The functional consequences of airway remodeling in asthma.

Structural changes in the airway walls involving extracellular matrix remodelling are prominent features of asthma. These changes are probably driven by mediators released as a consequence of chronic allergic inflammation. It is clear that changes in the extracellular matrix have the capacity to influence airway function in asthma. However, it is not clear how each of the many changes that occur in the airway wall contribute to altered airway function in asthma. Collagen deposition in the subepithelial matrix, and hyaluronan and versican deposition around and internal to the smooth muscle would be expected to oppose the effect of smooth muscle contraction. Conversely, geometric considerations would result in exaggerated airway narrowing for a given degree of smooth muscle shortening, as the airway wall is thickened by the deposition of these molecules internal to the smooth muscle. Elastin and cartilage reorganization and degradation in the airway walls would be expected to result in decreased airway wall stiffness and increased airway narrowing for a given amount of force generated by the smooth muscle. Degradation of matrix associated with the smooth muscle may both decrease the stiffness of the parallel elastic component and uncouple smooth muscle from the load provided by lung recoil, allowing exaggerated smooth muscle shortening. Increase in muscle mass may be associated with an increase, a decrease or no change in smooth muscle contractility. If an increase in muscle mass was associated with preservation of its contractile capacity modelling studies suggest that it could be the most important contributor to exaggerated airway narrowing. Modelling studies also suggest that the pattern of mucosal folding during smooth muscle contraction may be an important determinant of airway narrowing. The greater the number of folds, and the stiffer the subepithelial collagenous layer the more resistant the airway will be to narrowing.

High-resolution computed tomography of experimental hydrostatic pulmonary edema.

To better understand the distribution and clearance mechanisms of extravascular lung water (EVLW) in pulmonary edema, computed tomographic (CT) scans of isolated canine lungs were obtained. In this model, there is no active lymphatic drainage. Fourteen isolated lobes were inflated with oxygen, and edema was induced by infusion of normal saline solution. Two volumes of saline were used, 50 percent and 150 percent of initial wet lobar weight. Six 10-mm- and 1.5-mm-collimation CT scans were obtained at 10-mm intervals from the hilum to the periphery of the lobe before and after each of the two stages of pulmonary edema. The CT scans were reviewed independently by two chest radiologists and were assessed by CT densitometry. Both subjective analysis and CT densitometry showed a predominantly central peribronchial distribution of EVLW in the isolated lungs. Airway wall thickness also increased from the control value (average thickness, 1.0 mm) to 150 percent edema (average thickness, 1.5 mm) (p less than 0.001). We postulate that the peribronchial distribution of fluid is due to a pressure gradient from the alveolar interstitium to the interstitium around the blood vessels and airways at the hilum. This gradient may play a major role in the characteristic perihilar and peribronchial distribution of EVLW seen radiologically in patients with hydrostatic pulmonary edema.

Diaphragmatic plate electrode stimulation of the hamster diaphragm.

We developed a new technique of diaphragmatic stimulation by apposing plate electrodes directly against the diaphragm (DPS) in adult Golden Syrian hamsters. The electrophysiological and the mechanical responses to DPS were compared with those with phrenic nerve stimulation. In four animals, evaluation of the electromyogram before and after curare demonstrated that plate electrode stimulation occurred via the phrenic nerve filaments. In four animals, similar transdiaphragmatic pressure was produced at maximal current with DPS and phrenic nerve stimulation. Using DPS increasing current beyond a certain level resulted in recruitment of muscles besides the diaphragm. In six animals, an external abdominal pressure of 15 cmH2O produced maximal transdiaphragmatic pressure, suggesting that the diaphragm was contracting near optimal position with this external abdominal pressure. In another four animals the twitch and pressure-frequency characteristics with the use of DPS were found to be reproducible over a 2-h period. We conclude that DPS is an effective method of diaphragmatic stimulation and should prove to be a valuable technique to study the diaphragm in long-term studies of small rodents.

Diaphragmatic relaxation rate after voluntary contractions and uni- and bilateral phrenic stimulation.

