Airway hyperresponsiveness in asthma: a problem of limited smooth muscle relaxation with inspiration.

We hypothesized that hyperresponsiveness in asthma is caused by an impairment in the ability of inspiration to stretch airway smooth muscle. If the hypothesis was correct, we reasoned that the sensitivity to inhaled methacholine in normal and asthmatic subjects should be the same if the challenge was carried out under conditions where deep inspirations were prohibited. 10 asthmatic and 10 normal subjects received increasing concentrations of inhaled methacholine under conditions where forced expirations from a normal end-tidal inspiration were performed. When no deep inspirations were allowed, the response to methacholine was similar in the normal and asthmatic subjects, compatible with the hypothesis we propose. Completely contrary to our expectations, however, was the marked responsivity to methacholine that remained in the normal subjects after deep breaths were initiated. 6 of the 10 normal subjects had > 20% reduction in forced expiratory volume in one second (FEV 1) at doses of methacholine < 8 mg/ml, whereas there was < 15% reduction with 75 mg/ml during routine challenge. The ability of normal subjects to develop asthmatic responses when the modulating effects of increases in lung volume was voluntarily suppressed suggests that an intrinsic impairment of the ability of inspiration to stretch airway smooth muscle is a major feature of asthma.

Physiologic manifestations of human anaphylaxis.

In the course of a controlled study to evaluate different forms of immunotherapy for subjects with insect-sting hypersensitivity, we observed 11 subjects who had systemic cutaneous urticarial reactions and 3 subjects who experienced systemic anaphylaxis. With the exception of tachycardia, there were no cardiopulmonary changes in the subjects with urticaria, whereas the major manifestation of anaphylactic shock in the other three subjects was severe hypotension that was probably secondary to peripheral vasodilation. Significant abnormalities in gas exchange developed in two subjects. In one, bronchospasm precipitated a respiratory arrest followed by endotracheal intubation with mechanical ventilation. Although plasma histamine levels were not related to the development of cutaneous reactions, the plasma histamine levels correlated with the severity and duration of the cardiopulmonary changes observed during anaphylactic shock. The two subjects with the most severe shock showed evidence of intravascular coagulation characterized by a diminution of Factor V, Factor VIII, fibrinogen, and high molecular weight kininogen, as well as changes in components of the complement system. Standard therapy with epinephrine and fluids, usually recommended for the treatment of systemic anaphylaxis, did not immediately reverse either the hemodynamic or the respiratory abnormalities in the two subjects with the most severe anaphylactic shock. Hemodynamic recovery was gradual and did not seem directly related to any specific therapeutic intervention.

Structural basis for alterations in upper airway collapsibility.

To determine the structural basis for alterations in upper airway (UA) collapsibility, the pharyngeal critical pressure (Pcrit) was measured in an isolated feline upper airway preparation. The effect of airway elongation and dilation was explored by displacing the trachea caudally and the tongue anteriorly, respectively. With caudal-tracheal displacement, Pcrit fell progressively, a result that can be attributed to increased tension within the pharyngeal mucosa. In contrast, anterior-tongue displacement decreased Pcrit when the trachea had been caudally displaced but not with the trachea in the neutral position. These findings suggest that longitudinal tension within the airway mucosa modulates both Pcrit and the response in Pcrit to dilating forces. A mechanical model to account for these findings is discussed.

CPAP reduces inspiratory work more than dyspnea during hyperinflation with intrinsic PEEP.

