Matrix modulation of compensatory lung regrowth and progenitor cell proliferation in mice.

Mechanical stress is an important modulator of lung morphogenesis, postnatal lung development, and compensatory lung regrowth. The effect of mechanical stress on stem or progenitor cells is unclear. We examined whether proliferative responses of epithelial progenitor cells, including dually immunoreactive (CCSP and proSP-C) progenitor cells (CCSP+/SP-C+) and type II alveolar epithelial cells (ATII), are affected by physical factors found in the lung of emphysematics, including loss of elastic recoil, reduced elastin content, and alveolar destruction. Mice underwent single lung pneumonectomy (PNY) to modulate transpulmonary pressure (mechanical stress) and to stimulate lung regeneration. Control mice underwent sham thoracotomy. Plombage of different levels was employed to partially or completely abolish this mechanical stress. Responses to graded changes in transpulmonary pressure were assessed in elastin-insufficient mice (elastin +/-, ELN+/-) and elastase-treated mice with elastase-induced emphysema. Physiological regrowth, morphometry (linear mean intercept; Lmi), and the proliferative responses of CCSP+/SP-C+, Clara cells, and ATII were evaluated. Plombage following PNY significantly reduced transpulmonary pressure, regrowth, and CCSP+/SP-C+, Clara cell, and ATII proliferation following PNY. In the ELN+/- group, CCSP+/SP-C+ and ATII proliferation responses were completely abolished, although compensatory lung regrowth was not significantly altered. In contrast, in elastase-injured mice, compensatory lung regrowth was significantly reduced, and ATII but not CCSP+/SP-C+ proliferation responses were impaired. Elastase injury also reduced the baseline abundance of CCSP+/SP-C+, and CCSP+/SP-C+ were found to be displaced from the bronchioalveolar duct junction. These data suggest that qualities of the extracellular matrix including elastin content, mechanical stress, and alveolar integrity strongly influence the regenerative capacity of the lung, and the patterns of cell proliferation in the lungs of adult mice.

Circulatory heat sources for canine respiratory heat exchange.

We assessed the roles of the pulmonary and bronchial circulations as potential heat sources to the pulmonary airways during respiratory heat loss, by observing the changes in airstream temperature that accompanied temporary occlusion of the pulmonary or bronchial circulations. Baseline end-expiratory and end-inspiratory airstream temperatures were 35.4 +/- 0.2 degrees C (SEM) and 30.9 +/- 0.3 degrees C, respectively, among all trials. With occlusion of the lower lobe pulmonary arteries for 3 min ipsilateral end-expiratory and end-inspiratory airstream temperatures fell by 2.8 +/- 0.2 and 1.1 +/- 0.2 degrees C, respectively, during hyperpnea with room temperature air, and by 3.5 +/- 0.5 and 1.8 +/- 0.2 degrees C, respectively, during hyperpnea with frigid air. In marked contrast, interruption of the bronchial circulation for 3 min had no effect on airstream temperatures. These data indicate that under these conditions, the pulmonary circulation, but not the bronchial circulation, serves as an important local heat source for respiratory heat exchange within the pulmonary airways.

Utilization of venous thromboembolism prophylaxis in the medical intensive care unit.

We conducted a prospective survey of the utilization of venous thromboembolism (VTE) prophylaxis in 152 Medical ICU (MICU) patients. Utilization of prophylaxis was recorded daily, and commonly accepted risk factors for VTE were noted. Only 32.9 percent of patients received prophylaxis, and there was a delay of 2.0 +/- 2.8 days prior to institution. Eighty-seven percent of patients had one VTE risk factor and 52 percent had multiple factors. We conclude that utilization of prophylaxis is low in MICU patients even though they are at high risk for VTE.

Health-related quality of life improves following pulmonary rehabilitation and lung volume reduction surgery.

