurate estimates than Ztr data. After adding random noise to the simulated Zin data, we attempted to extract the original parameters by using a nonlinear regression applied to three frequency ranges: 4-32, 4-64, and 4-110 Hz. Estimated parameters were substantially incorrect when using only 4- to 32-Hz or 4- to 64-Hz data, but nearly correct when fitting 4- to 110-Hz data. These results indicate that respiratory system parameters can be more accurately extracted from Zin than Ztr, and to make physiological inferences from parameter estimates based on Zin impedance data in dogs, the data must include frequencies surrounding the second resonance.     

Effects of edema on small airway narrowing

Wagner, Elizabeth M. Effects of edema on small airwaynarrowing. J. Appl. Physiol. 83(3):784-791, 1997.Numerous mediators of inflammation have beendemonstrated to cause airway microvascular fluid and proteinextravasation. That fluid extravasation results in airway wall edemaleading to airway narrowing and enhanced reactivity has not beenconfirmed. In anesthetized, ventilated sheep(n = 30), airway vascularfluid extravasation was induced by infusing bradykinin(10⁶ M) through acannulated, blood-perfused bronchial artery. Airway wall edema andluminal narrowing were determined morphometrically. Airway reactivityto methacholine (MCh; 10 µg/ml, intrabronchial artery) was determinedby measuring conducting airway resistance (Raw) by forced oscillation.Raw measurements were made and lung lobes were excised and quick frozenbefore or after a 1-h bradykinin infusion. In 10 airways per lobe(range 0.2- to 2.0-mm relaxed diameter), wall area occupied 32 ± 2% (SE) of the total normalized airway area(n = 9). Bradykinin infusion increasedwall area to 42 ± 5% (P = 0.02);luminal area decreased by <5%; and smooth muscle perimeter, ameasure of smooth muscle constriction, was not altered(n = 5). Raw showed nochange from baseline (1.4 ± 0.4 cmH₂O · l¹ · s)after bradykinin infusion (n = 10).During MCh challenge, Raw increased by 3.2 ± 04 cmH₂O · l¹ · s,and this change did not differ after administration of bradykinin. MChchallenge caused similar decreases in smooth muscle perimeter (10%)and luminal area (72 vs. 68%) before and after bradykinin infusion.However, the time constant of recovery of Raw from MCh constriction wasincreased from control (40 ± 3 s) to 57 ± 10 s after bradykinininfusion (P = 0.03). When lung lobeswere excised at the same time after MCh challenge was terminated(n = 5), luminal area was greaterbefore bradykinin infusion than after (86 vs. 78%;P = 0.007), as was smooth muscleperimeter. The results of this study demonstrate that airway wall edemalimits relaxation after induced constriction rather than enhancingconstriction.

     

Effect of lung inflation in vivo on airways with smooth muscle tone or edema

Brown, Robert H., Wayne Mitzner, Yonca Bulut, and ElizabethM. Wagner. Effect of lung inflation in vivo on airways with smoothmuscle tone or edema. J. Appl.Physiol. 82(2): 491-499, 1997.Fibrousattachments to the airway wall and a subpleural surrounding pressurecan create an external load against which airway smooth muscle mustcontract. A decrease in this load has been proposed as a possible causeof increased airway narrowing in asthmatic individuals. To study theinteraction between the airways and the surrounding lung parenchyma, weinvestigated the effect of lung inflation on relaxed airways, airwayscontracted with methacholine, and airways made edematous by infusion ofbradykinin into the bronchial artery. Measurements were made inanesthetized sheep by using high-resolution computed tomography tovisualize changes in individual airways. During methacholine infusion,airway area was decreased but increased minimally with increases intranspulmonary pressure. Bradykinin infusion caused a 50% increase inairway wall area and a small decrease in airway luminal area. Incontrast to airways contracted with methacholine, the luminal areaafter bradykinin increased substantially with increases intranspulmonary pressure, reaching 99% of the relaxed area at totallung capacity. Thus airway edema by itself did not prevent fulldistension of the airway at lung volumes approaching total lungcapacity. Therefore, we speculate that if a deep inspiration fails torelieve airway narrowing in vivo, this must be a manifestation ofairway smooth muscle contraction and not airway wall edema.