Hyperinflation with intrinsic positive end-expiratory pressure (PEEPi) loads the respiratory muscles and causes dyspnea in obstructive lung disease. Continuous positive airway pressure (CPAP) has shown some efficacy in reducing inspiratory work and dyspnea. However, in obstructive lung disease, inspiratory work and dyspnea may be increased by additional factors that may not be affected by CPAP. Therefore, to study the effects of hyperinflation with intrinsic PEEP and CPAP in isolation, we used a mechanical analog of airway closure to increase end-expiratory lung volume in normal subjects. In five subjects in whom inspiratory work was measured, increasing end-expiratory lung volume by 1 and 2 L increased inspiratory work per breath from 0.42 +/- 0.04 J to 1.17 +/- 0.15 J (p < 0.05 compared with baseline) and 1.58 +/- 0.22 J (p < 0.05 compared with baseline and to the lesser level of hyperinflation). Although CPAP reduced work per breath and per minute to levels not significantly different from baseline, it had little effect on dyspnea. In ten subjects hyperinflated to 2.4 +/- 0.12 L above FRC, breathing could be sustained 19.5 +/- 4.5 min before quitting the load. This was increased to 26.7 +/- 5.2 min by 10 cm H2O CPAP (p = 0.052). Inspiratory dyspnea was modestly reduced by CPAP during these endurance trials. We conclude that CPAP can substantially ameliorate the respiratory work load induced by hyperinflation with intrinsic PEEP. However, the effects of CPAP on dyspnea and endurance are more limited. This suggests that the limits to breathing at high lung volumes are related to factors in addition to respiratory muscle work, and that CPAP may be of more value in reducing the work than in relieving the distress of obstructive lung disease.

Aspiration pneumonia: treatment with pulmonary vasodilators.

Experimental aspiration pneumonia induced in the isolated perfused ventilated canine pulmonary lobe by the intrabronchial instillation of hydrochloric acid is characterized by pulmonary edema, intrapulmonary shunting, and loss of lung compliance. In addition, pulmonary artery pressure increases. In an attempt to modify the injury response, we restricted the increase in pulmonary artery pressure in the isolated lobe model by administering vasodilator drugs. In control lobes perfused for 4 hours there was minimal weight gain (14 gm), pulmonary artery pressure remained stable (13 mm Hg), and intrapulmonary shunting did not occur. Following intrabronchial instillation of 0.2 ml of 0.1N HCl/gm of lobe weight, lobe weight tripled (183 gm), pulmonary artery pressure (20 mm Hg) was significantly increased, and significant intrapulmonary shunting (32%) developed. When sodium nitroprusside (2 micrograms/min/kg of dog body weight) was infused into the pulmonary artery 3 minutes after HCl instillation, the pulmonary artery pressure was significantly reduced (13 mm Hg) compared to that in untreated acid lobes. This was accompanied by a significant reduction in mean weight gain (100 gm) and intrapulmonary shunting (15%) compared to untreated acid lobes. Similarly, when isoproterenol (0.04 micrograms/min/kg dog body weight) was infused into the pulmonary artery following acid instillation, the pulmonary artery pressure (12.5 mm Hg) was significantly reduced compared to that in untreated acid lobes. This was also accompanied by a significant reduction in weight gain (60 gm) and intrapulmonary shunting (6%) compared to untreated acid lobes. These data demonstrate that the increase in pulmonary artery pressure following acid injury can be lowered pharmacologically and that a significant decrease in injury response follows. This suggests that the magnitude of the injury response is in part a function of pulmonary artery pressure.

Aspiration pneumonia: treatment with osmotically active agents.

Utilizing the ex vivo perfused ventilated canine pulmonary lobe, we evaluated the effects of three osmotically active agents on pulmonary function after acid aspiration. Control lobes were stable during a 44-hour perfusion with minimal weight gain, stable pulmonary artery and end-inspiratory pressures, and no increase in intrapulmonary shunting. After acid aspiration during a 44-hour perfusion period, massive weight gain occurred (228 gm), pulmonary artery and end-inspiratory pressure increased, and marked intrapulmonary shunting (44%) developed. When mannitol (molecular weight 182) or dextran 40 (molecular weight 40,000) were added to the perfusate of the acid-instilled lobes, no significant modifications of the acid-induced response were seen during the 44-hour perfusion. The administration of albumin (molecular weight 69,000), however, markedly modified the acid-induced response. Weight gain (53 gm) was almost completely eliminated, pulmonary artery and end-inspiratory pressures were stable, and intrapulmonary shunting increased only minimally (10%). It is concluded that despite the permeability change in the capillary-alveolar membrane produced by acid aspiration, albumin is retained within the vascular space and is effective in reducing the injury response.

