Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.

We delivered controlled radio frequency energy to the airways of anesthetized, ventilated dogs to examine the effect of this treatment on reducing airway narrowing caused by a known airway constrictor. The airways of 11 dogs were treated with a specially designed bronchial catheter in three of four lung regions. Treatments in each of the three treated lung regions were controlled to a different temperature (55, 65, and 75 degrees C); the untreated lung region served as a control. We measured airway responsiveness to local methacholine chloride (MCh) challenge before and after treatment and examined posttreatment histology to 3 yr. Treatments controlled to 65 degrees C as well as 75 degrees C persistently and significantly reduced airway responsiveness to local MCh challenge (P < or = 0.022). Airway responsiveness (mean percent decrease in airway diameter after MCh challenge) averaged from 6 mo to 3 yr posttreatment was 79 +/- 2.2% in control airways vs. 39 +/- 2.6% (P < or = 0.001) for airways treated at 65 degrees C, and 26 +/- 2.7% (P < or = 0.001) for airways treated at 75 degrees C. Treatment effects were confined to the airway wall and the immediate peribronchial region on histological examination. Airway responsiveness to local MCh challenge was inversely correlated to the extent of altered airway smooth muscle observed in histology (r = -0.54, P < 0.001). We conclude that the temperature-controlled application of radio frequency energy to the airways can reduce airway responsiveness to MCh for at least 3 yr in dogs by reducing airway smooth muscle contractility.     

The myth of maximal airway responsiveness in vivo

A sine quanon of hyperresponsive airway disease in asthmatic subjects is the lackof a maximal response with increasing doses of aerosol agonistchallenge. Normal subjects, however, often appear toexhibit an airway response plateau effect even when challenged withhigh concentrations of agonist. To investigate this question of maximalnarrowing in individual airways in vivo, we used high-resolutioncomputed tomography to visualize canine airways narrowed by two routesof agonist challenge. We compared airway narrowing induced bymethacholine (MCh) via the conventional aerosol route to that caused bylocal atomization of MCh directly to individual airways. Our resultsshowed that, with aerosol challenge, airway responses never reached atruly flat plateau even at the highest possible nebulizerconcentrations. Airway closure was never observed. However, when MChwas delivered directly to the airway luminal surface, airways could beeasily narrowed to complete closure at modest (10 mg/ml) agonistconcentrations. Thus neither the elastic recoil of the lung norlimitations of smooth muscle shortening can be responsible for theapparent plateauing of dose-response curves. We suggest that theplateau results from limitations associated with the delivery of highconcentration of agonists via the aerosol route.

     

In vivo evaluation of the effectiveness of bronchial thermoplasty with computed tomography.

A recent study has reported that the application of thermal energy delivered through a bronchoscope (bronchial thermoplasty) impairs the ability of airway smooth muscle to shorten in response to methacholine (MCh)(Danek CJ, Lombard CM, Dungworth DL, Cox PG, Miller JD, Biggs MJ, Keast TM, Loomas BE, Wizeman WJ, Hogg JC, and Leff AR. J Appl Physiol 97: 1946-1953, 2004). If such a technique is successful, it has the potential to serve as a therapy to attenuate airway narrowing in asthmatic subjects regardless of the initiating cause that stimulates the smooth muscle. In the present study, we have applied high-resolution computed tomography to accurately quantify the changes in airway area before and after a standard MCh aerosol challenge in airways treated with bronchial thermoplasty. We studied a total of 193 airways ranging from 2 to 15 mm in six dogs. These were divided into treated and control populations. The MCh dose-response curves in untreated airways and soon-to-be-treated airways were superimposable. In contrast, the dose-response curves in treated airways were shifted upward at all points, showing a significantly decreased sensitivity to MCh at both 2 and 4 wk posttreatment. These results thus show that treated airways have significantly increased luminal area at any dose of inhaled MCh compared with untreated airways. The work in this study thus supports the underlying concept that impairing the smooth muscle may be an effective treatment for asthma.     

Effects of salbutamol and Ro-20-1724 on airway and parenchymal mechanics in rats.