STUDY OBJECTIVES: To evaluate changes in health-related quality of life (HRQL) as assessed by the Medical Outcomes Study Short Form 36-item questionnaire (SF-36) after pulmonary rehabilitation and lung volume reduction surgery (LVRS). DESIGN: Prospective cohort study. PATIENTS: Nineteen patients with severe emphysema who underwent pulmonary rehabilitation in preparation for LVRS. INTERVENTIONS: Pulmonary rehabilitation followed by bilateral sequential LVRS. MEASUREMENTS AND RESULTS: HRQL assessed by the SF-36 was measured at baseline, after pulmonary rehabilitation, and 6 months after LVRS. One-way analysis of variance with repeated measures demonstrated no significant change from baseline in any of the eight domains after pulmonary rehabilitation. Scores for only one domain, vitality, improved significantly after LVRS compared with scores after pulmonary rehabilitation. However, significant improvements over baseline scores were demonstrated after combined preoperative pulmonary rehabilitation and LVRS in the domains of physical functioning, role limitations due to physical problems, social functioning, and vitality. Pulmonary rehabilitation contributed most to the overall improvements in role limitations due to physical problems, whereas LVRS contributed mainly to the overall improvements in physical functioning, social functioning, and vitality. CONCLUSIONS: Patients with severe emphysema experience significant improvements in both physical and social health status as assessed by the SF-36 after combined pulmonary rehabilitation and LVRS. Each intervention makes unique and complementary contributions to the overall improvements in HRQL.

Surveillance transbronchial lung biopsies: implication for survival after lung transplantation.

OBJECTIVES: We wished to determine whether early rejection after lung transplantation as assessed by surveillance transbronchial biopsy predicts for survival. METHODS: Between 1990 and 1997, 96 consecutive patients had lung transplantation: 89 had a minimum 1-month follow-up. For 71 consecutive patients we have 1-year follow-up and for 69 patients we have the results of the first 3 biopsies. Cytomegalovirus status, bronchiolitis obliterans prevalence, and use of total lymphoid irradiation are noted. Biopsies were done at 1 week and 1, 3, and 6 months. Standard immunosuppression consisted of induction antilymphocyte globulin and high-dose methylprednisolone induction for 1 week and standard maintenance triple therapy. Acute rejection treatment was with pulse methylprednisolone. Bronchiolitis obliterans syndrome was treated with total lymphoid irradiation and a change to tacrolimus and mycophenolate. Blinded grading using International Society for Heart and Lung Transplantation classification was done retrospectively. RESULTS: Survival at 1 month and 1, 2, and 3 years for the 96-patient cohort with 1-year follow-up was 93%, 74%, 62%, and 56%. Survival was not significantly different for subsets with rejection on any combination of the first 3 biopsies (1/3, 2/3, 3/3) or absence of rejection on the first 3 biopsies. Ninety-one positive biopsy results were graded. Eighteen of 71 patients had one or more moderate or severe rejection episodes without survival difference relative to the others. There was no statistically significant association between acute rejection on the first 3 surveillance biopsy results and bronchiolitis obliterans. CONCLUSIONS: Intensive induction and maintenance immunotherapy with surveillance transbronchial biopsies and aggressive treatment of acute rejection is associated with a survival similar to that of patients without early acute rejection. This regimen appears to uncouple the association between early acute rejection and bronchiolitis obliterans. Further study may elucidate this mechanism.

Causes of allograft dysfunction after single lung transplantation for emphysema: extrinsic restriction versus intrinsic obstruction. Brigham and Women's Hospital Lung Transplantation Group.

BACKGROUND: A subset of patients with emphysema who have undergone single lung transplantation (SLT) may subsequently present with dyspnea, worsening airways obstruction, hypoxemia, and progressive chronic native lung hyperinflation. The leading cause of late allograft dysfunction is bronchiolitis obliterans syndrome (BOS). However, extrinsic restriction manifests with a similar clinical presentation and is an additional mechanism to consider. We describe the use of the inspiratory lung resistance (RLi) to distinguish a decline in respiratory status due predominantly to either extrinsic restriction or BOS. METHODS: We studied five patients who underwent SLT for emphysema between 1992 and 1995, in whom the diagnoses of BOS and extrinsic restriction were subsequently entertained. Forced expiratory volume in 1 second (FEV1), RLi, static lung compliance, elastic recoil pressure at total lung capacity (TLC), and the slope of the maximum flow static recoil (MFSR) plot were measured. RESULTS: All patients had severe airflow obstruction, with mean FEV1 0.98 +/- 0.24 liter (26 +/- 5% predicted), elevated static lung compliance, reduced elastic recoil pressure at TLC, and reduced slope of the MFSR plot. Three patients had "low" RLi (9.3-12.8 cm H20/L/sec). Obstruction was attributed predominantly to extrinsic restriction. These patients underwent lung volume reduction surgery (LVRS) on the native lung; improvements in pulmonary mechanics were observed at 6 months. In contrast, two patients had markedly elevated RLi (17.3 and 17.4 cm H2O/L/sec). Obstruction was attributed predominantly to intrinsic airway disease from BOS that was subsequently documented at autopsy. CONCLUSIONS: The RLi appears to be a useful adjunct to the clinical history in distinguishing a decline in respiratory status due predominantly to either BOS or extrinsic restriction in patients who have undergone SLT for emphysema. Determination of the mechanism of allograft dysfunction may allow the selection of an appropriate subset of patients who would benefit from LVRS.