Aspiration pneumonia: beneficial and harmful effects of positive end-expiratory pressure.

With an ex vivo, isolated, ventilated, perfused canine pulmonary lobe, the effects of various levels of positive end-expiratory pressure (PEEP) were evaluated following acid injury. Following intrabronchial instillation of hydrochloric acid, eight lobes were ventilated with 5 cm of H2O of PEEP, 12 lobes with 10 cm of PEEP, and eight lobes with 15 cm of PEEP during a 4 hour perfusion period. Blood flow was kept constant in all preparations. Lobes with 5 cm of PEEP developed a 39% intrapulmonary shunt and increased their weight by 220%. When PEEP was increased to 10 cm, weight gain was similar (184%), but shunting decreased markedly, to 7%. When PEEP was increased further to 15 cm, shunting remained low (13%), but weight gain increased markedly, to 411% of the initial lobe weight. This study demonstrates the beneficial effects of PEEP in aspiration pneumonia, but it also points out that increasing levels of PEEP can magnify acid-pulmonary injury by causing a further increase in interstitial and intralveolar edema.

Pulmonary injury caused by free fatty acid: evaluation of steroid and albumin therapy.

Intrapulmonary free fatty acid (FFA) release has been suggested as a pathogenetic mechanism in respiratory failure caused by acute pancreatitis and fat embolism. Utilizing the isolated perfused ventilated canine pulmonary lobe, we evaluated the effects of FFA infusion and its subsequent modification by albumin and steroid therapy. In control lobes perfused for a 4-hour period, there was minimal weight gain (11 gm), intrapulmonary shunting did not occur, and compliance remained within normal limits. When 1 ml of oleic acid was infused into the pulmonary artery lobe weight tripled (188 gm), intrapulmonary shunting (20%) developed, and compliance was significantly decreased compared to controls. When 30 gm of human salt-poor albumin was added to the perfusate immediately after FFA infusion, the lobe response was similar to that of untreated oleic acid lobes. In contrast, when 400 mg of methylprednisolone succinate was added to the perfusate immediately after FFA infusion, lobe weight gain was significantly reduced (94 gm) compared to oleic acid lobes, intrapulmonary shunting did not occur, and compliance was within normal limits. This study suggests that steroids may be of benefit in the treatment of respiratory insufficiency secondary to acute pancreatitis and fat embolism.

Model of gas transport during high-frequency ventilation.

We analyze gas exchange during high-frequency ventilation (HFV) by a stochastic model that divides the dead space into N compartments in series where each compartment has a volume equal to tidal volume (V). We then divide each of these compartments into alpha subcompartments in series, where each subcompartment receives a well-mixed concentration from one compartment and passes a well-mixed concentration to another in the direction of flow. The number of subcompartments is chosen on the basis that 1/alpha = (sigma t/-t)2, where -t is mean transit time across a compartment of volume, and sigma t is standard deviation of transit times. If (sigma t/-t)D applies to the transit times of the entire dead space, the magnitude of gas exchange is proportional to (sigma t/-t)D, frequency, and V raised to some power greater than unity in the range where V is close to VD. When V is very small in relation to VD, gas exchange is proportional to (sigma t/-t)2D, frequency, and V raised to a power equal to either one or two depending on whether the flow is turbulent or streamline, respectively. (sigma t/-t)D can be determined by the relation between the concentration of alveolar gas at the air outlet and volume expired as in a Fowler measurement of the volume of the dead space.

Hyperinflation with intrinsic PEEP and respiratory muscle blood flow.