     

Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo

Brown, Robert H., Wayne Mitzner, and Elizabeth M. Wagner.Interaction between airway edema and lung inflation onresponsiveness of individual airways in vivo. J. Appl.Physiol. 83(2): 366-370, 1997.Inflammatorychanges and airway wall thickening are suggested to cause increasedairway responsiveness in patients with asthma. In fivesheep, the dose-response relationships of individual airways weremeasured at different lung volumes to methacholine (MCh) before andafter wall thickening caused by the inflammatory mediator bradykininvia the bronchial artery. At 4 cmH₂O transpulmonary pressure(Ptp), 5 µg/ml MCh constricted the airways to a maximum of 18 ± 3%. At 30 cmH₂O Ptp, MCh resultedin less constriction (to 31 ± 5%). Bradykinin increased airwaywall area at 4 and 30 cmH₂O Ptp(159 ± 6 and 152 ± 4%, respectively;P < 0.0001). At 4 cmH₂O Ptp, bradykinin decreasedairway luminal area (13 ± 2%; P < 0.01), and the dose-response curve was significantly lower (P = 0.02). At 30 cmH₂O, postbradykinin, the maximalairway narrowing was not significantly different (26 ± 5%;P = 0.76). Bradykinin produced substantial airway wall thickening and slight potentiation ofthe MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin increased wall thickness but had no effecton the MCh-induced airway constriction. We conclude that inflammatoryfluid leakage in the airways cannot be a primary cause of airwayhyperresponsiveness.

     

Parallel airways inhomogeneity and lung tissue mechanics in transition to constricted state in rabbits

Toinvestigate whether changes of tissue resistance (Rti) duringmethacholine (MCh)-induced constriction correspond to an intrinsicmechanism or are an artifact of increased airways inhomogeneity, rabbits were studied after exposure to air(n = 7) or 1.5 parts/million O₃(n = 6). Animals were anesthetized andmechanically ventilated. Tracheal flow and pressure (Ptr) and fouralveolar capsule pressures (Pcap) were measured during 3 min afteradministration of an intrajugular bolus of 0.8 mg/ml MCh. By adjustmentof the equation of motion [P(t) = E · V(t) + R · dV(t)/dt + P₀] [whereP(t), V(t), and dV(t)/dt are pressure, volume, and flow as a function of time, respectively, Eis elastance, R is resistance, and P₀ is end-expiratorypressure] to Ptr, lung resistance(RL) and dynamic elastance(EL) were determined breath bybreath. Rti and airways resistance (Raw) were determined from Pcap in phase with rate of change of pulmonary expansion. Hysteresivity () was calculated. Parallel inhomogeneity wasestimated from the coefficients of variation (CV) of every Pcap at endinspiration and end expiration. Increase in CV significantly laggedRti, RL, and . A linearrelationship between EL and Rawwas observed. Our results suggest that changes in tissue mechanicsduring the transition to the constricted state are not artifactual.

     

Effect of expiratory flow limitation on respiratory mechanical impedance: a model study

Peslin, R., R. Farré, M. Rotger, and D. Navajas.Effect of expiratory flow limitation on respiratory mechanicalimpedance: a model study. J. Appl.Physiol. 81(6): 2399-2406, 1996.Large phasicvariations of respiratory mechanical impedance (Zrs) have been observedduring induced expiratory flow limitation (EFL) (M. Vassiliou, R. Peslin, C. Saunier, and C. Duvivier. Eur. Respir. J. 9: 779-786, 1996). To clarify themeaning of Zrs during EFL, we have measured from 5 to 30 Hz the inputimpedance (Zin) of mechanical analogues of the respiratory system,including flow-limiting elements (FLE) made of easily collapsiblerubber tubing. The pressures upstream (Pus) and downstream (Pds) fromthe FLE were controlled and systematically varied. Maximal flow(max) increased linearly with Pus, was close to thevalue predicted from wave-speed theory, and was obtained for Pus-Pds of4-6 hPa. The real part of Zin started increasing abruptlywith flow () >85%max and either further increased or suddenlydecreased in the vicinity of max. The imaginary part of Zin decreased markedly and suddenly above 95%max. Similar variations of Zin during EFL were seenwith an analogue that mimicked the changes of airwaytransmural pressure during breathing. After pressure and measurements upstream and downstream from the FLEwere combined, the latter was analyzed in terms of a serial (Zs) and ashunt (Zp) compartment. Zs was consistent with a large resistance andinertance, and Zp with a mainly elastic element having an elastanceclose to that of the tube walls. We conclude that Zrs data during EFLmainly reflect the properties of the FLE.

