An isolated perfused lung model with real time data collection and analysis of lung function.

Our primary purpose in making this report has been to describe an isolated perfused lung system which permits the real time collection and analysis of lung mechanical functioning. The distinct advantage of our system lies in its capacity for breath by breath data acquisition and analysis. In addition, because of the modular nature of the components, the system can be readily expanded or contracted depending on the type of experiment being conducted. As configured, the lung mechanic parameters of air flow, lung volume, transpulmonary pressure, pulmonary artery pressure, weight, resistance, elastance (inverse of compliance), and positive end expiratory pressure were monitored, recorded, and evaluated simultaneously throughout the experimental period. We present the results of a 3-h study with control lungs illustrating the stability of these measurements throughout the entire period. Also included is a brief discussion of 3-h studies which show a progressive loss of viability in lungs treated with the redox cycler nitrofurantoin.

Effect of cold and warm dry air hyperventilation on canine airway blood flow.

Tracheobronchial blood flow increases with cold air hyperventilation in the dog. The present study was designed to determine whether the cooling or the drying of the airway mucosa was the principal stimulus for this response. Six anesthetized dogs (group 1) were subjected to four periods of eucapnic hyperventilation for 30 min with warm humid air [100% relative humidity (rh)], cold dry air (-12 degrees C, 0% rh), warm humid air, and warm dry air (43 degrees C, 0% rh). Five minutes before the end of each period of hyperventilation, tracheal and central airway blood flow was determined using four differently labeled 15-micron diam radioactive microspheres. We studied another three dogs (group 2) in which 15- and 50-micron microspheres were injected simultaneously to determine whether there were any arteriovenous communications in the bronchovasculature greater than 15 micron diam. After the last measurements had been made, all dogs were killed, and the lungs, including the trachea, were excised and blood flow to the trachea, left lung bronchi, and parenchyma was calculated. Warm dry air hyperventilation produced a consistently greater increase in tracheobronchial blood flow (P less than 0.01) than cold dry air hyperventilation, despite the fact that there was a smaller fall (6 degrees C) in tracheal tissue temperature during warm dry air hyperventilation than during cold dry air hyperventilation (11 degrees C), suggesting that drying may be a more important stimulus than cold for increasing airway blood flow. In group 2, the 15-micron microspheres accurately reflected the distribution of airway blood flow but did not always give reliable measurements of parenchymal blood flow.

Site of bronchodilatation with inhaled ipratropium bromide and fenoterol in normal subjects.

To assess the effectiveness and site of action of bronchodilatation with an inhaled anticholinergic bronchodilator, ipratropium bromide, and a beta adrenergic agonist, fenoterol, we measured the density dependence of maximal flow and the density dependence of pulmonary resistance using a digital computerized averaging circuit. Eight normal subjects were studied on two separate days, before and after the bronchodilators were administered in a double blind manner. Both drugs resulted in significant and equivalent bronchodilatation. However, there were no significant changes in the density dependence of maximal flow or pulmonary resistance with either agent. These results in normal subjects, therefore, do not support the hypothesis of a preferential site of action of inhaled anticholinergic agents and beta-adrenergic agents.

Effect of breathing dry air on structure and function of airways.

We compared the effect of breathing dry air (0.70 mg H2O/l) with that of breathing room air (8.62 mg H2O/l) in guinea pigs anesthetized with urethane. The data showed that breathing dry air caused a reduction of extravascular water (EVW) in the trachea (P less than 0.01) but not the lung. Structural analysis showed that this water loss occurred from the loose connective tissue of the submucosa. Histamine dose response curves performed on the animals showed that breathing dry air caused an increase in the maximum response (delta max RL) (P less than 0.01) without changing either the dose required to produce 50% of the delta max RL or the ratio of delta max RL to this dose. We conclude that breathing dry air produces an acute reduction of EVW of the loose connective tissue of the airways and an increase in the maximum response to histamine.

Pathophysiologic correlations in asbestos-induced airway disease in the guinea pig.