We investigated the effects of a selective beta(2)-agonist, salbutamol, and of phosphodiesterase type 4 inhibition with 4-(3-butoxy-4-methoxy benzyl)-2-imidazolidinone (Ro-20-1724) on the airway and parenchymal mechanics during steady-state constriction induced by MCh administered as an aerosol or intravenously (iv). The wave-tube technique was used to measure the lung input impedance (ZL) between 0.5 and 20 Hz in 31 anesthetized, paralyzed, open-chest adult Brown Norway rats. To separate the airway and parenchymal responses, a model containing an airway resistance (Raw) and inertance (Iaw), and a parenchymal damping (G) and elastance (H), was fitted to ZL spectra under control conditions, during steady-state constriction, and after either salbutamol or Ro-20-1724 delivery. In the Brown Norway rat, the response to iv MCh infusion was seen in Raw and G, whereas continuous aerosolized MCh challenge produced increases in G and H only. Both salbutamol, administered either as an aerosol or iv, and Ro-20-1724 significantly reversed the increases in Raw and G when MCh was administered iv. During the MCh aerosol challenge, Ro-20-1724 significantly reversed the increases in G and H, whereas salbutamol had no effect. These results suggest that, after MCh-induced changes in lung function, salbutamol increases the airway caliber. Ro-20-1724 is effective in reversing the airway narrowings, and it may also decrease the parenchymal constriction.     

Airway and tissue mechanics in a murine model of asthma: alveolar capsule vs. forced oscillations.

To better address the functional consequences of inflammation on bronchial responsiveness, we studied two groups of BALB/c mice: a nonimmunized control group (n = 8) and a group immunized and challenged with inhaled ovalbumin (n = 8). An alveolar capsule (AC) measured airway resistance (Raw(AC)) and lung elastance (EL). A forced oscillation (FO) technique independently estimated airway resistance (Raw(FO)) and a parameter H(ti) related to tissue elastance. Ovalbumin-immunized and -challenged mice had increased numbers of eosinophils in bronchoalveolar lavage and increased responsiveness to methacholine (MCh). Corresponding parameters from the AC and FO techniques were correlated: Raw(AC) vs. Raw(FO) (r = 0.76) and EL vs. H(ti) (r = 0.88, P < 0.0001 in all cases). AC and FO techniques showed significant increases in tissue elastance in response to MCh but no significant increases in airway resistance. These results demonstrated that the AC and FO techniques yield essentially equivalent results in mice, even when the lung is inhomogeneous, and that the bronchoconstrictive responses to MCh and inflammation in mice are predominantly located in the lung periphery.     

Effect of PEEP on induced constriction is enhanced in decorin-deficient mice

Decorin (Dcn), a small leucine-rich proteoglycan, is present in the extracellular matrix of the airways and lung tissues, contributes to lung mechanical properties, and its deposition is altered in asthma. The effect of Dcn deficiency on airway parenchymal interdependence was examined during induced bronchoconstriction. Studies were performed in C57Bl/6 mice in which the Dcn gene was disrupted by targeted deletion (Dcn(-/-)) and in wild-type controls (Dcn(+/+)). Mice were mechanically ventilated, and respiratory system impedance was measured during in vivo ventilation at positive end-expiratory pressure (PEEP) = 2 and 10 cmH(2)0, before and after aerosol delivery of methacholine (MCh). Length vs. tension curves in isolated tracheal rings were measured in vitro. Dcn distribution in +/+ mice airways was characterized by immunofluorescence; differences in collagen structure in Dcn(+/+) and Dcn(-/-) mouse lungs was examined by electron microscopy. MCh caused similar increases in airway resistance (Raw) and tissue elastance (H) in Dcn(+/+) and Dcn(-/-) mice. During MCh-induced constriction, increasing PEEP caused a decrease in Raw that was greater in Dcn(-/-) mice and a decrease in H in Dcn(-/-) mice only. Tracheal ring compliance was greater in Dcn (-/-) mice. Imaging studies showed that Dcn was deposited primarily in the airway adventitial layer in Dcn(+/+) mice; in Dcn(-/-) mice, collagen had an irregular appearance, especially in the lung periphery. These results show that lack of Dcn alters the normal interaction between airways and lung parenchyma; in asthma, changes in Dcn could potentially contribute to abnormal airway physiology.     

Selected contribution: airway caliber in healthy and asthmatic subjects: effects of bronchial challenge and deep inspirations.