We compared the rate of relaxation of the diaphragm (RRdi) after unilateral phrenic nerve stimulation, bilateral phrenic nerve stimulations, and short sharp voluntary contractions (sniffs). RRdi was measured as the maximum rate of decline in transdiaphragmatic pressure (Pdi) corrected for the change in Pdi [maximum relaxation rate (MRR)/delta Pdi], the time constant (tau) of the later exponential decline in Pdi, and the time to half relaxation (1/2 RT). In five subjects there was no difference in mean RRdi apart from a smaller MRR/delta Pdi (P less than 0.05) for left unilateral compared with either right unilateral or bilateral needle stimulation. However, RRdi varied unpredictably between unilateral and bilateral stimulation of the phrenic nerve in individual subjects. In the same five subjects, sniffs were found to have a slower RRdi than bilateral stimulations (MRR/delta Pdi 0.0064 +/- 0.0007 vs. 0.0074 +/- 0.0018/ms, tau 57.2 +/- 8.7 vs. 48.2 +/- 7.4 ms, 1/2 RT 108.9 +/- 10.9 vs. 73.9 +/- 6.0 ms; all P less than 0.05). The application and inflation of an abdominal binder to an external pressure of 60 mmHg resulted in a decrease in functional residual capacity (-710 +/- 70 ml), but there was no effect on relaxation parameters. Our findings suggest that in the evaluation of RRdi 1) unilateral hemidiaphragmatic stimulations may not accurately reflect the in vivo contractile properties of the diaphragm, 2) sniff maneuvers are not voluntary equivalents of phrenic nerve stimulations, and 3) RRdi is not affected by abdominal binder inflation up to 60 mmHg.

Dietary supplementation and respiratory muscle performance in patients with COPD.

We studied the effects of oral nutritional supplementation on respiratory muscle (RM) performance in 25 ambulatory patients with severe chronic obstructive pulmonary disease (COPD). There was a relationship between body weight and anthropometric parameters of nutritional status (triceps skinfold thickness [r = 0.67; p less than 0.005], midarm muscle circumference (r = 0.53; p less than 0.005), but body weight did not correlate with daily caloric intake, serum albumin, transferrin, or blood lymphocyte count. None of these measurements of nutritional status correlated with any measure of RM strength or endurance. In a randomized observer-blinded crossover trial, patients were allocated to one of two groups. In the first eight weeks of the study, group A received nutritional supplementation, and patients in group B were control subjects. In the second eight weeks, patients in group A were control subjects, and group B received supplement. Mean daily caloric intake and body weight increased in both groups while receiving supplement (both p less than 0.05). Calories provided by the supplement were frequently substituted for normal dietary calories. Any increases in RM performance in the group receiving supplement were matched by increases (due to learning) in controls. We conclude that oral dietary supplements have no important effects on RM performance in ambulatory patients with COPD.

Variability in measurements of pressure-volume curves in normal subjects.

Changes in lung elasticity as measured by the pressure-volume curve are used in clinical investigative studies to diagnose abnormalities in lung function and to evaluate changes in a patient either over time or with an acute intervention. To assess the intrinsic variability of parameters derived from this technique, 4 static deflation curves per day on 5 separate days during a 2-month period were constructed for 10 healthy adults. The pressure-volume data were fitted to the exponential equation: V = A-Be-KP. The coefficients of variation for maximal elastic recoil pressure, transpulmonary pressures at 90, 80, 70, and 60% total lung capacity, static expiratory compliance, and the constants A, B, and k were determined. No significant correlation was found between the variability of daily curves and that of curves performed on separate occasions. The natural log of the exponential constant showed the lowest coefficient of variation, indicating that this parameter is the most reproducible.

Positive end-expiratory pressure decreases bronchial blood flow in the dog.

Positive end-expiratory pressure (PEEP) increases pulmonary vascular resistance, but its effect on the bronchial circulation is unknown. We have compared two techniques for measuring bronchial blood flow in anesthetized, open-chest, ventilated dogs at varying levels of PEEP. Bronchial blood flow ( Qbr ) to the left lower lobe (LLL) and trachea was measured with radiolabeled microspheres. Total Qbr was partitioned into tracheal, bronchial, and parenchymal fractions. We also measured the bronchopulmonary anastomotic flow ( Qbra ) by attaching cannulas from the lobar pulmonary artery and vein to reservoirs, interrupting the LLL pulmonary blood flow and collecting the flow going into the reservoirs. We measured Qbr and Qbra in 10 animals ventilated with varying levels of PEEP (3, 10, and 15 cmH2O) applied randomly. Pulmonary venous pressure was kept at 0 cmH2O. There was no difference observed between Qbr and Qbra at PEEP 3 and 10 cmH2O, but at PEEP 15 cmH2O, Qbr was greater than Qbra , suggesting that at low left atrial pressures bronchial blood flow drains mainly to the left atrium, whereas at elevated alveolar pressures a larger fraction empties into the right side of the heart. PEEP decreased LLL Qbr and Qbra (P less than 0.01). That fraction of Qbr going to the trachea did not change with PEEP. However, the bronchial and parenchymal fractions decreased.