     

Methacholine causes reflex bronchoconstriction

To determine whether methacholine causes vagally mediated reflexconstriction of airway smooth muscle, we administered methacholine tosheep either via the bronchial artery or as an aerosol via tracheostomyinto the lower airways. We then measured the contraction of anisolated, in situ segment of trachealis smooth muscle and determinedthe effect of vagotomy on the trachealis response. Administeringmethacholine to the subcarinal airways via the bronchial artery(0.5-10.0 µg/ml) caused dose-dependent bronchoconstriction andcontraction of the tracheal segment. At the highest methacholine concentration delivered, trachealis smooth muscle tension increased anaverage of 186% over baseline. Aerosolized methacholine (5-7 breaths of 100 mg/ml) increased trachealis tension by 58% and airwaysresistance by 183%. As the bronchial circulation in the sheep does notsupply the trachea, we postulated that the trachealis contraction wascaused by a reflex response to methacholine in the lower airways.Bilateral vagotomy essentially eliminated the trachealis response andthe airways resistance change after lower airways challenge (either viathe bronchial artery or via aerosol) with methacholine. We concludethat 1) methacholine causes asubstantial reflex contraction of airway smooth muscle and2) the assumption may not be validthat a response to methacholine in humans or experimental animalsrepresents solely the direct effect on smooth muscle.

     

Estimation of thickness of airwaysurface liquid in ferret trachea in vitro

Duneclift, S., U. Wells, and J. Widdicombe. Estimationof thickness of airway surface liquid in ferret trachea in vitro. J. Appl. Physiol. 83(3): 761-767, 1997.The tracheae of ferrets and rabbits were mounted in vitro inorgan baths. While the tracheae were liquid filled, the permeabilitycoefficient ( P) was determined, and then while thetracheae were air filled, the percent clearance for^99mTc-labeleddiethylenetriaminepentaacetic acid (DTPA) was determined. The thicknessof airway surface liquid (ASL) was estimated by three methods.1) The initial concentration of^99mTc-DTPA and the total amount of^99mTc-DTPA (the sum of thatentering the outside medium, that draining from the trachea, and thatwashed out at the end of 40 min) gave the initial volume of ASL andthus its thickness. Mean values were 45.7 µm for the ferret and 41.9 µm for the rabbit. 2) Estimates ofASL thickness at the end of the 40-min period, based on the final^99mTc-DTPA concentration and theamount in the washout, were 42.9 µm for ferret and 45.4 µm forrabbit. 3) The ratio of Pto percent clearance gave mean ASL thickness values of 49.2 µm forthe ferret and 40.3 µm for the rabbit. Thus three separate methodsfor determining ASL thickness give very similar results, with means inthe range 40-49 µm. Administration of methacholine or atropineto ferret tracheae did not significantly change ASL thickness.

     

Temporal dynamics of acute isovolume bronchoconstriction in the rat

Bates, Jason H. T., Thomas F. Schuessler, Carrie Dolman, andDavid H. Eidelman. Temporal dynamics of acute isovolume bronchoconstriction in the rat. J. Appl.Physiol. 82(1): 55-62, 1997.The time course oflung impedance changes after intravenous injection of bronchial agonisthave produced significant insights into the mechanisms ofbronchoconstriction in the dog (J. H. T. Bates, A.-M. Lauzon, G. S. Dechman, G. N. Maksym, and T. F. Shuessler. J. Appl.Physiol. 76: 616-626, 1994). We studied the timecourse of acute induced bronchoconstriction in five anesthetizedparalyzed open-chest rats injected intravenously with a bolus ofmethacholine. For the 16 s immediately after injection, we held thelung volume constant while applying small-amplitude flow oscillationsat 1.48, 5.45, and 19.69 Hz simultaneously, which provided us withcontinuous estimates of lung resistance(RL) and elastance(EL) at eachfrequency. This procedure was repeated at initial lung inflationpressures of 0.2, 0.4, and 0.6 kPa. BothRL andEL increased progressively aftermethacholine administration; however, the rate of change ofEL increased dramatically asfrequency was increased, whereas RL remained relativelyindependent of frequency. We interpret these findings in terms of athree-compartment model of the rat lung, featuring two parallelalveolar compartments feeding into a central airway compartment. Modelsimulations support the notions that both central airway shunting andregional ventilation inhomogeneity developed to a significant degree inour constricted rats. We also found that the rates of increase in bothRL andEL were greatly enhanced as theinitial lung inflation pressure was reduced, in accord with the notionthat parenchymal tethering is an important mechanism limiting theextent to which airways can narrow when their smooth muscle isstimulated to contract.