In 9 healthy and 14 asthmatic subjects before and after a standard bronchial challenge and a modified [deep inspiration (DI), inhibited] bronchial challenge and after albuterol, we tracked airway caliber by synthesizing a method to measure airway resistance (Raw; i.e., lung resistance at 8 Hz) in real time. We determined the minimum Raw achievable during a DI to total lung capacity and the subsequent dynamics of Raw after exhalation and resumption of tidal breathing. Results showed that even after a bronchial challenge healthy subjects can dilate airways maximally, and the dilation caused by a single DI takes several breaths to return to baseline. In contrast, at baseline, asthmatic subjects cannot maximally dilate their airways, and this worsens considerably postconstriction. Moreover, after a DI, the dilation that does occur in airway caliber in asthmatic subjects constricts back to baseline much faster (often after a single breath). After albuterol, asthmatic subjects could dilate airways much closer to levels of those of healthy subjects. These data suggest that the asthmatic smooth muscle resides in a stiffer biological state compared with the stimulated healthy smooth muscle, and inhibiting a DI in healthy subjects cannot mimic this.     

Modeling stochastic and spatial heterogeneity in a human airway tree to determine variation in respiratory system resistance

Asthma is a variable disease with changes in symptoms and airway function over many time scales. Airway resistance (Raw) is variable and thought to reflect changes in airway smooth muscle activity, but just how variation throughout the airway tree and the influence of gas distribution abnormalities affect Raw is unclear. We used a multibranch airway lung model to evaluate variation in airway diameter size, the role of coherent regional variation, and the role of gas distribution abnormalities on mean Raw (Raw) and variation in Raw as described by the SD (SDRaw). We modified an anatomically correct airway tree, provided by Merryn Tawhai (The University of Auckland, New Zealand), consisting of nearly 4,000 airways, to produce temporal and spatial heterogeneity. As expected, we found that increasing the diameter variation by twofold, with no change in the mean diameter, increased SDRaw more than fourfold. Perhaps surprisingly, Raw was proportional to SDRaw under several conditions-when either mean diameter was fixed, and its SD varied or when mean diameter varied, and SD was fixed. Increasing the size of a regional absence in gas distribution (ventilation defect) also led to a proportionate increase in both Raw and SDRaw. However, introducing regional dependence of connected airways strongly increased SDRaw by as much as sixfold, with little change in Raw. The model was able to predict previously reported Raw distributions and correlation of SDRaw on Raw in healthy and asthmatic subjects. The ratio of SDRaw to Raw depended most strongly on interairway coherent variation and only had a slight dependence on ventilation defect size. These findings may explain the linear correlation between variation and mean values of Raw but also suggest that regional alterations in gas distribution and local coordination in ventilation amplify any underlying variation in airway diameters throughout the airway tree.     

Neutrophils play a critical role in development of LPS-induced airway disease

We investigated the role of neutrophils in the development of endotoxin-induced airway disease via systemic neutrophil depletion of C3H/HeBFeJ mice and coincident inhalation challenge with lipopolysaccharide (LPS) over a 4-wk period. Mice were made neutropenic with intraperitoneal injections of neutrophil antiserum before and throughout the exposure period. Experimental conditions included LPS-exposed, antiserum-treated; LPS-exposed, control serum-treated; air-exposed, antiserum-treated; and air-exposed, control serum-treated groups. Physiological, biological, and morphological assessments were performed after a 4-wk exposure and again after a 4-wk recovery period. After the 4-wk exposure, LPS-induced inflammation of the lower airways was significantly attenuated in the neutropenic mice, although airway responsiveness (AR) to methacholine (MCh) remained unchanged. After the recovery period, LPS-exposed neutrophil-replete mice had increased AR to MCh when compared with the LPS-exposed neutropenic animals. Morphometric data indicate that the 4-wk exposure to LPS leads to a substantial expansion of the subepithelial area of the medium-sized airways (90-129 microm diameter) in nonneutropenic mice but not neutropenic mice, and this difference persisted even after the recovery period. Expression of bronchial epithelial and subepithelial transforming growth factor-beta1 (TGF-beta1) was diminished in the challenged neutropenic mice compared with the neutrophil-sufficient mice. These studies demonstrate that neutrophils play a critical role in the development of chronic LPS-induced airway disease.     