Tissue resistance in the guinea pig at baseline and during methacholine constriction.

Total lung resistance (RL), airway resistance (Raw), and tissue resistance (Rti) were measured in unconstricted and methacholine (MCh)-constricted guinea pigs while tidal volume, lung volume, and breathing frequency were varied. Measurements were made in tracheostomized ventilated guinea pigs with use of alveolar capsules. Relationships between Raw and Rti at different breathing frequencies, lung volumes, tidal volumes, and levels of constriction were compared with previously reported values in other species. Our results demonstrate that, at fixed tidal volume, Rti was inversely related to breathing frequency (Rti approximately f-0.64, where f is breathing frequency in Hz) and increased with increasing lung volume. Rti was a significantly greater percentage of RL after MCh administration (40-50%) than at baseline (15-35%), indicating a greater tissue than airway constrictor response. Rti was also 0.5 log dose more responsive to intravenous MCh than Raw on the basis of the dose required to produce 100% increase in resistance from baseline (PD100). These data show that, in the guinea pig, Rti changes with lung volume, breathing frequency, and constrictor tone in a manner similar to other species previously reported and that Rti can be an important determinant of lung dysfunction during constriction, even in species for which it is small in relation to Raw at baseline.

Effects of acute lung injury on dynamic tissue properties.

The dynamic properties of lung tissue after acute injury (ALI) were characterized by studying parenchymal strips prepared from guinea pigs endobronchially treated with hydrochloric acid. Forty-eight-hour samples (10 x 4 x 4 mm) from control (C), acid-damaged (D), and uninvolved (U) lungs of treated animals had elastance and resistance measured in a perfused organ bath system during uniaxial length oscillation at a mean force of 750 mg over a 1.5 (0.1-3 Hz)-fold decade frequency range and 5-fold (1-5%) strain amplitude range. Results were interpreted using a quasi-linear viscoelastic model with tissue stress expressed as an exponential function of strain. Among C strips, elastance increased linearly with the logarithm of frequency, whereas resistance decreased hyperbolically with frequency; both were strain amplitude independent. In contrast, elastance among D strips was uniformly greater (P < 0.0001) and was inversely strain amplitude dependent (P < 0.01); resistance was markedly elevated (P < 0.0001) but decreased hyperbolically with frequency similar to C strips. Resistance and elastance changes among U strips were intermediate between those for D and C strips. Histological grading of cellular infiltration, alveolar septal thickening, and hemorrhage correlated with functional changes. The frequency and amplitude dependencies and magnitude changes for resistance and elastance were similar to those previously observed in intact dog lungs after ALI. These findings suggest that ALI can affect the rheological properties of lung parenchyma independently of surfactant and that changes in lung mechanics after ALI may, in part, be determined at the parenchymal level.

Dynamic properties of lung parenchyma: mechanical contributions of fiber network and interstitial cells.

We investigated the contributions of the connective tissue fiber network and interstitial cells to parenchymal mechanics in a surfactant-free system. In eight strips of uniform dimension from guinea pig lung, we assessed the storage (G') and loss (G") moduli by using pseudo-random length oscillations containing a specially designed set of seven frequencies from 0.07 to 2.4 Hz at baseline, during methacholine (MCh) challenge, and after death of the interstitial cells. Measurements were made at mean forces of 0.5 and 1 g and strain amplitudes of 5, 10, and 15% and were repeated 12 h later in the same, but nonviable samples. The results were interpreted using a linear viscoelastic model incorporating both tissue damping (G) and stiffness (H). The G' and G" increased linearly with the logarithm of frequency, and both G and H showed negative strain amplitude and positive mean force dependence. After MCh challenge, the G' and G" spectra were elevated uniformly, and G and H increased by < 15%. Tissue stiffness, strain amplitude, and mean force dependence were virtually identical in the viable and nonviable samples. The G and hence energy dissipation were approximately 10% smaller in the nonviable samples due to absence of actin-myosin cross-bridge cycling. We conclude that the connective tissue network may also dominate parenchymal mechanics in the intact lung, which can be influenced by the tone or contraction of interstitial cells.

Autonomic regulation of tissue resistance in the guinea pig lung.

