Altered Lung Mechanics Research Articles

Influence of expiratory loading and hyperinflation on cardiac output during exercise.

Patients with obstructive lung disease are exposed to expiratory loads (ELs) and dynamic hyperinflation as a consequence of expiratory flow limitation. To understand how these alterations in lung mechanics might affect cardiac function, we examined the influence of a 10-cm H2O EL, alone and in combination with voluntary hyperinflation (ELH), on pulmonary pressures [esophageal (Pes) and gastric (Pg)] and cardiac output (CO) in seven healthy subjects. CO was determined by using an acetylene method at rest and at 40 and 70% of peak work. At rest and during exercise, EL resulted in an increase in Pes and Pg (7-18 cm H2O; P < 0.05) and a decrease in CO (from 5.3 +/- 1.8 to 4.5 +/- 1.4, 12.2 +/- 2.2 to 11.2 +/- 2.2, and 16.3 +/- 3.3 to 15.2 +/- 3.2 l/min for rest, 40% peak work, and 70% peak work, respectively; P < 0.05), which remained depressed after an additional 2 min of EL. With ELH, CO increased at rest and both exercise loads (relative to EL only) but remained below control values. The changes in CO were due to a reduction in stroke volume with a tendency for stroke volume to fall further with prolonged EL. There was a negative correlation between CO and the increase in expiratory Pes and Pg with EL (R = -0.58 and -0.60; P < 0.01), whereas the rise in CO with subsequent hyperinflation was related to a more negative Pes (R = 0.72; P < 0.01). In conclusion, EL leads to a reduction in CO, which appears to be primarily related to increases in expiratory abdominal and intrathoracic pressure, whereas ELH resulted in an improved CO, suggesting that lung inflation has little impact on cardiac function.

The Pulmonary Surfactant: Impact of Tobacco Smoke and Related Compounds on Surfactant and Lung Development

Cigarette smoking, one of the most pervasive habits in society, presents many well established health risks. While lung cancer is probably the most common and well documented disease associated with tobacco exposure, it is becoming clear from recent research that many other diseases are causally related to smoking. Whether from direct smoking or inhaling environmental tobacco smoke (ETS), termed secondhand smoke, the cells of the respiratory tissues and the lining pulmonary surfactant are the first body tissues to be directly exposed to the many thousands of toxic chemicals in tobacco. Considering the vast surface area of the lung and the extreme attenuation of the blood-air barrier, it is not surprising that this organ is the primary route for exposure, not just to smoke but to most environmental contaminants. Recent research has shown that the pulmonary surfactant, a complex mixture of phospholipids and proteins, is the first site of defense against particulates or gas components of smoke. However, it is not clear what effect smoke has on the surfactant. Most studies have demonstrated that smoking reduces bronchoalveolar lavage phospholipid levels. Some components of smoke also appear to have a direct detergent-like effect on the surfactant while others appear to alter cycling or secretion. Ultimately these effects are reflected in changes in the dynamics of the surfactant system and, clinically in changes in lung mechanics. Similarly, exposure of the developing fetal lung through maternal smoking results in postnatal alterations in lung mechanics and higher incidents of wheezing and coughing. Direct exposure of developing lung to nicotine induces changes suggestive of fetal stress. Furthermore, identification of nicotinic receptors in fetal lung airways and corresponding increases in airway connective tissue support a possible involvement of nicotine in postnatal asthma development. Finally, at the level of the alveoli of the lung, colocalization of nicotinic receptors and surfactant-specific protein in alveolar cells is suggestive of a role in surfactant metabolism. Further research is needed to determine the mechanistic effects of smoke and its components on surfactant function and, importantly, the effects of smoke components on the developing pulmonary system.

The pulmonary surfactant: impact of tobacco smoke and related compounds on surfactant and lung development.