Airway disease in upper and lower lobes in lungs of patients with and without emphysema.

To determine whether pathological changes in the small airways are evenly distributed throughout the lung and whether there is an association of small airway disease with emphysema, pathological abnormalities of the small airways were graded in the upper and lower lobes of 13 surgical lung specimens. Except for slightly increased degrees of respiratory bronchiolar inflammation in the lower lobe, no differences were found between the two sites, nor was there any relationship between the presence of pathological abnormalities in the small airways and the presence of centrilobular emphysema. It is concluded that the predilection of centrilobular emphysema for the upper lung zone is not associated with a difference in intensity of airway disease between upper and lower lobes.

Increased airway mucosal permeability of smokers. Relationship to airway reactivity.

We studied pulmonary epithelial permeability and bronchial reactivity in 10 smoking and 8 nonsmoking adults. Permeability was measured as the disappearance half-life (T 1/2) of aerosolized 99mTc-DTPA from the lungs, and a permeability index (PI) calculated that reflected the appearance of the tracer in the blood. Smokers had increased permeability with a T 1/2 of 44.6 +/- 12.2 min and PI values at 10, 25, and 60 min of 27.3 +/- 13.2, 32.5 +/- 10.2, and 34.3 +/- 9.9, compared with those in nonsmokers with a T 1/2 of 110.0 +/- 62.7 min and PI values of 9.4 +/- 5.7, 14.9 +/- 8.3, and 23.1 +/- 9.0. Bronchial reactivity to histamine was measured with and without prior exposure to aerosolized propranolol (to achieve beta-blockade of airway smooth muscle). Reactivity increased significantly (p less than 0.001) in both groups after beta-blockade, but no difference was found between smokers and nonsmokers. Despite the increased permeability in smokers, there was no evidence of increased reactivity.

Errors in the measurement of total lung capacity in chronic obstructive lung disease.

The standard plethysmographic method of measuring total lung capacity (TLC) has been reported to result in spuriously high estimates in patients with severe airway obstruction. The helium-dilution method is known to underestimate TLC in the same patients. To determine the magnitude of these possible errors we measured TLC by four methods in 20 patients with varying degrees of chronic obstructive lung disease and in 11 normal subjects. TLC was measured by (1) helium dilution (TLCHe); (2) a volume-displacement body plethysmograph, box volume being plotted against mouth pressure (TLCm); (3) the same body plethysmograph with volume plotted against pressure measured with an oesophageal balloon (TLCes); and (4) a radiological technique (TLCxr). In normal subjects there was no difference between TCLm (6.57 +/- 1.20) and TLCes (6.51 +/- 1.24). In the patients with chronic obstructive lung disease TLCm gave results significantly higher than those of any other method. If TLCes is taken as the closest estimate of true TLC, TLCm consistently overestimates and TLCHe underestimates TLC. There was no relationship between the degree of airway obstruction and (TLCm - TLCes) but there was between (TLCes - TLCHe) and severity of airway obstruction. We conclude that using mouth pressure in the plethysmographic measurement of TLC in patients with chronic obstructive lung disease results in consistent but slight overestimation of TLC.

Morphology of peripheral airways in current smokers and ex-smokers.

To investigate the effect of smoking status on pulmonary function and pathologic changes in the peripheral airways, we studied 97 patients who underwent thoracotomy for coin lesions. The patients were divided into 4 groups: nonsmokers (n = 9), current smokers (n = 51), and those who had ceased smoking for less than (n = 18) or more than (n = 19) 2 yr prior to surgery. We found that current smokers had evidence of air-flow obstruction with abnormal lung volumes when compared with nonsmokers. Ex-smokers had lung volumes similar to those of nonsmokers, but showed evidence of obstruction, with the FEV1/FVC between the values found for nonsmokers and current smokers. Examination of the small airways showed that the membranous bronchioles of current smokers and ex-smokers displayed only increased goblet cell metaplasia when compared with those in nonsmokers; the respiratory bronchioles of current and ex-smokers showed increases in intraluminal and airway wall inflammatory cells, wall fibrosis, and pigment deposition. We conclude that patients who currently smoke cigarettes have reduced lung function that is associated with abnormalities of airway structure. Although those who have stopped smoking have function that is closer to the nonsmoking group, there is no apparent difference in structural change between current and ex-smokers.