Although the autonomic nervous system is known to influence airway tone and resistance in both the normal and inflamed lung, its effects on tissue resistance (Rti) have not been defined. To characterize autonomic neural control of Rti in the lung, we measured airway resistance (Raw) and Rti, lung elastance, and lung hysteresivity after adrenergic, cholinergic, and nonadrenergic noncholinergic (NANC) blockade in anesthetized mechanically ventilated guinea pigs by using the alveolar capsule technique. Five animals received 1 mg/kg i.v. phentolamine (alpha-blocker), eight received 1 mg/kg i.v. propranolol (beta-blocker), six received 0.1 mg/kg i.v. atropine (parasympatholytic), six had surgical bilateral vagotomy, and five were treated 14 days before study with 50 mg/kg sc capsaicin (peptidergic neurotransmitter depleter). Measurements were recorded at 5- to 10-min intervals for 120 min after pharmacological induction of autonomic blockade. Capsaicin treatment resulted in decreases in lung resistance (RL), Raw, and dynamic elastance (Edyn) compared with controls but Rti was not significantly affected. beta-Blockade resulted in significant increases in RL, Raw, and Edyn but did not affect Rti. alpha-Blockade and vagolytic maneuvers had no effect on RL, Raw, Rti, or Edyn. Furthermore, there was no effect of cholinergic, adrenergic, or NANC blockade on the relationship between Rti or elastance and breathing frequency or mean lung volume during tidal breathing. Our results suggest that, in the normal guinea pig lung, baseline Raw is modulated by both the beta-adrenergic and NANC nervous systems but Rti tone is largely independent of nervous system regulation.

Responsiveness, inflammation, and effects of deep breaths on obstruction in mild asthma.

Using cellular and biochemical characteristics of bronchoalveolar lavage (BAL) liquid as an index of inflammation, we examined the relationships between change of airway caliber after a deep inhalation (DI), degree of base-line airway hyperresponsiveness, and peripheral airway inflammation in a group of 16 atopic asymptomatic mild asthmatics and 6 normal subjects. Compared with normal subjects, asthmatics demonstrated 1) significantly higher BAL concentrations of histamine, total protein, the sulfidopeptide leukotrienes (SRS-A), and leukotiene B4; 2) a decrease in specific airway conductance (sGaw) with a DI at base line vs. an increase in normal subjects (before vs. after percent change in sGaw, -10 vs. 12, P less than 0.05); and 3) no significant difference in BAL total cell count or leukocyte differential. Significant correlations were demonstrated between 1) percent of BAL eosinophils vs. degree of airway hyperresponsiveness; 2) base-line level of airway obstruction vs. degree of hyperresponsiveness; 3) effects of a DI vs. BAL concentrations of eosinophils, total protein, and histamine; 4) base-line forced expired volume in 1 s vs. BAL concentrations of total protein and histamine; and 5) BAL concentrations of the various mediators with each other. These data support the notion that 1) the response to a DI in mild, stable asthmatics represents a physiological indicator of peripheral obstruction because of inflammation and 2) this inflammation is associated with increases in several known mediators of airway inflammation and hyperreactivity.

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

The contribution of airway resistance (Raw) and tissue resistance (Rti) to total lung resistance (RL) during breathing in humans is poorly understood. We have recently developed a method for separating Raw and Rti from measurements of RL and lung elastance (EL) alone. In nine healthy, awake subjects, we applied a broad-band optimal ventilator waveform (OVW) with energy between 0.156 and 8.1 Hz that simultaneously provides tidal ventilation. In four of the subjects, data were acquired before and during a methacholine (MCh)-bronchoconstricted challenge. The RL and EL data were first analyzed by using a model with a homogeneous airway compartment leading to a viscoelastic tissue compartment consisting of tissue damping and elastance parameters. Our OVW-based estimates of Raw correlated well with estimates obtained by using standard plethysmography and were responsive to MCh-induced bronchoconstriction. Our data suggest that Rti comprises approximately 40% of total RL at typical breathing frequencies, which corresponds to approximately 60% of intrathoracic RL. During mild MCh-induced bronchoconstriction, Raw accounts for most of the increase in RL. At high doses of MCh, there was a substantial increase in RL at all frequencies and in EL at higher frequencies. Our analysis showed that both Raw and Rti increase, but most of the increase is due to Raw. The data also suggest that widespread peripheral constriction causes airway wall shunting to produce additional frequency dependence in EL.

Dynamic surface tension of surfactant TA: experiments and theory.