Cigarette smoking, one of the most pervasive habits in society, presents many well established health risks. While lung cancer is probably the most common and well documented disease associated with tobacco exposure, it is becoming clear from recent research that many other diseases are causally related to smoking. Whether from direct smoking or inhaling environmental tobacco smoke (ETS), termed secondhand smoke, the cells of the respiratory tissues and the lining pulmonary surfactant are the first body tissues to be directly exposed to the many thousands of toxic chemicals in tobacco. Considering the vast surface area of the lung and the extreme attenuation of the blood-air barrier, it is not surprising that this organ is the primary route for exposure, not just to smoke but to most environmental contaminants. Recent research has shown that the pulmonary surfactant, a complex mixture of phospholipids and proteins, is the first site of defense against particulates or gas components of smoke. However, it is not clear what effect smoke has on the surfactant. Most studies have demonstrated that smoking reduces bronchoalveolar lavage phospholipid levels. Some components of smoke also appear to have a direct detergent-like effect on the surfactant while others appear to alter cycling or secretion. Ultimately these effects are reflected in changes in the dynamics of the surfactant system and, clinically in changes in lung mechanics. Similarly, exposure of the developing fetal lung through maternal smoking results in postnatal alterations in lung mechanics and higher incidents of wheezing and coughing. Direct exposure of developing lung to nicotine induces changes suggestive of fetal stress. Furthermore, identification of nicotinic receptors in fetal lung airways and corresponding increases in airway connective tissue support a possible involvement of nicotine in postnatal asthma development. Finally, at the level of the alveoli of the lung, colocalization of nicotinic receptors and surfactant-specific protein in alveolar cells is suggestive of a role in surfactant metabolism. Further research is needed to determine the mechanistic effects of smoke and its components on surfactant function and, importantly, the effects of smoke components on the developing pulmonary system.

Arm positioning alters lung volumes in subjects with COPD and healthy subjects

Subjects with chronic obstructive pulmonary disease (COPD) have difficulty performing arm exercise, particularly if the arms are unsupported and elevated. The purpose of this study was to evaluate the effect of arm position on static lung volumes in COPD and healthy subjects. Lung volumes were measured by plethysmography in nine COPD subjects (mean age +/- SD = 67.3 +/- 10.3 years; % pred FEV1 +/- SD = 39.7 +/- 10.9%) and nine healthy subjects (mean age +/- SD = 55.8 +/- 8.8 years; % pred FEV1 +/- SD = 102.9 +/- 12.2%) with the arms below 90 degrees shoulder flexion, at 90 degrees shoulder flexion and above 90 degrees shoulder flexion. In all subjects a significant increase in functional residual capacity (FRC) and reduction in inspiratory capacity (IC) was shown with arms above 90 degrees shoulder flexion when compared with both arms below 90 degrees shoulder flexion (mean increase in FRC (95% CI) was 0.17 L (0.06 to 0.27) for COPD and 0.29 L (0.11 to 0.47) for healthy subjects; mean reduction in IC (95% CI) was 0.24 L (0.1 to 0.38) for COPD and 0.45 L (0.22 to 0.68) for healthy subjects) and arms at 90 degrees shoulder flexion (mean increase in FRC (95% CI) was 0.15 L (0.01 to 0.29) for COPD and 0.22 L (0.11 to 0.34) for healthy subjects; mean reduction in IC (95% CI) was 0.14 L (0.01 to 0.26) for COPD and was 0.29 L (0.17 to 0.42) for healthy subjects). These changes may alter lung mechanics and, in COPD subjects, may affect their ability to perform arm exercise above shoulder height

Role of endogenous histamine in altered lung mechanics in rabbits.

Unlike the effects of exogenous histamine, those of endogenous histamine on the lung mechanics have not yet been characterized. The site of endogenous histamine liberation by mivacurium was determined, as were the effects of this histamine on the airway and parenchymal mechanics in control rabbits (group C) and rabbits pretreated with H1 and H2 receptor blockers (group AH). The effectiveness of the receptor blockade was ensured by challenges with exogenous histamine. Pulmonary input impedance at low frequencies (ZL) was measured in anesthetized mechanically ventilated open-chest rabbits under control conditions and every minute after administration of an intravenous bolus of mivacurium (2 mg/kg) and exogenous histamine (10 microg/kg). Histamine levels were determined in serum samples taken from the carotid artery and jugular vein before and 1, 3, and 6 min after mivacurium injection. Parameters of airway resistance (Raw) and inertance and parenchymal damping (G) and elastance (H) were extracted from ZL spectra. Mivacurium induced significant increases in plasma histamine levels, with the venous concentrations being significantly higher than those in the artery. The mivacurium-induced increase in Raw (28.7 +/- 2.3%; mean +/- SD) in group C was significantly higher than that in group AH (6.6 +/- 3.4%), whereas the responses in G were not inhibited significantly (23.9 +/- 6.9% vs. 15.5 +/- 3.0%). The significant increases in Raw (70.6 +/- 12.6%) and G (21.0 +/- 4.9%) after exogenous histamine administration were virtually completely abolished by antihistamine pretreatment (3.6 +/- 3.7% and 0.3 +/- 2.6%). After mivacurium administration, endogenous histamine is liberated at least partly in the systemic circulation, and it induces primarily a heterogeneous airway constriction with minor changes in the parenchymal properties. This response was considerably reduced but not abolished by antihistamine pretreatment, a circumstance suggesting that mivacurium may liberate other constrictor mediators that might also contribute to the airway and parenchymal constriction.