Airway constriction measured from tantalum bronchograms in conscious mice in response to methacholine

A single-projection X-ray technique showed an increase in functional residual capacity (FRC) in conscious mice in response to aerosolized methacholine (MCh) with little change in airway resistance (Raw) measured using barometric plethysmography (Lai-Fook SJ, Houtz PK, Lai Y-L. J Appl Physiol 104: 521-533, 2008). The increase in FRC presumably prevented airway constriction by offsetting airway contractility. We sought a more direct measure of airway constriction. Anesthetized Balb/c mice were intubated with a 22-G catheter, and tantalum dust was insufflated into the lungs to produce a well-defined bronchogram. After overnight recovery, the conscious mouse was placed in a sealed box, and bronchograms were taken at maximum and minimum points of the box pressure cycle before (control) and after 1-min exposures to 25, 50, and 100 mg/ml MCh aerosol. After overnight recovery, each mouse was studied under both room and body temperature box air conditions to correct for gas compression effects on the control tidal volume (Vt) and to determine Vt and Raw with MCh. Airway diameter (D), FRC, and Vt were measured from the X-ray images. Compared with control, D decreased by 24%, frequency decreased by 35%, FRC increased by 120%, and Raw doubled, to reach limiting values with 100 mg/ml MCh. Vt was unchanged with MCh. The limiting D occurred near zero airway elastic recoil, where the maximal contractility was relatively small. The conscious mouse adapted to MCh by breathing at a higher lung volume and reduced frequency to reach a limit in constriction.     

Bronchial circulatory reversal of methacholine-induced airway constriction

Although a role for the bronchial circulation in clearance of bronchoactive agents has been frequently proposed, experimental evidence is limited. In this study, we determined the importance of bronchial blood flow (QBA) in the recovery from methacholine-(MCh) induced bronchoconstriction. In 10 pentobarbital-anesthetized ventilated sheep, the bronchial branch of the bronchoesophageal artery was cannulated and perfused (0.7 ml.min-1.kg-1) with blood pumped from the femoral artery. MCh was infused directly into the bronchial artery at increasing concentrations (10(-7) to 10(-5) M). MCh infusion caused a concentration-dependent increase in airway resistance at constant QBA. However, the time constant of recovery (TC) from airway constriction after cessation of the MCh infusion was not dependent on the MCh concentration or the magnitude of the increases in airway resistance. When QBA was at 50, 100, and 200% of control level, with constant MCh concentration, TC was 44 +/- 6, 25 +/- 2, and 24 +/- 2 (SE) s at each flow level, respectively. TC at 50% of control QBA was significantly greater than at control QBA (P less than 0.01). Thus the magnitude of QBA can alter the time course of recovery from MCh-induced increases in airway resistance. These results document the importance of QBA in reversing agonist-induced constriction and suggest that an impaired bronchial circulation may contribute to the mechanism of airway hyperreactivity.     

IL-10 gene knockout attenuates allergen-induced airway hyperresponsiveness in C57BL/6 mice

Intratracheal administration of interleukin-10 (IL-10) has been reported to inhibit allergic inflammation but augment airway hyperresponsiveness (AHR). In the present study, airway and smooth muscle responsiveness to methacholine (MCh) were compared in wild-type (WT) and IL-10-deficient (IL-10-KO) mice to investigate the role of endogenous IL-10 in AHR development. Naive WT and IL-10-KO mice exhibited similar dose-dependent increases in airway resistance (Raw) to intravenous MCh. Sensitization and challenge with ragweed (RW) induced a twofold increase in responsiveness to intravenous MCh in WT mice, but hyperresponsiveness was not observed in similarly treated IL-10-KO mice. Likewise, tracheal rings from RW-sensitized and -challenged WT mice exhibited a fourfold greater responsiveness to MCh than IL-10-KO tracheal preparations. Measurements of airway constriction by whole body plethysmography further supported the Raw and tracheal ring data (i.e., AHR was not observed in the absence of IL-10). Interestingly, factors previously implicated in the development of AHR, including IL-4, IL-5, IL-13, IgA, IgG1, IgE, eosinophilia, and lymphocyte recruitment to the airways, were upregulated in the IL-10-KO mice. Treatment with recombinant murine IL-10 at the time of allergen challenge reduced the magnitude of inflammation but reinstated AHR development in IL-10-KO mice. Adoptive transfer of mononuclear splenocytes to IL-10-sufficient severe combined immunodeficient mice indicated that lymphocytes were an important source of the IL-10 impacting AHR development. These results provide evidence that IL-10 expression promotes the development of allergen-induced smooth muscle hyperresponsiveness.     

A fractal analysis of the radial distribution of bronchial capillaries around large airways.