A bubble surfactometer was used to measure the surface tension of an aqueous suspension of surfactant TA as a function of bubble area over a range of cycling rates and surfactant bulk concentrations. Results of the surface tension-interfacial area loops exhibited a rich variety of phenomena, the character of which varied systematically with frequency and bulk concentration. A model was developed to interpret and explain these data and for use in describing the dynamics of surface layers under more general circumstances. Surfactant was modeled as a single component with surface tension taken to depend on only the interfacial surfactant concentration. Two distinct mechanisms were considered for the exchange of surfactant between the bulk phase and interface. The first is described by a simple kinetic relationship for adsorption and desorption that pertains only when the interfacial concentration is below its maximum equilibrium value. The second mechanism is "squeeze-out" by which surfactant molecules are expelled from an interface compressed past a maximum packing state. The model provided good agreement with experimental measurements for cycling rates from 1 to 100 cycles/min and for bulk concentrations between 0.0073 and 7.3 mg/ml.

Effects of collagenase and elastase on the mechanical properties of lung tissue strips.

The dynamic stiffness (H), damping coefficient (G), and harmonic distortion (k(d)) characterizing tissue nonlinearity of lung parenchymal strips from guinea pigs were assessed before and after treatment with elastase or collagenase between 0.1 and 3.74 Hz. After digestion, data were obtained both at the same mean length and at the same mean force of the strip as before digestion. At the same mean length, G and H decreased by approximately 33% after elastase and by approximately 47% after collagenase treatment. At the same mean force, G and H increased by approximately 7% after elastase and by approximately 25% after collagenase treatment. The k(d) increased more after collagenase (40%) than after elastase (20%) treatment. These findings suggest that, after digestion, the fraction of intact fibers decreases, which, at the same mean length, leads to a decrease in moduli. At the same mean force, collagen fibers operate at a higher portion of their stress-strain curve, which results in an increase in moduli. Also, G and H were coupled so that hysteresivity (G/H) did not change after treatments. However, k(d) was decoupled from elasticity and was sensitive to stretching of collagen, which may be of value in detecting structural alterations in the connective tissue of the lung.

How does airway inflammation modulate asthmatic airway constriction? An antigen challenge study.

During the late-phase (LP) response to inhaled allergen, mediators from neutrophils and eosinophils are released within the airways, resembling what occurs during an asthma attack. We compared the distribution of obstruction and degree of reversibility that follows a deep inspiration (DI) during early-phase (EP) and LP responses in nine asthmatic subjects challenged with allergen. Heterogeneity of constriction was assayed by determining frequency dependence of dynamic lung resistance and elastance, airway caliber by tracking airway resistance during a DI, and airway inflammation by measuring inflammatory cells in induced sputum postchallenge. Despite a paucity of eosinophils in the sputum at baseline (<1% of nonsquamous cells), asthmatic subjects showed a substantial EP response with highly heterogeneous constriction and reduced capacity to maximally dilate airways. The LP was associated with substantial airway inflammation in all subjects. However, five subjects showed only mild LP constriction, whereas four showed more marked LP constriction characterized by heterogeneous constriction similar to EP. Bronchoconstriction during LP was fully alleviated by administration of a bronchodilator. These findings, together with the impaired bronchodilatory response during a DI, indicate a physiological abnormality in asthma at the smooth muscle level and indicate that airway inflammation in asthma is associated with a highly nonuniform pattern of constriction. These data support the hypothesis that variability in responsiveness among asthmatic subjects derives from intrinsic differences in smooth muscle response to inflammation.

Longitudinal distribution of canine respiratory heat and water exchanges.

We assessed the longitudinal distribution of intra-airway heat and water exchanges and their effects on airway wall temperature by directly measuring respiratory fluctuations in airstream temperature and humidity, as well as airway wall temperature, at multiple sites along the airways of endotracheally intubated dogs. By comparing these axial thermal and water profiles, we have demonstrated that increasing minute ventilation of cold or warm dry air leads to 1) further penetration of unconditioned air into the lung, 2) a shift of the principal site of total respiratory heat loss from the trachea to the bronchi, and 3) alteration of the relative contributions of conductive and evaporative heat losses to local total (conductive plus evaporative) heat loss. These changes were not accurately reflected in global measurements of respiratory heat and water exchange made at the free end of the endotracheal tube. Raising the temperature of inspired dry air from frigid to near body temperature principally altered the mechanism of airway cooling but did not influence airway mucosal temperature substantially. When local heat loss was increased from both trachea and bronchi (by increasing minute ventilation), only the tracheal mucosal temperature fell appreciably (up to 4.0 degrees C), even though the rise in heat loss from the bronchi about doubled that in the trachea. Thus it appears that the bronchi are better able to resist changes in airway wall temperature than is the trachea. These data indicate that the sites, magnitudes, and mechanisms of respiratory heat loss vary appreciably with breathing pattern and inspired gas temperature and that these changes cannot be predicted from measurements made at the mouth. In addition, they demonstrate that local heat (and presumably, water) sources that replenish mucosal heat and water lost to the airstream are important in determining the degree of local airway cooling (and presumably, drying).