Maternal nicotine exposure upregulates collagen gene expression in fetal monkey lung. Association with alpha7 nicotinic acetylcholine receptors.

The recent identification of nicotinic acetylcholine receptors (nAChR) in pulmonary fibroblasts suggests that in utero nicotine exposure may alter collagen expression by these cells in the developing lung. To test this hypothesis, timed-pregnant rhesus monkeys were administered nicotine (1-1.5 mg/kg/d, subcutaneously) using osmotic minipumps from Days 26-134 or 26-160 of gestation (term = 165 d). In utero nicotine exposure significantly increased airway wall area per unit epithelial basement membrane. Collagen type I and III mRNA expression and immunostaining were significantly increased in the airway and alveolar walls of the nicotine-treated group. Elastin mRNA expression increased, but protein expression in parenchyma remained unchanged. Dual labeling studies colocalized alpha7 nAChR and collagen to the same cells in airway wall cells, and colocalization of alpha7 nAChR and collagen was confirmed in isolated pulmonary fibroblasts. These findings suggest that nicotine may directly interact with alpha7 nAChR to increase collagen accumulation in airway and alveolar walls following in utero nicotine exposure. These data suggest that passage of nicotine across the placenta to increase collagen deposition and therefore increase airway wall dimensions in fetal lung may partially explain the observed alterations in lung mechanics in the infants of mothers who smoke during pregnancy.

Acute hypoxia and reoxygenation impairs exhaled nitric oxide release and pulmonary mechanics

Objective: Changes in exhaled nitric oxide levels often accompany conditions associated with elevated pulmonary vascular resistance and altered lung mechanics. However, it is unclear whether changes in exhaled nitric oxide reflect altered vascular or bronchial nitric oxide production. This study determined the effects of acute hypoxia and reoxygenation on pulmonary mechanics, plasma nitrite levels, and exhaled nitric oxide production. Methods: Ten piglets underwent 90 minutes of hypoxia (fraction of inspired oxygen = 12%), 1 hour of reoxygenation on cardiopulmonary bypass, and 2 hours of recovery. Five additional animals underwent bypass without hypoxia. Exhaled nitric oxide, plasma nitrite levels, and pulmonary mechanics were measured. Results: Exhaled nitric oxide decreased to 36% of baseline by end hypoxia (34 ± 14 vs 12 ± 9 ppb, P = .005) and declined further to 20% of baseline at end recovery (7 ± 6 ppb). Aortic nitrite levels decreased from baseline during hypoxia (from 102 ± 13 to 49 ± 7 μmol/L, P = .05) but returned to baseline during recovery. Pulmonary arterial nitrite also decreased during hypoxia (from 31.4 ± 7.8 to 22.9 ± 9.5 μmol/L, P = .04) and returned to baseline at end recovery. Decreased production of exhaled nitric oxide was associated with impaired gas exchange (alveolar-arterial gradient = 32 mm Hg at baseline and 84 mm Hg at end recovery), decreased pulmonary compliance (6.6 ± 0.9 mL/cm H 2O at baseline, 5.0 ± 0.7 mL/cm H 2O at end hypoxia, and 5.4 ± 0.7 mL/cm H 2O at end recovery), and increased inspiratory airway resistance (41 ± 4 cm H 2O · L –1 · s –1 at baseline, 56 ± 4.9 cm H 2O · L –1 · s –1 at end hypoxia, and 50 ± 5 cm H 2O · L –1 · s –1 at end recovery). Conclusions: A decrease in exhaled nitric oxide persisted after hypoxia, and plasma nitrite levels returned to baseline on reoxygenation, indicating that alterations in exhaled nitric oxide during hypoxia-reoxygenation might be unrelated to plasma nitrite levels. Furthermore, decreased exhaled nitric oxide corresponded with altered pulmonary mechanics and gas exchange. Reduced exhaled nitric oxide after hypoxia-reoxygenation might reflect bronchial epithelial dysfunction associated with acute lung injury. (J Thorac Cardiovasc Surg 2000;119:931-8)

Altered lung mechanics after double-lung transplantation.