We analyzed published measurements of the bronchial circulation and airway wall (Anderson JC, Bernard SL, Luchtel DL, Babb AL, and Hlastala MP. Respir Physiol Neurobiol 132: 329-339, 2002) and determined that the radial distribution of bronchial capillary cross-sectional area was fractal. We limited our analysis to bronchial capillaries, diameter < or =10 mum, that resided between the epithelial basement membrane and adventitia-alveolar boundary, the airway wall tissue. Thirteen different radial distributions of capillary-to-tissue area were constructed simply by changing the number of annuli (i.e., the annular size) used to form each distribution. For the 13 distributions created, these annuli ranged in size from to of the size of the airway wall area. Radial distributions were excluded from the fractal analysis if the sectioning procedure resulted in an annulus with a radial thickness less than the diameter of a capillary. To determine the fractal dimension for a given airway, the coefficient of variation (CV) for each distribution was calculated, and ln(CV) was plotted against the logarithm of the relative piece area. For airways with diameter >2.4 mm, this relationship was linear, which indicated the radial distribution of bronchial capillary cross-sectional area was fractal with an average fractal dimension of 1.27. The radial distribution of bronchial capillary cross-sectional area was not fractal around airways with diameter <1.5 mm. We speculated on how the fractal nature of this circulation impacts the distribution of bronchial blood flow and the efficiency of mass transport during health and disease. A fractal analysis can be used as a tool to quantify and summarize investigations of the bronchial circulation.     

Signal Transduction in Smooth Muscle: Selected Contribution: Airway caliber in healthy and asthmatic subjects: effects of bronchial challenge and deep inspirations

In 9 healthy and 14 asthmatic subjects before and after astandard bronchial challenge and a modified [deep inspiration (DI), inhibited] bronchial challenge and after albuterol, we tracked airwaycaliber by synthesizing a method to measure airway resistance (Raw;i.e., lung resistance at 8 Hz) in real time. We determined the minimumRaw achievable during a DI to total lung capacity and the subsequentdynamics of Raw after exhalation and resumption of tidal breathing.Results showed that even after a bronchial challenge healthy subjectscan dilate airways maximally, and the dilation caused by a single DItakes several breaths to return to baseline. In contrast, at baseline,asthmatic subjects cannot maximally dilate their airways, and thisworsens considerably postconstriction. Moreover, after a DI, thedilation that does occur in airway caliber in asthmatic subjectsconstricts back to baseline much faster (often after a single breath).After albuterol, asthmatic subjects could dilate airways much closer tolevels of those of healthy subjects. These data suggest that theasthmatic smooth muscle resides in a stiffer biological state comparedwith the stimulated healthy smooth muscle, and inhibiting a DI inhealthy subjects cannot mimic this.

     

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.

     

Assessment of heterogeneous airway constriction in dogs: a structure-function analysis

Obstructive lung diseases are often characterized by heterogeneous patterns of bronchoconstriction, although specific relationships between structural heterogeneity and lung function have yet to be established. We measured respiratory input impedance (Zrs) in eight anesthetized dogs using broadband forced oscillations at baseline and during intravenous methacholine (MCh) infusion. We also obtained high-resolution computed tomographic (HRCT) scans in 4 dogs and identified 20-30 individual airway segments in each animal. The Zrs spectra and HRCT images were obtained before and 5 min following a deep inspiration (DI) to 35 cmH(2)O. Each Zrs spectrum was fitted with two different models of the respiratory system: 1) a lumped airways model consisting of a single airway compartment, and 2) a distributed airways model incorporating a continuous distribution of airway resistances. For the latter, we found that the mean level and spread of airway resistances increased with MCh dose. Whereas a DI had no effect on average airway resistance during MCh infusion, it did increase the level of airway heterogeneity. At baseline and low-to-moderate doses of MCh, the lumped airways model was statistically more appropriate to describe Zrs in the majority of dogs. At the highest doses of MCh, the distributed airways model provided a superior fit in half of the dogs. There was a significant correlation between heterogeneity assessed with inverse modeling and the standard deviation of airway diameters obtained from HRCT. These data demonstrate that increases in airway heterogeneity as assessed with forced oscillations and inverse modeling can be linked to specific structural alterations in airway diameters.     

Interdependence of bronchial circulation and clearance of 99mTc-DTPA from the airway surface.