To determine whether asbestos-induced changes in the structure of the walls of small airways might be associated with abnormalities of pulmonary function, guinea pigs were given 10 mg of amosite asbestos (test group) or saline (control group) by intratracheal instillation. Pulmonary function tests performed 6 months later revealed significant increases in FRC, RV, and TLC in the test group. Measurement of airway wall thickness showed that both membranous and respiratory bronchioles were significantly thickened in the test group; this group also had airways of smaller internal diameter than the controls. Analysis for lung collagen content as hydroxyproline showed a 50% increase in the asbestos exposed animals. There was, however, only minimal and very focal interstitial fibrosis (asbestosis) in the lung parenchyma. Analysis of fiber size indicated that the fibers obtained by digestion of the tissue or from the lavage fluid were significantly longer and wider than those in the original asbestos sample; however, the tissue contained considerably larger fibers than the lavage fluid. We conclude that: Asbestos can produce airway fibrosis and narrowing causing air trapping on pulmonary function examination; this process occurs in the absence of significant interstitial fibrosis of the parenchyma (asbestosis), implying that abnormalities of pulmonary function which are consistent with airflow obstruction in asbestos exposed animals can be caused by pathologic changes in the small airways alone; long asbestos fibers are preferentially retained in the lung, and the longest fibers appear to be in a compartment inaccessible to lavage, presumably, in this model, in airway walls. Enhanced penetration of long fibers into tissue may be one reason why long fibers are more pathogenic than short ones.

Density-dependence of maximal expiratory flow and its correlation with small airway disease in smokers.

Density-dependence of maximal expiratory flow was measured in 110 patients prior to resection for peripheral coin lesions. The resected lung or lobe was examined morphologically and graded for emphysema, membranous bronchiolitis, and respiratory bronchiolitis. Density dependence did not decrease with increasing airway obstruction, and there was no relationship between density-dependence and peripheral airway abnormality or emphysema in the group as a whole. When patients were arbitrarily divided into those with forced expiratory volume in one second (FEV1) greater than 80% predicted (n = 80) and FEV1 less than 80% predicted (n = 30), density-dependence correlated significantly and negatively with membranous bronchiolitis in those with FEV1 greater than 80% predicted and significantly but positively in those with more advanced airway obstruction. We conclude that density-dependence of maximal expiratory flow is not an accurate predictor of peripheral airway abnormality in patients with mild to moderate air-flow obstruction.

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.

Role of tracheal and bronchial circulation in respiratory heat exchange.

Due to their anatomic configuration, the vessels supplying the central airways may be ideally suited for regulation of respiratory heat loss. We have measured blood flow to the trachea, bronchi, and lung parenchyma in 10 anesthetized supine open-chest dogs. They were hyperventilated (frequency, 40; tidal volume 30-35 ml/kg) for 30 min or 1) warm humidified air, 2) cold (-20 degrees C dry air, and 3) warm humidified air. End-tidal CO2 was kept constant by adding CO2 to the inspired ventilator line. Five minutes before the end of each period of hyperventilation, measurements of vascular pressures (pulmonary arterial, left atrial, and systemic), cardiac output (CO), arterial blood gases, and inspired, expired, and tracheal gas temperatures were made. Then, using a modification of the reference flow technique, 113Sn-, 153Gd-, and 103Ru-labeled microspheres were injected into the left atrium to make separate measurements of airway blood flow at each intervention. After the last measurements had been made, the dogs were killed and the lungs, including the trachea, were excised. Blood flow to the trachea, bronchi, and lung parenchyma was calculated. Results showed that there was no change in parenchymal blood flow, but there was an increase in tracheal and bronchial blood flow in all dogs (P less than 0.01) from 4.48 +/- 0.69 ml/min (0.22 +/- 0.01% CO) during warm air hyperventilation to 7.06 +/- 0.97 ml/min (0.37 +/- 0.05% CO) during cold air hyperventilation.

Platelet sequestration in lung with hemorrhagic shock and reinfusion in dogs.

We compared red blood cell (RBC) and platelet transit through the pulmonary vascular bed under control conditions (n = 8) and during hemorrhagic shock (n = 8) in anesthetized spontaneously breathing dogs, using a modification of the indicator-dilutor technique. Platelets and RBCs from each animal were labeled with 51Cr and 99mTc, respectively, and were rapidly injected into the right atrium while blood was sampled from the ascending aorta. The mean transit time (MTT), volume of distribution, and percent recovery for RBCs and platelets were calculated, as was the percent extraction of platelets. We found 1) the the difference between RBC and platelet MTT increased (p less than 0.01), 2) that the percent extraction of platelets increased (p less than 0.001), and 3) that the percent recovery of platelets fell (p less than 0.01) during the shock period. These values all returned to control levels after reinfusion of the shed blood. The relationship between a transient reduction in blood flow and platelet extraction was then studied in a third group of dogs (n = 5) where inflation of a balloon in the inferior vena cava was used to reduce cardiac output (CO). These studies showed that platelet extraction was inversely related to CO. We conclude that the increased platelet sequestration seen in the lung during hemorrhagic shock is primarily related to decreased blood flow.