We studied lung mechanics and small airways function in 15 patients after double-lung (DL) transplantation. Patients were classified as stable (DL-S, n = 11), or having obliterative bronchiolitis syndrome (DL-OBS, n = 4). We performed pulmonary function tests (PFT), measured slope of phase 3 of the single-breath nitrogen test (N2SP3), and obtained pressure-volume curves and values: chord compliance (Cst,L), specific chord compliance (SCst,L), and elastic recoil pressure at 90% TLC. PFT showed mild restrictive pattern in DL-S and severe obstructive lung disease in DL-OBS. The N2SP3 measurement indicated small airways dysfunction in 82% of DL-S and in all DL-OBS patients. The Cst,L was 0.24 +/- 0.08 L/cm H2O in DL-S and 0.16 +/- 0.05 L/cm H2O in DL-OBS, both lower than control subjects 0.34 +/- 0. 09 L/cm H2O (p < 0.01; p < 0.001). Moreover, SCst,L was 0.09 +/- 0. 03 cm H2O-1 in DL-S, and 0.05 +/- 0.02 cm H2O-1 in DL-OBS, significantly lower than control subjects 0.12 +/- 0.02 cm H2O-1 (p < 0.05; p < 0.001). Elastic recoil at 90% TLC was normal in 14 of 15 patients. We found a linear correlation between N2SP3 and FEV1, and between FEV1 and Cst,L and SCst,L for combined DL-S and DL-OBS. Reduced compliance near FRC with normal elastic recoil at high lung volumes does not suggest changes in lung parenchyma. We speculate that structural or functional alterations in small airways may have contributed to low compliance measurements. Of special concern are our findings that DL-S had significant small airways dysfunction and reduced compliance in a pattern similar to the DL-OBS, only smaller in magnitude.

Cyclooxygenase Products Contribute to Endothelin-induced Pulmonary Hypertension and Altered Lung Mechanics in Sheep

Endothelins have potent biological effect in vivo which may, in part, be mediated by stimulation of cyclooxygenase metabolism of arachidonic acid. We administered endothelins (ETs) intravenously to chronically instrumented awake sheep with and without pretreatment with meclofenamate (n=8). 30 μg doses of ET-1, ET-2, and ET-3 caused similar degrees of acute elevation of pulmonary artery pressure (PPA), reduction of the dynamic compliance of the lungs (Cdyn), and increases in lung lymph flow. Pretreatment with meclofenamate inhibited the rise in PPAand reduction in Cdyn, but had no effect on lung lymph flow. We conclude that the biological effects of the endothelins on PPAand Cdyn, but not lung fluid balance, are mediated in part by cyclooxygenase products of arachidonic acid metabolism.

Effect of Nitrous Acid on Lung Function in Asthmatics: A Chamber Study

Nitrous acid, a component of photochemical smog and a common indoor air pollutant, may reach levels of 100 ppb where gas stoves and unvented portable kerosene heaters are used. Nitrous acid is a primary product of combustion and may also be a secondary product by reaction of nitrogen dioxide with water. Because the usual assays for nitrogen dioxide measure several oxides of nitrogen (including nitrous acid) together, previous studies of indoor nitrogen dioxide may have included exposure to and health effects of nitrous acid. To assess the respiratory effects of nitrous acid exposure alone, we carried out a double-blinded crossover chamber exposure study with 11 mildly asthmatic adult subjects. Each underwent 3-hr exposures to 650 ppb nitrous acid and to filtered room air with three 20-min periods of moderate cycle exercise. Symptoms, respiratory parameters during exercise, and spirometry after exercise were measured. A statistically significant decrease in forced vital capacity was seen on days when subjects were exposed to nitrous acid. This effect was most marked at 25 min and 85 min after exposure began. Aggregate respiratory and mucous membrane symptoms were also significantly higher with nitrous acid. We conclude that this concentration and duration of exposure to nitrous acid alters lung mechanics slightly, does not induce significant airflow obstruction, and produces mild irritant symptoms in asthmatics.

Effect of nitrous acid on lung function in asthmatics: a chamber study.

