Effects of rapid saline infusion on lung mechanics and airway responsiveness in humans.

Lung mechanics and airway responsiveness to methacholine (MCh) were studied in seven volunteers before and after a 20-min intravenous infusion of saline. Data were compared with those of a time point-matched control study. The following parameters were measured: 1-s forced expiratory volume, forced vital capacity, flows at 40% of control forced vital capacity on maximal (Vm(40)) and partial (Vp(40)) forced expiratory maneuvers, lung volumes, lung elastic recoil, lung resistance (Rl), dynamic elastance (Edyn), and within-breath resistance of respiratory system (Rrs). Rl and Edyn were measured during tidal breathing before and for 2 min after a deep inhalation and also at different lung volumes above and below functional residual capacity. Rrs was measured at functional residual capacity and at total lung capacity. Before MCh, saline infusion caused significant decrements of forced expiratory volume in 1 s, Vm(40), and Vp(40), but insignificantly affected lung volumes, elastic recoil, Rl, Edyn, and Rrs at any lung volume. Furthermore, saline infusion was associated with an increased response to MCh, which was not associated with significant changes in the ratio of Vm(40) to Vp(40). In conclusion, mild airflow obstruction and enhanced airway responsiveness were observed after saline, but this was not apparently due to altered elastic properties of the lung or inability of the airways to dilate with deep inhalation. It is speculated that it was likely the result of airway wall edema encroaching on the bronchial lumen.     

Effects of elastase-induced emphysema on airway responsiveness to methacholine in rats

We examined the effects of elastase-induced emphysema on lung volumes, pulmonary mechanics, and airway responses to inhaled methacholine (MCh) of nine male Brown Norway rats. Measurements were made before and weekly for 4 wk after elastase in five rats. In four rats measurements were made before and at 3 wk after elastase; in these same animals the effects of changes in end-expiratory lung volume on the airway responses to MCh were evaluated before and after elastase. Airway responses were determined from peak pulmonary resistance (RL) calculated after 30-s aerosolizations of saline and doubling concentrations of MCh from 1 to 64 mg/ml. Porcine pancreatic elastase (1 IU/g) was administered intratracheally. Before elastase RL rose from 0.20 +/- 0.02 cmH2O.ml-1.s (mean +/- SE; n = 9) to 0.57 +/- 0.06 after MCh (64 mg/ml). A plateau was observed in the concentration-response curve. Static compliance and the maximum increase in RL (delta RL64) were significantly correlated (r = 0.799, P less than 0.01). Three weeks after elastase the maximal airway response to MCh was enhanced and no plateau was observed; delta RL64 was 0.78 +/- 0.07 cmH2O.ml-1.s, significantly higher than control delta RL64 (0.36 +/- 0.7, P less than 0.05). Before elastase, increase of end-expiratory lung volume to functional residual capacity + 1.56 ml (+/- 0.08 ml) significantly reduced RL at 64 mg MCh/ml from 0.62 +/- 0.05 cmH2O.ml-1.s to 0.50 +/- 0.03, P less than 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung tissue behavior during methacholine challenge in rabbits in vivo.

Previous studies have shown that lung challenge with smooth muscle agonists increases tissue viscance (Vti), which is the pressure drop between the alveolus and the pleura divided by the flow. Passive inflation also increases Vti. The purpose of the present study was to measure the changes in Vti during positive end-expiratory pressure- (PEEP) induced changes in lung volume and with a concentration-response curve to methacholine (MCh) in rabbits and to compare the effects of induced constriction vs. passive lung inflation on tissue mechanics. Measurements were made in 10 anesthetized open-chest mechanically ventilated New Zealand male rabbits exposed first to increasing levels of PEEP (3-12 cmH2O) and then to increasing concentrations of MCh aerosol (0.5-128 mg/ml). Lung elastance (EL), lung resistance (RL), and Vti were determined by adjusting the equation of motion to tracheal and alveolar pressures during tidal ventilation. Our results show that under baseline conditions, Vti accounted for a major proportion of RL; during both passive lung inflation and MCh challenge this proportion increased progressively. For the same level of change in EL, however, the increase in Vti was larger during MCh challenge than during passive inflation; i.e., the relationship between energy storage and energy dissipation or hysteresivity was dramatically altered. These results are consistent with a MCh-induced change in the intrinsic rheological properties of lung tissues unrelated to lung volume change per se. Lung tissue constriction is one possible explanation.     