Increased end-expiratory lung volume and intrinsic positive end-expiratory pressure (PEEP) are common in obstructive lung disease, especially during exacerbations or exercise. This loads the respiratory muscles and may also stress the circulatory system, causing a reduction or redistribution of cardiac output. We measured the blood flow to respiratory muscles and systemic organs using colored microspheres in 10 spontaneously breathing anesthetized tracheotomized dogs. Flows during baseline breathing (BL) were compared with those during hyperinflation (HI) induced by a mechanical analogue of airway closure and with those during an inspiratory resistive load (IR) that produced an equivalent increase in inspiratory work and time-integrated transdiaphragmatic pressure. Cardiac output was unchanged during IR (3.19 +/- 0.27 l/min at BL, 3.09 +/- 0.34 l/min during IR) but was reduced during HI (2.14 +/- 0.29 l/min; P < 0.01). Among the organs studied, flow was unaltered by IR but decreased to the liver and pancreas and increased to the brain during HI. For the respiratory muscles, flow to the diaphragm increased during IR. However, despite a 1.9-fold increase in inspiratory work per minute and a 2.5-fold increase in integrated transdiaphragmatic pressure during HI, blood flow to the diaphragm was unchanged and flow to the scalenes and sternomastoid fell. The only respiratory muscle to which flow increased during HI was the transversus abdominis, an expiratory muscle. We conclude that the circulatory effects of hyperinflation in this model impair inspiratory muscle perfusion and speculate that this may contribute to respiratory muscle dysfunction in hyperinflated states.

Flow-volume characteristics in the pulmonary circulation.

Isolated ferret and canine lungs were used to validate a method for assessing determinants of vascular volume in the pulmonary circulation. With left atrial pressure (Pla) constant at 5 mmHg, flow (Q) was raised in steps over a physiological range. Changes in vascular volume (delta V) with each increment in Q were determined as the opposite of changes in perfusion system reservoir weight or from the increase in lung weight. At each level of Q, the pulmonary arterial and left atrial cannulas were simultaneously occluded, allowing all vascular pressures to equilibrate at the same static pressure (Ps), which was equal to the compliance-weighted average pressure in the circulation before occlusion. Hypoxia (inspired PO2 25 Torr) in ferret lungs, which causes intense constriction in arterial extra-alveolar vessels, had no effect on the slope of the Ps-Q relationship, interpreted to represent the resistance downstream from compliance (control 0.025 +/- 0.006 mmHg.ml-1.min, hypoxia 0.030 +/- 0.013). The Ps-axis intercept increased from 8.94 +/- 0.50 to 13.43 +/- 1.52 mmHg, indicating a modest increase in the effective back-pressure to flow downstream from compliant regions. The compliance of the circulation, obtained from the slope of the relationship between delta V and Ps, was unaffected by hypoxia (control 0.52 +/- 0.08 ml/mmHg, hypoxia 0.56 +/- 0.08). In contrast, histamine in canine lungs, which causes constriction in veins, caused the slope of the Ps-Q relationship to increase from 0.013 +/- 0.007 to 0.032 +/- 0.006 mmHg.ml-1.min (P less than 0.05) and the compliance to decrease from 3.51 +/- 0.56 to 1.68 +/- 0.37 ml/mmHg (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid reversibility of the allergen-induced pulmonary late-phase reaction by an intravenous beta2-agonist.

This study was performed to determine the degree to which beta2-adrenergic receptor agonists can reverse the allergen-induced late reduction in lung function. On two occasions, seven asthmatic subjects were administered terbutaline or its vehicle by intravenous infusion 7 h after inhaled allergen, at which point the forced expiratory volume in 1 s was 57% of baseline. On another occasion, terbutaline was infused at baseline to determine maximal attainable bronchodilation. After allergen challenge, terbutaline rapidly improved lung function. At the end of terbutaline infusion, the forced expiratory volume in 1 s reached 100 +/- 1.3% of baseline and 84.2 +/- 4.3% of maximal attainable value, but the bronchodilating effect of the beta-agonist did not plateau. The values for forced vital capacity were 102 +/- 1.3% of baseline and 95.1 +/- 3% of maximal attainable value. The kinetics of the terbutaline effect, when it was infused at baseline, were similar to those in the late phase. Because the late-phase reduction in lung function is rapidly reversible by beta2-adrenergic agonists, we conclude that it is caused mainly by bronchial smooth muscle spasm.