Nitrous acid, a component of photochemical smog and a common indoor air pollutant, may reach levels of 100 ppb where gas stoves and unvented portable kerosene heaters are used. Nitrous acid is a primary product of combustion and may also be a secondary product by reaction of nitrogen dioxide with water. Because the usual assays for nitrogen dioxide measure several oxides of nitrogen (including nitrous acid) together, previous studies of indoor nitrogen dioxide may have included exposure to and health effects of nitrous acid. To assess the respiratory effects of nitrous acid exposure alone, we carried out a double-blinded crossover chamber exposure study with 11 mildly asthmatic adult subjects. Each underwent 3-hr exposures to 650 ppb nitrous acid and to filtered room air with three 20-min periods of moderate cycle exercise. Symptoms, respiratory parameters during exercise, and spirometry after exercise were measured. A statistically significant decrease in forced vital capacity was seen on days when subjects were exposed to nitrous acid. This effect was most marked at 25 min and 85 min after exposure began. Aggregate respiratory and mucous membrane symptoms were also significantly higher with nitrous acid. We conclude that this concentration and duration of exposure to nitrous acid alters lung mechanics slightly, does not induce significant airflow obstruction, and produces mild irritant symptoms in asthmatics.

Practical factors in neonatal lung imaging using electrical impedance tomography.

IN NEWBORN infants, hyaline membrane disease, meconium aspiration and pneumonia may cause severe respiratory distress with alterations in lung mechanics. Assessment of the lung function in infants receiving intensive care suggests that measurement of dynamic compliance may provide useful information about the severity of lung disease, prognosis and the likelihood of complications (GREENHOUGH and MORLEY, 1986). At present, there is no technique available to study regional changes in lung volume versus compliance both non-invasively and at the cot side. The development of electrical impedance tomography (EIT) (BARBER et al., 1983) could allow this. EIT also has the potential to monitor lung expansion continuously on a real-time basis. Continuous monitoring will allow the early detection of pneumothorax, airway obstruction and localised lung collapse, conditions which normally lead to deficiency in blood oxygen and ultimately to brain damage.

Exercise ventilatory response to upright and aero-posture cycling

The aero-cycling posture has become increasingly popular among cyclists. Because of the potential for altered lung mechanics in the aero-cycling posture, the ventilatory and gas exchange profiles of 10 moderately trained males (31.1 +/- 6.3 yr, mean +/- SD) exercising on a cycle ergometer in the upright posture (UC) and aero-cycling (AC) posture were studied. Exercise consisted of 3-min work stages with 50-W incremental changes until volitional exhaustion. Ventilatory and gas exchange responses to exercise were averaged each minute. Maximal oxygen consumption (54.3 +/- 6.3 vs 53.4 +/- 6.9 ml.kg-1.min-1) in the UC and AC were not significantly different. Maximal values for ventilation (132.5 +/- 32.3 vs 128.0 +/- 28.7 l.min-1), tidal volume (2.7 +/- 0.5 vs 2.6 +/- 0.3 1.br-1), breathing frequency (50.0 +/- 8.0 vs 47.0 +/- 5.0 br.min-1), and submaximal ventilatory and heart rate responses in the UC were not significantly different compared with the AC. No significant difference existed between postures for mean inspiratory flow and inspiratory duty cycle at comparable submaximal power outputs. These results indicate that at absolute power outputs, ventilatory responses, as determined by respiratory pattern and timing, and metabolic cost, were similar in the UC and AC. Thus, the AC does not impair physiologic responses to high intensity exercise.

Inspiratory muscle activity during pulmonary edema in anesthetized dogs

Pulmonary edema is known to induce a rapid and shallow breathing pattern. However, its effects on the level and pattern of distribution of motor activity to the respiratory muscles is unclear. In the present study we evaluated the effect of oleic acid induced pulmonary edema on the electrical activity of the inspiratory muscles (costal and crural diaphragm and parasternal and external intercostal muscles) in the dog, and related it to the transdiaphragmatic pressure and ventilatory parameters over the course of CO 2 rebreathing. Pulmonary edema, reflected by a 7.1 ± 0.6 wet to dry ratio, decreased lung compliance by 57%, increased pulmonary shunt to 35%, and was associated with a rapid and shallow breathing pattern. When compared at equal levels of P CO 2 during CO 2 rebreathing before and during edema, ventilation and mean inspiratory flow were increased only at lower levels of hypercapnia and their responses to increasing levels of P CO 2 were significantly diminished during edema. Transdiaphragmatic pressures were elevated during edema as compared to control values. The rate of rise of the electrical activity of all inspiratory muscles increased significantly during edema at all levels of P CO 2 . Peak activity, however, remained unchanged, due to shortening of the inspiratory duration. The EMG responses to progressive hypercapnia were not affected by edema. Pulmonary edema did not change the pattern of breathing and neural output to the inspiratory muscles in vagotomized dogs. We conclude that stimulation of pulmonary proprioreceptors during edema increases neural output to all inspiratory muscles. The neural response to hypercapnia is not altered by edema, and is additive to the vagal input. The ventilatory response to CO 2 is blunted during severe edema, due to alterations in lung mechanics.