Volume infusion produces abdominal distension, lung compression, and chest wall stiffening in pigs.

The effect of severe generalized edema on respiratory system mechanics is not well described. We measured airway pressure, gastric pressure, and four vertical pleural pressures in 13 anesthetized paralyzed pigs ventilated in the upright position. Pressure-volume relationships of the respiratory system, chest wall, and lung were measured on deflation from total lung capacity to residual volume and during tidal breathing both before (control) and 50 min after one of two interventions. In one series of experiments, a volume equal to 15-20% of the pig's body weight was infused intravenously. In a second series, a balloon was placed in the peritoneal space to distend the abdomen to the same gastric pressures as achieved in the first series. Measurements were compared before and after either abdominal balloon inflation or volume infusion. Volume infusion increased the pleural pressure in dependent lung regions, decreased both total lung capacity (34%) and functional residual capacity (62%) (both P less than 0.05), and markedly shifted the respiratory system and chest wall pressure-volume curves to the right, but it only moderately affected the lung deflation curve. Tidal compliances of the respiratory system, chest wall, and lung decreased 36, 31, and 49%, respectively (all P less than 0.05). The effect of abdominal balloon inflation on respiratory system mechanics was similar to that of volume infusion. We conclude that infusing large volumes of fluid markedly alters chest wall mechanics, mainly by causing abdominal distension that prohibits descent of the diaphragm.     

Methacholine-induced bronchoconstriction in dogs: effects of lung volume and O3 exposure

The maximal effect induced by methacholine (MCh) aerosols on pulmonary resistance (RL), and the effects of altering lung volume and O3 exposure on these induced changes in RL, was studied in five anesthetized and paralyzed dogs. RL was measured at functional residual capacity (FRC), and lung volumes above and below FRC, after exposure to MCh aerosols generated from solutions of 0.1-300 mg MCh/ml. The relative site of response was examined by magnifying parenchymal [RL with large tidal volume (VT) at fast frequency (RLLS)] or airway effects [RL with small VT at fast frequency (RLSF)]. Measurements were performed on dogs before and after 2 h of exposure to 3 ppm O3. MCh concentration-response curves for both RLLS and RLSF were sigmoid shaped. Alterations in mean lung volume did not alter RLLS; however, RLSF was larger below FRC than at higher lung volumes. Although O3 exposure resulted in small leftward shifts of the concentration-response curve for RLLS, the airway dominated index of RL (RLSF) was not altered by O3 exposure, nor was the maximal response using either index of RL. These data suggest O3 exposure does not affect MCh responses in conducting airways; rather, it affects responses of peripheral contractile elements to MCh, without changing their maximal response.     

Effects of corticosteroid treatment on airway inflammation, mechanics, and hyperpolarized ³He magnetic resonance imaging in an allergic mouse model

The purpose of this study was to assess the effects of corticosteroid therapy on a murine model of allergic asthma using hyperpolarized (3)He magnetic resonance imaging (MRI) and respiratory mechanics measurements before, during, and after methacholine (MCh) challenge. Three groups of mice were prepared, consisting of ovalbumin sensitized/ovalbumin challenged (Ova/Ova, n = 5), Ova/Ova challenged but treated with the corticosteroid dexamethasone (Ova/Ova+Dex, n = 3), and ovalbumin-sensitized/saline-challenged (Ova/PBS, n = 4) control animals. All mice underwent baseline 3D (3)He MRI, then received a MCh challenge while 10 2D (3)He MR images were acquired for 2 min, followed by post-MCh 3D (3)He MRI. Identically treated groups underwent respiratory mechanics evaluation (n = 4/group) and inflammatory cell counts (n = 4/group). Ova/Ova animals exhibited predominantly large whole lobar defects at baseline, with significantly higher ventilation defect percentage (VDP = 19 ± 4%) than Ova/PBS (+2 ± 1%, P = 0.01) animals. Such baseline defects were suppressed by dexamethasone (0%, P = 0.009). In the Ova/Ova group, MCh challenge increased VDP on both 2D (+30 ± 8%) and 3D MRI scans (+14 ± 2%). MCh-induced VDP changes were diminished in Ova/Ova+Dex animals on both 2D (+21 ± 9%, P = 0.63) and 3D scans (+7 ± 2%, P = 0.11) and also in Ova/PBS animals on 2D (+6 ± 3%, P = 0.07) and 3D (+4 ± 1%, P = 0.01) scans. Because MCh challenge caused near complete cessation of ventilation in four of five Ova/Ova animals, even as large airways remained patent, this implies that small airway (<188 μm) obstruction predominates in this model. This corresponds with respiratory mechanics observations that MCh challenge significantly increases elastance and tissue damping but only modestly affects Newtonian airway resistance.     