Effect of ventilation on vascular permeability and cyclic nucleotide concentrations in ischemic sheep lungs.

Ventilation during ischemia attenuates ischemia-reperfusion lung injury, but the mechanism is unknown. Increasing tissue cyclic nucleotide levels has been shown to attenuate lung ischemia-reperfusion injury. We hypothesized that ventilation prevented increased pulmonary vascular permeability during ischemia by increasing lung cyclic nucleotide concentrations. To test this hypothesis, we measured vascular permeability and cGMP and cAMP concentrations in ischemic (75 min) sheep lungs that were ventilated (12 ml/kg tidal volume) or statically inflated with the same positive end-expiratory pressure (5 Torr). The reflection coefficient for albumin (sigmaalb) was 0.54 +/- 0.07 and 0.74 +/- 0. 02 (SE) in nonventilated and ventilated lungs, respectively (n = 5, P < 0.05). Filtration coefficients and capillary blood gas tensions were not different. The effect of ventilation was not mediated by cyclic compression of alveolar capillaries, because negative-pressure ventilation (n = 4) also was protective (sigmaalb = 0.78 +/- 0.09). The final cGMP concentration was less in nonventilated than in ventilated lungs (0.02 +/- 0.02 and 0.49 +/- 0. 18 nmol/g blood-free dry wt, respectively, n = 5, P < 0.05). cAMP concentrations were not different between groups or over time. Sodium nitroprusside increased cGMP (1.97 +/- 0.35 nmol/g blood-free dry wt) and sigmaalb (0.81 +/- 0.09) in nonventilated lungs (n = 5, P < 0.05). Isoproterenol increased cAMP in nonventilated lungs (n = 4, P < 0.05) but had no effect on sigmaalb. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester had no effect on lung cGMP (n = 9) or sigmaalb (n = 16) in ventilated lungs but did increase pulmonary vascular resistance threefold (P < 0.05) in perfused sheep lungs (n = 3). These results suggest that ventilation during ischemia prevented an increase in pulmonary vascular protein permeability, possibly through maintenance of lung cGMP by a nitric oxide-independent mechanism.

Nature and distribution of vascular resistance in hypoxic pig lungs.

We used the vascular occlusion technique in pig lungs isolated in situ to describe the effects of hypoxia on the distribution of vascular resistance and to determine whether the resistive elements defined by this technique behaved as ohmic or Starling resistors during changes in flow at constant outflow pressure, changes in outflow pressure at constant flow, and reversal of flow. During normoxia, the largest pressure gradient occurred across the middle compliant region of the vasculature (delta Pm). The major effect of hypoxia was to increase delta Pm and the gradient across the relatively noncompliant arterial region (delta Pa). The gradient across the noncompliant venous region (delta Pv) changed only slightly, if at all. Both delta Pa and delta Pv increased with flow but delta Pm decreased. The pressure at the arterial end of the middle region was independent of flow and, when outflow pressure was increased, did not increase until the outflow pressure of the middle region exceeded 8.9 Torr during normoxia and 18.8 Torr during hypoxia. Backward perfusion increased the total pressure gradient across the lung, mainly because of an increase in delta Pm. These results can be explained by a model in which the arterial and venous regions are represented by ohmic resistors and the middle region is represented by a Starling resistor in series and proximal to an ohmic resistor. In terms of this model, hypoxia exerted its major effects by increasing the critical pressure provided by the Starling resistor of the middle region and the ohmic resistance of the arterial region.

Effect of positive-pressure breathing on cardiovascular and thermoregulatory responses to exercise.