Partitioning of respiratory mechanics in mechanically ventilated patients

In ten mechanically ventilated patients, six with chronic obstructive pulmonary disease (COPD) and four with pulmonary edema, we have partitioned the total respiratory system mechanics into the lung (l) and chest wall (w) mechanics using the esophageal balloon technique together with the airway occlusion technique during constant-flow inflation (J. Appl. Physiol. 58: 1840-1848, 1985). Intrinsic positive end-expiratory pressure (PEEPi) was present in eight patients (range 1.1-9.8 cmH2O) and was due mainly to PEEPi,L (80%), with a minor contribution from PEEPi,w (20%), on the average. The increase in respiratory elastance and resistance was determined mainly by abnormalities in lung elastance and resistance. Chest wall elastance was slightly abnormal (7.3 +/- 2.2 cmH2O/l), and chest wall resistance contributed only 10%, on the average, to the total. The work performed by the ventilator to inflate the lung (WL) averaged 2.04 +/- 0.59 and 1.25 +/- 0.21 J/l in COPD and pulmonary edema patients, respectively, whereas Ww was approximately 0.4 J/l in both groups, i.e., close to normal values. We conclude that, in mechanically ventilated patients, abnormalities in total respiratory system mechanics essentially reflect alterations in lung mechanics. However, abnormalities in chest wall mechanics can be relevant in some COPD patients with a high degree of pulmonary hyperinflation.

Site of action of hypertonic saline in the canine lung

The site of action of inhaled hypertonic saline was determined in 8- to 10-wk-old puppies by combining measurements of respiratory mechanics, made during mechanical ventilation and after midexpiratory flow interruptions, with direct measurements of alveolar pressure. Under both control conditions and after inhalation of 10% saline, we were able to partition lung mechanics into components representing the airways and tissue viscoelastic properties. Hypertonic saline challenge altered lung mechanics by increasing airway resistance and did not have any effect on elastic or viscoelastic properties of the lung.

Effects of substance P and calcitonin gene-related peptide on the pulmonary circulation

To assess the in vivo effects of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) on the pulmonary vascular bed, the hemodynamic responses to both CGRP and SP were examined in the in situ-perfused lung lobe of open-chest anesthetized pigs. Peptides were infused into the lobar artery under conditions of elevated pulmonary vascular tone by prostaglandin F2 alpha (PGF2 alpha, 20 micrograms/min). Pulmonary airway lobar dynamic compliance (Cdyn) and airway resistance (Re) were computed from simultaneously measured airway pressure and airflow entering the lobe through a Carlens endobronchial divider. PGF2 alpha infusion slightly reduced Cdyn (-20%) and increased Re (+11%) while lobar arterial pressure rose from 14 +/- 1 to 31 +/- 2 mmHg (n = 12). In these conditions, lobar artery infusion of SP (0.5-50 pmol/min) or CGRP (15-5,000 pmol/min) produced a dose-dependent decrease in the pressor response to PGF2 alpha, reaching -54 +/- 3 and -64 +/- 7%, respectively, without alterations in lung mechanics. On a molar basis, SP was more effective than CGRP; its vasodilatory effect was more rapid and of shorter duration. Higher CGRP infusion rates were not studied because of marked systemic hypotension. SP infused at 150, 500, and 1,000 pmol/min significantly reduced Cdyn by 12 +/- 2, 24 +/- 4, and 62 +/- 7%, respectively, but also induced a rise in lobar arterial pressure and a fall in systemic arterial pressure. The results show that both SP and CGRP are potent pulmonary vasodilators. In contrast to CGRP, which did not affect lung mechanics, high infusion rates of SP decreased Cdyn and increased Re.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Pulmonary Inflammation in Altered Airway Responsiveness in Three Sheep Models of Acute Lung Injury