Lung volumes and respiratory mechanics in elastase-induced emphysema in mice

Absolute lung volumes such as functional residual capacity, residual volume (RV), and total lung capacity (TLC) are used to characterize emphysema in patients, whereas in animal models of emphysema, the mechanical parameters are invariably obtained as a function of transrespiratory pressure (Prs). The aim of the present study was to establish a link between the mechanical parameters including tissue elastance (H) and airway resistance (Raw), and thoracic gas volume (TGV) in addition to Prs in a mouse model of emphysema. Using low-frequency forced oscillations during slow deep inflation, we tracked H and Raw as functions of TGV and Prs in normal mice and mice treated with porcine pancreatic elastase. The presence of emphysema was confirmed by morphometric analysis of histological slices. The treatment resulted in an increase in TGV by 51 and 44% and a decrease in H by 57 and 27%, respectively, at 0 and 20 cmH(2)O of Prs. The Raw did not differ between the groups at any value of Prs, but it was significantly higher in the treated mice at comparable TGV values. In further groups of mice, tracheal sounds were recorded during inflations from RV to TLC. All lung volumes but RV were significantly elevated in the treated mice, whereas the numbers and size distributions of inspiratory crackles were not different, suggesting that the airways were not affected by the elastase treatment. These findings emphasize the importance of absolute lung volumes and indicate that tissue destruction was not associated with airway dysfunction in this mouse model of emphysema.     

Sustained inflation during HFOV improves pulmonary mechanics and oxygenation

Effective use of high-frequency oscillatory ventilation (HFOV) may require maintenance of adequate lung volume to optimize gas exchange. To determine the impact of inflation during HFOV, sustained inflation was applied at pressures of 5, 10, and 15 cmH2O above mean airway pressure for 3, 10, and 30 s to 15 intubated, paralyzed, anesthetized rabbits after saline lavage to induce surfactant deficiency. Arterial blood gases were recorded in all rabbits while static compliance, resistance, time constant, and changes in functional residual capacity were recorded using the interrupter technique and plethysmograph in seven rabbits. Parameters were recorded before and 2 min after sustained inflation. Arterial PO2, compliance of the respiratory system, and functional residual capacity increased after sustained inflation at pressure levels of at least 10 cmH2O and 10-s duration. As the presence or duration of a sustained inflation was increased, oxygenation improved (P less than or equal to 0.01), but arterial PCO2 increased as longer sustained inflations were used (P less than or equal to 0.005). Sustained inflations of 5 cmH2O above mean airway pressure or of 3-s duration were ineffective. We conclude that either a critical pressure or duration of sustained inflation is needed to improve oxygenation and pulmonary mechanics during HFOV.     

Hyperresponsiveness to inhaled but not intravenous methacholine during acute respiratory syncytial virus infection in mice

Background

To characterise the acute physiological and inflammatory changes induced by low-dose RSV infection in mice.

Methods

BALB/c mice were infected as adults (8 wk) or weanlings (3 wk) with 1 × 10⁵ pfu of RSV A2 or vehicle (intranasal, 30 μl). Inflammation, cytokines and inflammatory markers in bronchoalveolar lavage fluid (BALF) and airway and tissue responses to inhaled methacholine (MCh; 0.001 – 30 mg/ml) were measured 5, 7, 10 and 21 days post infection. Responsiveness to iv MCh (6 – 96 μg/min/kg) in vivo and to electrical field stimulation (EFS) and MCh in vitro were measured at 7 d. Epithelial permeability was measured by Evans Blue dye leakage into BALF at 7 d. Respiratory mechanics were measured using low frequency forced oscillation in tracheostomised and ventilated (450 bpm, flexiVent) mice. Low frequency impedance spectra were calculated (0.5 – 20 Hz) and a model, consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)] and a constant-phase tissue compartment [coefficients of tissue damping (G) and elastance (H)] was fitted to the data.