The extent to which the systemic vasculature is involved in soluble-particle uptake in the conducting airways has not been studied extensively. In anesthetized, ventilated sheep, 6-10 microl of technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) was delivered through a microspray nozzle to a fourth-generation airway. Perfusion of the cannulated bronchial artery was varied between control flow (0.6 ml x min(-1) x kg(-1)), high flow (1.8 ml x min(-1) x kg(-1)) or no flow (the infusion pump was stopped). Airway retention of the radioactive tracer was monitored using gamma camera imaging, and venous blood was sampled. During control perfusion, tracer retention at the site of deposition at 30 min averaged 20 +/- 6% (n = 7). With no flow, retention was significantly elevated to 32 +/- 8% (P = 0.03). In another group of sheep (n = 5) with a control retention of 13 +/- 4%, high flow resulted in an increase in tracer (25 +/- 4%; P = 0.04). Maximum blood uptake of tracer was calculated by estimating circulating blood volume and averaged 16% of total activity during control flow. Only during high-flow conditions was 99mTc-DTPA in the blood decreased (10%; P = 0.04). Most of the tracer was cleared by mucociliary clearance as visualized by imaging. This component was substantially decreased during no flow. The results demonstrate that both decreased and increased airway perfusion limit removal of soluble tracer applied to the conducting airways.     

Tissue viscance during induced constriction in rabbit lungs: morphological-physiological correlations.

Tissue viscance (Vti), the pressure drop across the lung tissues in phase with flow, increases after induced constriction. To gain information about the possible site of response, we induced increases in Vti with methacholine (MCh) and attempted to correlate these changes with alterations in lung morphology. We measured tracheal (Ptr) and alveolar pressure (PA) in open-chest rabbits during mechanical ventilation [frequency = 1 Hz, tidal volume = 5 ml/kg, positive end-expiratory pressure (PEEP) = 5 cmH2O] under control conditions and after administration of saline or MCh (32 or 128 mg/ml) aerosols. We calculated lung elastance (EL), lung resistance (RL), Vti, and airway resistance (Raw) by fitting the equation of motion to changes in Ptr and PA. The lungs were then frozen in situ with liquid nitrogen (PEEP = 5 cmH2O), excised, and processed using freeze substitution techniques. Airway constriction was assessed by measuring the ratio of the airway lumen (A) to the ideally relaxed area (Ar). Tissue distortion was assessed by measuring the mean linear intercept between alveolar walls (Lm), the standard deviation of Lm (SDLm), and an atelectasis index (ATI) derived by calculating the ratio of tissue to air space using computer image analysis. RL, Vti, and EL were significantly increased after MCh, and Raw was unchanged. A/Ar, Lm, SDLm, and ATI all changed significantly with MCh. Log-normalized change (% of baseline) in Vti significantly correlated with A/Ar (r = -0.693), Lm (r = 0.691), SDLm (r = 0.648), and ATI (r = 0.656). Hence, changes in lung tissue mechanics correlated with changes in morphometric indexes of parenchymal distortion and airway constriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.

     

Airway responsiveness to methacholine: effects of deep inhalations and airway inflammation.

We determined the dose-response curves to inhaled methacholine (MCh) in 16 asthmatic and 8 healthy subjects with prohibition of deep inhalations (DIs) and with 5 DIs taken after each MCh dose. Flow was measured on partial expiratory flow-volume curves at an absolute lung volume (plethysmographically determined) equal to 25% of control forced vital capacity (FVC). Airway inflammation was assessed in asthmatic subjects by analysis of induced sputum. Even when DIs were prohibited, the dose of MCh causing a 50% decrease in forced partial flow at 25% of control FVC (PD(50)MCh) was lower in asthmatic than in healthy subjects (P < 0.0001). In healthy but not in asthmatic subjects, repeated DIs significantly decreased the maximum response to MCh [from 90 +/- 4 to 62 +/- 8 (SD) % of control, P < 0.001], increased PD(50)MCh (P < 0.005), without affecting the dose causing 50% of maximal response. In asthmatic subjects, neither PD(50)MCh when DIs were prohibited nor changes in PD(50)MCh induced by DIs were significantly correlated with inflammatory cell numbers or percentages in sputum. We conclude that 1) even when DIs are prohibited, the responsiveness to MCh is greater in asthmatic than in healthy subjects; 2) repeated DIs reduce airway responsiveness in healthy but not in asthmatic subjects; and 3) neither airway hyperresponsiveness nor the inability of DIs to relax constricted airways in asthmatic subjects is related to the presence of inflammatory cells in the airways.