Five healthy male volunteers performed 20 min of both seated and supine cycle-ergometer exercise (intensity, 50% maximal O2 uptake) in a warm environment (Tdb = 30 degrees C, relative humidity = 40-50%) with and without breathing 10 cmH2O of continuous positive airway pressure (CPAP). The final esophageal temperature (Tes) at the end of 20 min of seated exercise was significantly higher during CPAP (mean difference = 0.18 +/- 0.04 degree C, P less than 0.05) compared with control breathing (C). The Tes threshold for forearm vasodilation was significantly higher (P less than 0.05) during seated CPAP exercise than C (C = 37.16 +/- 0.13 degrees C, CPAP = 37.38 + 0.12 degree C). The highest forearm blood flow (FBF) at the end of exercise was significantly lower (P less than 0.05) during seated exercise with CPAP (mean +/- SE % difference from C = -30.8 +/- 5.8%). During supine exercise, there were no significant differences in the Tes threshold, highest FBF, or final Tes with CPAP compared with C. The added strain on the cardiovascular system produced by CPAP during seated exercise in the heat interacts with body thermoregulation as evidenced by elevated vasodilation thresholds, reduced peak FBF, and slightly higher final esophageal temperatures.

Effects of systolic and diastolic positive pleural pressure pulses with altered cardiac contractility.

Positive pleural pressure (Ppl) decreases left ventricular afterload and preload. The resulting change in cardiac output (CO) in response to these altered loading conditions varies with the baseline level of cardiac contractility. In an isolated canine heart-lung preparation, we studied the effects of positive Ppl applied phasically during systole or diastole on CO and on the cardiac function curve (the relationship between CO and left atrial transmural pressure). When baseline cardiac contractility was enhanced by epinephrine infusion, systolic and diastolic positive Ppl decreased CO equally (1,931 +/- 131 to 1,419 +/- 124 and 1,970 +/- 139 to 1,468 +/- 139 ml/min, P less than 0.01) and decreased the pressure gradient driving venous return. However, neither shifted the position of the cardiac function curve, suggesting that the predominant effect of positive Ppl was decreased preload. When baseline cardiac contractility was depressed by severe respiratory acidosis, diastolic positive Ppl pulses caused no significant change in CO (418 +/- 66 to 386 +/- 52 ml/min), the cardiac function curve, or the pressure gradient for venous return. However, systolic positive Ppl pulses increased CO from 415 +/- 70 to 483 +/- 65 ml/min (P less than 0.01) and significantly shifted the cardiac function curve to the left. Thus the effect of Ppl pulsations on CO works through different mechanisms, depending on the state of cardiac contractility.

Separate effects of ischemia and reperfusion on vascular permeability in ventilated ferret lungs.

In systemic organs, ischemia-reperfusion injury is thought to occur during reperfusion, when oxygen is reintroduced to hypoxic ischemic tissue. In contrast, the ventilated lung may be more susceptible to injury during ischemia, before reperfusion, because oxygen tension will be high during ischemia and decrease with reperfusion. To evaluate this possibility, we compared the effects of hyperoxic ischemia alone and hyperoxic ischemia with normoxic reperfusion on vascular permeability in isolated ferret lungs. Permeability was estimated by measurement of filtration coefficient (Kf) and osmotic reflection coefficient for albumin (sigma alb), using methods that did not require reperfusion to make these measurements. Kf and sigma alb in control lungs (n = 5), which were ventilated with 14% O2-5% CO2 after minimal (15 +/- 1 min) ischemia, averaged 0.033 +/- 0.004 g.min-1.mmHg-1.100 g-1 and 0.69 +/- 0.07, respectively. These values did not differ from those reported in normal in vivo lungs of other species. The effects of short (54 +/- 9 min, n = 10) and long (180 min, n = 7) ischemia were evaluated in lungs ventilated with 95% O2-5% CO2. Kf and sigma alb did not change after short ischemia (Kf = 0.051 +/- 0.006 g.min-1.mmHg-1.100 g-1, sigma alb = 0.69 +/- 0.07) but increased significantly after long ischemia (Kf = 0.233 +/- 0.049 g.min-1 x mmHg-1 x 100 g-1, sigma alb = 0.36 +/- 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of reduced LV afterload by systolic and diastolic positive pleural pressure.