Biophysical characterization and modeling of lung surfactant components.

The present study characterizes the dynamic interfacial properties of calf lung surfactant (CLS) and samples reconstituted in a stepwise fashion from phospholipid (PL), hydrophobic apoprotein (HA), surfactant apoprotein A (SP-A), and neutral lipid fractions. Dipalmitoylphosphatidylcholine (DPPC), the major PL component of surfactant, was examined for comparison. Surface tension was measured over a range of oscillation frequencies (1-100 cycles/min) and bulk phase concentrations (0.01-1 mg/ml) by using a pulsating bubble surfactometer. Distinct differences in behavior were seen between samples. These differences were interpreted by using a previously validated model of surfactant adsorption kinetics that describes function in terms of 1) adsorption rate coefficient (k1), 2) desorption rate coefficient (k2), 3) minimum equilibrium surface tension (gamma*), 4) minimum surface tension at film collapse (gammamin), and 5) change in surface tension with interfacial area for gamma < gamma* (m2). Results show that DPPC and PL have k1 and k2 values several orders of magnitude lower than CLS. PL had a gammamin of 19-20 dyn/cm, significantly greater than CLS (nearly zero). Addition of the HA to PL restored dynamic interfacial behavior to nearly that of CLS. However, m2 remained at a reduced level. Addition of the SP-A to PL + HA restored m2 to a level similar to that of CLS. No further improvement in function occurred with the addition of the neutral lipid. These results support prior studies that show addition of HA to the PL markedly increases adsorption and film stability. However, SP-A is required to completely normalize dynamic behavior.

Effects of increasing doses of beta-agonists on airway and parenchymal hysteresis.

We examined the effects of a deep inhalation on airway caliber before and after increasing doses of a beta-agonist in eight subjects, including one former and two current but mild asthmatics. With bronchodilation the increase in maximal flow on the partial flow-volume curve (P), initiated from functional residual capacity, exceeded that seen on the maximal curve (M), initiated from total lung capacity, such that isovolumic maximal flows diminished after a deep inhalation; i.e., M/P ratios fell with bronchodilation, as we and others have found. Five of eight reversed this downward trend in M/P ratios at higher cumulative doses. Quasistatic pressure-volume curves (QSPV) were simultaneously performed on two of these five and demonstrated a decrease in pressure-volume hysteresis (PVH) at the higher doses associated with a rising M/P ratio. Three of eight had continuing low and diminishing M/P ratio up to the highest dose given. QSPV were performed in two of these three and indicated no change in PVH at any of the doses. One of these two had a repeat study using a subcutaneous beta-agonist after the inhaled drug was given, and the M/P ratio rose as QSPV PVH fell. These data support the relative hysteresis analysis of airway and parenchyma as an explanation for volume history effects on airway caliber.

Effects of lung volume, volume history, and methacholine on lung tissue viscance.

We examined the effects of lung volume change and volume history on lung resistance (RL) and its components before and during induced constriction. Eleven subjects, including three current and four former asthmatics, were studied. RL, airway resistance (Raw), and, by subtraction, tissue viscance (Vtis) were measured at different lung volumes before and after a deep inhalation and were repeated after methacholine (MCh) aerosols up to maximal levels of constriction. Vtis, which average 9% of RL at base line, was unchanged by MCh and was not changed after deep inhalation but increased directly with lung volume. MCh aerosols induced constriction by increasing Raw, which was reversed by deep inhalation in inverse proportion to responsiveness. such that the more responsive subjects reversed less after a deep breath. Responsiveness correlated directly with the degree of maximal constriction, as more responsive subjects constricted to a greater degree. These results indicate that in humans Vtis comprises a small fraction of overall RL, which is clearly volume-dependent but unchanged by MCh-induced constriction and unrelated to the degree of responsiveness of the subject.

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.