Pulmonary inflammation may contribute to increased airway responsiveness in experimental models of acute lung injury. Infusions of endotoxin, phorbol myristate acetate (PMA), or zymosan-activated plasma (ZAP) all result in the accumulation of polymorphonuclear leukocytes (PMNs) in the lung and alterations in lung mechanics. These three interventions have strikingly different effects on airway responses to aerosol histamine: ZAP does not increase airway responsiveness, whereas endotoxin causes a greater increase in airway responsiveness than does PMA. The present histologic study examines the question of whether the pattern and severity of PMN and mast cell accumulation in large- and medium-sized airways and lung periphery could contribute to the differences in airway responsiveness to histamine. Minimally instrumented sheep were given either an infusion of endotoxin (0.5 microgram/kg over 20 min), a bolus injection of PMA (5 micrograms/kg), or repetitive boluses of autologous ZAP (5 ml). Four and a half hours later, the animals were killed, and the left lung was removed and fixed in the distended state. Three levels of the left lung were examined by light microscopy: the large hilar bronchus, a medium-sized bronchus, and peripheral lung. The number of PMNs and mast cells in the airway wall were expressed as cells/mm length of airway circumference and in the lung periphery as cells/100 alveolar profiles. Both endotoxin and PMA caused a significant 2- to 3-fold increase in number of PMNs/mm of large airway circumference, the majority of PMNs being in the blood vessels of the lamina propria and submucosa; ZAP caused only minimal PMN accumulation in the blood vessels of the submucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Repetitive Bolus Injections of Zymosan-activated Plasma on Lung Mechanics and Airway Responsiveness in Awake Sheep

We studied the pulmonary effects of repetitive bolus injections of autologous zymosan-activated plasma (ZAP) in nine chronically instrumented awake sheep. Aerosol histamine responsiveness was determined 1 h before and 4.5 h after the first bolus injection of ZAP. Each sheep received in the pulmonary artery a total of eight 5-ml bolus injections of ZAP separated by 30 min. On a separate day, with the order of experimentation varied to avoid sequential bias, six of the nine sheep also received "control" plasma (plasma prepared in the identical fashion as ZAP but not incubated with zymosan). "Control" plasma caused reproducible transient increases in pulmonary artery pressure, but it did not cause alterations in any of the other measured variables. Repetitive bolus injections of ZAP caused reproducible alterations in lung mechanics, pulmonary hemodynamics, lung fluid and solute exchange, oxygenation, and peripheral leukocyte counts. The increases in thromboxane-B2 concentrations in lung lymph and plasma were greatest after the first bolus injection of ZAP, with the magnitude of these changes diminishing on succeeding injections of ZAP. Aerosol histamine responsiveness did not increase after the eight bolus injections of ZAP.

Effect of Platelet-activating Factor Receptor Antagonism on Endotoxin-induced Lung Dysfunction in Awake Sheep

To test the hypothesis that PAF partially mediates endotoxin-induced lung dysfunction, we studied the effects of two structurally dissimilar PAF receptor antagonists (SRI 63-441 and WEB 2086) on endotoxin-induced lung dysfunction in chronically instrumented awake sheep. Each animal was studied three times in varied order: infusion of endotoxin alone (Escherichia coli endotoxin 0.5 micrograms/kg over 20 min [E]), infusion of the competitive platelet-activating factor (PAF) receptor antagonist alone, or with endotoxin given 1 h after beginning the 6-h drug infusion (E + SRI, E + WEB). Neither drug alone had significant effects on any of the measured variables, but both were able to abolish the pulmonary pressor effect of a 0.25-micrograms/kg bolus of PAF. SRI 63-441 (10 to 20 mg/kg/h) attenuated the endotoxin-induced pulmonary hypertension (peak pulmonary arterial pressure, 53 +/- 12 versus 65 +/- 7 cm H2O; p greater than 0.05) and fall in dynamic compliance of the lungs (to 65.1 +/- 9.8% baseline versus 32.6 +/- 5.1% baseline). Lung lymph flow increased 6.1- and 5.8-fold at 2 and 5 h for (E) versus 1.9- and 2.5-fold at identical time points for (E + SRI). SRI 63-441 attenuated the acute leukopenia noted after endotoxemia. WEB 2086 (20 mg/kg/h) similarly attenuated the late alterations in lung mechanics and lymph flow caused by endotoxin, but it had little effect on the early pulmonary hypertension and lung mechanic changes. Both agents significantly attenuated the rise in lymph thromboxane B2 levels after endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)