To investigate the mechanism by which increased pleural pressure (Ppl) assists left ventricular (LV) ejection, we compared the effects of phasic systolic or diastolic increases in Ppl (40-60 mmHg) with use of an isolated canine heart-lung preparation with constant venous return. Positive Ppl during systole (S) caused left atrial transmural pressure (Platm = Pla - Ppl) to decrease by 1.25 +/- 0.46 (SE) mmHg (P less than 0.025). Central blood volume (CBV), the volume of blood in the heart, lungs, and thoracic great vessels, decreased by 29 +/- 4.0 (SE) ml (P less than 0.001). When Ppl was raised for an equal duration during diastole (D), the decrease in Platm was not significant, but there was a significant decrease in CBV (10.5 +/- 4.1 ml, P less than 0.05). With constant venous return, these changes suggested that phasic elevations in Ppl in either S or D assisted LV ejection by decreasing LV afterload. To test the hypothesis that positive Ppl during D reduced afterload by emptying the thoracic aorta, we compared the effects of diastolic positive Ppl with a rigid aorta vs. a compliant aorta. Although there was no statistical difference in the effects of diastolic positive Ppl on Platm, the decrease in CBV was significantly greater when the aorta was compliant than when it was rigid (23 +/- 2.2 vs. 17 +/- 2.7 ml, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Potent bronchoprotective effect of deep inspiration and its absence in asthma.

In the absence of deep inspirations, healthy individuals develop bronchoconstriction with methacholine inhalation. One hypothesis is that deep inspiration results in bronchodilation. In this study, we tested an alternative hypothesis, that deep inspiration acts as a bronchoprotector. Single-dose methacholine bronchoprovocations were performed after 20 min of deep breath inhibition, in nine healthy subjects and in eight asthmatics, to establish the dose that reduces forced expiratory volume in 1 s by >15%. The provocation was repeated with two and five deep inspirations preceding methacholine. Additional studies were carried out to assess optimization and reproducibility of the protocol and to rule out the possibility that bronchoprotection may result from changes in airway geometry or from differential spasmogen deposition. In healthy subjects, five deep inspirations conferred 85% bronchoprotection. The bronchoprotective effect was reproducible and was not attributable to increased airway caliber or to differential deposition of methacholine. Deep inspirations did not protect the bronchi of asthmatics. We demonstrated that bronchoprotection is a potent physiologic function of lung inflation and established its absence, even in mild asthma. This observation deepens our understanding of airway dysfunction in asthma.

Factors influencing measurement of protein reflection coefficient by filtered volume technique.

In isolated perfused organs, the protein reflection coefficient (sigma) can be estimated by comparing increases in hematocrit (Hct) and protein concentration (CP) during transvascular fluid filtration. In this study, we developed an equation for sigma to examine the potential influences of perfusate leak, evaporation, and hemolysis-induced changes in red blood cell volume and perfusate water. We also performed experiments in isolated ferret lungs to quantitate the magnitude of these potential sources of error and the effects of free hemoglobin on measurements of CP. These studies demonstrated that 1) perfusate leak does not cause an error because its effects on changes in Hct and CP counteract each other; 2) evaporation causes an overestimation of sigma, but in our experiments this effect was small; 3) hemolysis-induced changes in red blood cell and perfusate water volumes may cause an over- or underestimation of sigma, but these effects are small; 4) overestimations of CP due to increasing free perfusate hemoglobin concentration can cause substantial overestimations of sigma; and 5) values of sigma calculated from previous equations and from our equation were virtually identical, suggesting that the assumptions necessary for the previous equations were not significant sources of error. In agreement with previous workers, we conclude that the most important potential source of error is hemolysis-induced increases in free perfusate hemoglobin.