Results

Inflammation in adult mouse BALF peaked at 7 d (RSV 15.6 (4.7 SE) vs. control 3.7 (0.7) × 10⁴ cells/ml; p < 0.001), resolving by 21 d, with no increase in weanlings at any timepoint. RSV-infected mice were hyperresponsive to aerosolised MCh at 5 and 7 d (PC₂₀₀ Raw adults: RSV 0.02 (0.005) vs. control 1.1 (0.41) mg/ml; p = 0.003) (PC₂₀₀ Raw weanlings: RSV 0.19 (0.12) vs. control 10.2 (6.0) mg/ml MCh; p = 0.001). Increased responsiveness to aerosolised MCh was matched by elevated levels of cysLT at 5 d and elevated VEGF and PGE₂ at 7 d in BALF from both adult and weanling mice. Responsiveness was not increased in response to iv MCh in vivo or EFS or MCh challenge in vitro. Increased epithelial permeability was not detected at 7 d.

Conclusion

Infection with 1 × 10⁵ pfu RSV induced extreme hyperresponsiveness to aerosolised MCh during the acute phase of infection in adult and weanling mice. The route-specificity of hyperresponsiveness suggests that epithelial mechanisms were important in determining the physiological effects. Inflammatory changes were dissociated from physiological changes, particularly in weanling mice.     

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.     

Meconium aspiration produces airway hyperresponsiveness and eosinophilic inflammation in a murine model

Meconium aspiration syndrome is a cause of significant morbidity and mortality in the perinatal period and has been implicated in the pathogenesis of airway dysfunction. In this study, we developed a murine model to evaluate the effects of meconium aspiration on airway physiology and lung cellular responses. Under light anesthesia, BALB/c mice received a single intratracheal instillation of meconium or physiological saline. Respiratory mechanics were measured in unrestrained animals and expressed as percent increase in enhanced pause to increasing concentrations of methacholine (MCh). Furthermore, we assessed the changes in cells and cytokines into the bronchoalveolar lavage fluid (BALF). We found meconium aspiration produced increased airway responsiveness to MCh at 7 days. These functional changes were associated with lymphocytic/eosinophilic inflammation, goblet cell metaplasia, and increased concentrations of IL-5 and IL-13 in the BALF. Our findings suggest meconium aspiration leads to alterations of airway function, lung eosinophilia, goblet cell metaplasia, and cytokine imbalance, thus providing the first evidence of meconium-induced airway dysfunction in a mouse model.     

A new ventilator for monitoring lung mechanics in small animals.

Researchers investigating the genetic component of various disease states rely increasingly on murine models. We have developed a ventilator to simplify respiratory research in small animals down to murine size. The new ventilator provides constant-flow inflation and tidal volume delivery independent of respiratory parameter changes. The inclusion of end-inspiratory and end-expiratory pauses simplifies the measurement of airway resistance and compliance and allows the detection of dynamic hyperinflation (auto-positive end-expiratory pressure). After bench testing, we performed intravenous methacholine challenge on two strains of mice (A/J and C57bl/bj) known to differ in their responses by using the new ventilator. Dynamic hyperinflation and a decrease in compliance developed during methacholine challenge whenever respiratory rates of 60-120 breaths/min were employed. In contrast, if dynamic hyperinflation was prevented by lengthening expiratory time, (respiratory rate = 20 breaths/min), static compliance remained constant. More importantly, the coefficient of variation of the results decreased when lung volume shifts were prevented. In conclusion, airway challenge studies have greater precision when dynamic hyperinflation is prevented.     

Frequency dependence of respiratory system mechanics during induced constriction in a murine model of asthma.

Airway dysfunction in asthma is characterized by hyperresponsiveness, heterogeneously narrowed airways, and closure of airways. To test the hypothesis that airway constriction in ovalbumin (OVA)-sensitized OVA-intranasally challenged (OVA/OVA) mice produces mechanical responses that are similar to those reported in asthmatic subjects, respiratory system resistance (Rrs) and elastance (Edyn,rs) spectra were obtained in OVA/OVA and control mice during intravenous methacholine (MCh) infusions. In control mice, MCh at 1,700 microg x kg(-1) x min(-1) produced 1) a 495 and 928% increase of Rrs at 0.5 Hz and 19.75 Hz, respectively, 2) a 33% rise in Edyn,rs at 0.5 Hz, and 3) a mild frequency (f)-dependent increase of Edyn,rs. The same MCh dose in OVA/OVA mice produced 1) elevations of Rrs at 0.5 Hz and 19.75 Hz of 1,792 and 774%, respectively, 2) a 390% rise in Edyn,rs at 0.5 Hz, and 3) marked f-dependent increases of Edyn,rs. During constriction, the f dependence of mechanics in control mice was consistent with homogeneous airway narrowing; however, in OVA/OVA mice, f dependence was characteristic of heterogeneously narrowed airways, closure of airways, and airway shunting. These mechanisms amplify the pulmonary mechanical responses to constrictor stimuli at physiological breathing rates and have important roles in the pathophysiology of human asthma.     

Respiratory mechanics and maximal expiratory flow in the anesthetized mouse.

Mice have been widely used in immunologic and other research to study the influence of different diseases on the lungs. However, the respiratory mechanical properties of the mouse are not clear. This study extended the methodology of measuring respiratory mechanics of anesthetized rats and guinea pigs and applied it to the mouse. First, we performed static pressure-volume and maximal expiratory flow-volume curves in 10 anesthetized paralyzed C57BL/6 mice. Second, in 10 mice, we measured dynamic respiratory compliance, forced expiratory volume in 0.1 s, and maximal expiratory flow before and after methacholine challenge. Averaged total lung capacity and functional residual capacity were 1.05 +/- 0.04 and 0.25 +/- 0.01 ml, respectively, in 20 mice weighing 22.2 +/- 0.4 g. The chest wall was very compliant. In terms of vital capacity (VC) per second, maximal expiratory flow values were 13.5, 8.0, and 2.8 VC/s at 75, 50, and 25% VC, respectively. Maximal flow-static pressure curves were relatively linear up to pressure equal to 9 cm H(2)O. In addition, methacholine challenge caused significant decreases in respiratory compliance, forced expiratory volume in 0.1 s, and maximal expiratory flow, indicating marked airway constriction. We conclude that respiratory mechanical parameters of mice (after normalization with body weight) are similar to those of guinea pigs and rats and that forced expiratory maneuver is a useful technique to detect airway constriction in this species.     

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.     

Tidal midexpiratory flow as a measure of airway hyperresponsiveness in allergic mice

A method for the noninvasive measurement of airway responsiveness was validated in allergic BALB/c mice. With head-out body plethysmography and the decrease in tidal midexpiratory flow (EF(50)) as an indicator of airway obstruction, responses to inhaled methacholine (MCh) and the allergen ovalbumin were measured in conscious mice. Allergen-sensitized and -challenged mice developed airway hyperresponsiveness as measured by EF(50) to aerosolized MCh compared with that in control animals. This response was associated with increased allergen-specific IgE and IgG1 production, increased levels of interleukin-4 and interleukin-5 in bronchoalveolar lavage fluid and eosinophilic lung inflammation. Ovalbumin aerosol challenge elicited no acute bronchoconstriction but resulted in a significant decline in EF(50) baseline values 24 h after challenge in allergic mice. The decline in EF(50) to MCh challenge correlated closely with simultaneous decreases in pulmonary conductance and dynamic compliance. The decrease in EF(50) was partly inhibited by pretreatment with the inhaled beta(2)-agonist salbutamol. We conclude that measurement of EF(50) to inhaled bronchoconstrictors by head-out body plethysmography is a valid measure of airway hyperresponsiveness in mice.     

Induction and maintenance of airway responsiveness to allergen challenge are determined at the age of initial sensitization

Age is an important factor in determining the quantity and quality of immune responses when challenged with allergen. In a model of allergen-induced airway hyperresponsiveness and inflammation, where the sensitization phase and challenge phases can be dissociated in time, we examined the impact of age on these two phases. Sensitization of young mice (1-20 wk), but not older animals (30-40 wk), led to the development of airway hyperresponsiveness, airway eosinophilia, Th2 cytokine responses, and allergen-specific IgE, regardless of the age when the challenge phase was conducted. Thus, age at the time of initial sensitization was shown to be the critical factor dictating the nature of the response to later allergen challenge, as older mice remained responsive to allergen challenge if sensitized at a young age. These effects were shown to be mediated by lung T cells from sensitized young mice. Moreover, the failure of old sensitized mice to mediate these effects was shown not to be the result of active suppression of the responses. These data define the importance of age at initial allergen exposure in dictating subsequent responses in the lung when exposed to allergen and may help to define why asthma, even in adults, is most often initiated in early childhood.     

Tracking of airway and tissue mechanics during TLC maneuvers in mice.

A tracking impedance estimation technique was developed to follow the changes in total respiratory impedance (Zrs) during slow total lung capacity maneuvers in six anesthetized and mechanically ventilated BALB/c mice. Zrs was measured with the wave-tube technique and pseudorandom forced oscillations at nine frequencies between 4 and 38 Hz during inflation from a transrespiratory pressure of 0-20 cmH2O and subsequent deflation, each lasting for approximately 20 s. Zrs was averaged for 0.125 s and fitted by a model featuring airway resistance (Raw) and inertance, and tissue damping and elastance (H). Lower airway conductance (Glaw) was linearly related to volume above functional residual capacity (V) between 0 and 75-95% maximum V, with a mean slope of dGlaw/dV = 13.6 +/- 4.6 cmH2O-1. s-1. The interdependence of Raw and H was characterized by two distinct and closely linear relationships for the low- and high-volume regions, separated at approximately 40% maximum V. Comparison of Raw with the highest-frequency resistance of the total respiratory system revealed a marked volume-dependent contribution of tissue resistance to total respiratory system resistance, resulting in the overestimation of Raw by 19 +/- 8 and 163 +/- 40% at functional residual capacity and total lung capacity, respectively, whereas the lowest frequency reactance was proportional to H; these findings indicate that single-frequency resistance values may become inappropriate as surrogates of Raw when tissue impedance is changing.     

Bronchodilation response to deep inspirations in asthma is dependent on airway distensibility and air trapping

In healthy individuals, deep inspirations (DIs) have a potent bronchodilatory ability against methacholine (MCh)-induced bronchoconstriction. This is variably attenuated in asthma. We hypothesized that inability to bronchodilate with DIs is related to reduced airway distensibility. We examined the relationship between DI-induced bronchodilation and airway distensibility in 15 asthmatic individuals with a wide range of baseline lung function [forced expired volume in 1 s (FEV(1)) = 60-99% predicted]. After abstaining from DIs for 20 min, subjects received a single-dose MCh challenge and then asked to perform DIs. The effectiveness of DIs was assessed by the ability of the subjects to improve FEV(1). The same subjects were studied by two sets of high-resolution CT scans, one at functional residual capacity (FRC) and one at total lung capacity (TLC). In each subject, the areas of 21-41 airways (0.8-6.8 mm diameter at FRC) were matched and measured, and airway distensibility (increase in airway diameter from FRC to TLC) was calculated. The bronchodilatory ability of DIs was significantly lower in individuals with FEV(1) <75% predicted than in those with FEV(1) ≥75% predicted (15 ± 11% vs. 46 ± 9%, P = 0.04) and strongly correlated with airway distensibility (r = 0.57, P = 0.03), but also with residual volume (RV)/TLC (r = -0.63, P = 0.01). In multiple regression, only RV/TLC was a significant determinant of DI-induced bronchodilation. These relationships were lost when the airways were examined after maximal bronchodilation with albuterol. Our data indicate that the loss of the bronchodilatory effect of DI in asthma is related to the ability to distend the airways with lung inflation, which is, in turn, related to the extent of air trapping and airway smooth muscle tone. These relationships only exist in the presence of airway tone, indicating that structural changes in the conducting airways visualized by high-resolution CT do not play a pivotal role.     

In vivo characterization of lung morphology and function in anesthetized free-breathing mice using micro-computed tomography.

Lung morphology and function in human subjects can be monitored with computed tomography (CT). Because many human respiratory diseases are routinely modeled in rodents, a means of monitoring the changes in the structure and function of the rodent lung is desired. High-resolution images of the rodent lung can be attained with specialized micro-CT equipment, which provides a means of monitoring rodent models of lung disease noninvasively with a clinically relevant method. Previous studies have shown respiratory-gated images of intubated and respirated mice. Although the image quality and resolution are sufficient in these studies to make quantitative measurements, these measurements of lung structure will depend on the settings of the ventilator and not on the respiratory mechanics of the individual animals. In addition, intubation and ventilation can have unnatural effects on the respiratory dynamics of the animal, because the airway pressure, tidal volume, and respiratory rate are selected by the operator. In these experiments, important information about the symptoms of the respiratory disease being studied may be missed because the respiration is forced to conform to the ventilator settings. In this study, we implement a method of respiratory-gated micro-CT for use with anesthetized free-breathing rodents. From the micro-CT images, quantitative analysis of the structure of the lungs of healthy unconscious mice was performed to obtain airway diameters, lung and airway volumes, and CT densities at end expiration and during inspiration. Because the animals were free breathing, we were able to calculate tidal volume (0.09 +/- 0.03 ml) and functional residual capacity (0.16 +/- 0.03 ml).