Effect of age on lung mechanics and airway reactivity in lambs

We studied airway reactivity (AR) to aerosolized histamine, carbachol, and citric acid in lambs 1 mo of age to adulthood. Awake lambs were intubated and studied in a plethysmograph that measured dynamic compliance (Cdyn), resistance of the lung (RL), and functional residual capacity (FRC). Pleural pressure was measured using a Silastic balloon in the pleural space, and airway opening pressure (Pao) was measured using a catheter placed 1-2 cm distal to the nasotracheal tube. At the ages of 1, 3, 5, and 7 mo and adulthood, measurements of Cdyn, RL, and FRC were obtained in 46 sheep (22 males, 24 females). AR to carbachol, histamine, and citric acid was measured in each sheep in randomized order on three separate days by giving increasing concentrations of the drug in a noncumulative fashion. The dose that would have caused a 35% reduction in Cdyn (ED65Cdyn), a doubling of RL (ED200RL), or a 50% increase in FRC (ED150FRC) was calculated. In both males and females, base-line Cdyn increased (r = 0.81, P less than 0.01) with age, as did FRC (r = 0.87, P less than 0.01). There was no significant change in RL in either sex with age or in the group as a whole. There was a significant increase in AR to both histamine and carbachol with increasing age as measured by a decrease in ED65Cdyn (P less than 0.01 and P less than 0.05, respectively) with age. There was no significant change in AR with age as measured by RL or FRC for any of the three bronchoconstrictors tested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Airway reactivity in ponies with recurrent airway obstruction (heaves)

We measured lung function and airway reactivity to histamine administered by aerosol in two groups of ponies. Principal ponies had a history of heaves, a disease characterized by recurrent airway obstruction when ponies are housed in a barn and fed hay; control ponies had no history of airway obstruction. Ponies were paired (principal and control) and measurements were made when principal ponies were at pasture and in clinical remission (period A), following barn housing when principal ponies had acute airway obstruction (period B), and after a further 1 and 2 wk at pasture (periods C and D). At periods A, C, and D dynamic compliance (Cdyn), pulmonary resistance (RL), arterial O2 tension (PaO2), and CO2 tension (PaCO2) of principals and controls did not differ. Barn housing (period B) decreased Cdyn and PaO2 and increased RL in principals but not controls. The ED65Cdyn (the dose of histamine to reduce Cdyn to 65% of base line) did not differ in principals and controls at periods A, C, and D. At period B, ED65Cdyn decreased by 2.5-log doses of histamine in principals while ED65Cdyn was not affected in controls. There was no correlation between changes in airway reactivity and changes in RL and Cdyn. We conclude that ponies in clinical remission from heaves are not hyperreactive to histamine aerosol. This model of lung disease is similar to some forms of industrial asthma in which hyperreactivity occurs only during acute airway obstruction. The lack of correlation between ED65Cdyn and the degree of airway obstruction suggests that the hyperreactivity of principal ponies to histamine aerosol cannot be explained solely by alterations in baseline airway caliber.     

Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep

The macrophage- and monocyte-produced cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as a major mediator of endotoxin-induced injury. To determine if TNF alpha could reproduce the effects of endotoxin on the lung, we intravenously administered 10 micrograms/kg of human recombinant TNF alpha into five chronically instrumented unanesthetized sheep on two occasions to characterize the TNF alpha response and its reproducibility. We assessed changes in lung mechanics, pulmonary and systemic hemodynamics, gas exchange, and the number and type of peripheral blood leukocytes. We also determined airway reactivity by use of aerosolized histamine before and after TNF alpha infusion. Pulmonary arterial pressure (Ppa) peaked within 30 min of initiating the TNF alpha infusion [47.7 +/- 2.2 vs. 15.9 +/- 0.4 (SE) cmH2O at base line] and then returned toward base line over 4 h. There was a brief decline in left atrial pressure after TNF alpha. Pulmonary hypertension was accompanied by leukopenia, neutropenia, and increases in the alveolar-arterial O2 difference (AaDO2). Dynamic lung compliance (Cdyn) declined after TNF alpha, reaching a nadir within 15 min of the initiation of the TNF alpha infusion [0.045 +/- 0.007 vs. 0.093 +/- 0.007 (+/- SE) l/cmH2O at base line]. Resistance to airflow across the lung (RL) increased from 1.2 +/- 0.2 cmH2O.l-1.s at base line, peaking at 5.4 +/- 1.3 cmH2O.l-1.s 30 min after the start of the TNF alpha infusion. Alterations in Cdyn and RL persisted for 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia

Neonates and infants presenting with pulmonary hypertension and chronic hypoxia often exhibit airway obstruction. To investigate this association, we utilized a system in which neonatal calves are exposed to chronic hypobaric hypoxia and develop severe pulmonary hypertension. For the present study, one of each pair of six age-matched pairs of neonatal calves was continuously exposed to hypobaric hypoxia at 4,500 m (CH); the other remained at 1,500 m. At 2 wk of age, mean pulmonary arterial pressure (MPAP), dynamic lung compliance (Cdyn), resistance (RL), and static respiratory system compliance (Crs) were measured at 4,500 m in both CH and control calves exposed acutely to hypoxia (C). These measurements were repeated after cumulative administrations of nebulized methacholine (MCh). Tissues were removed for histological examination and assessment of bronchial ring contractility to MCh and KCl. After 2 wk of hypobaric hypoxia, MPAP (C 35 +/- 1.7 vs. CH 120 +/- 7 mmHg, P less than 0.001) and RL (C 2.64 +/- 0.16 vs CH 4.99 +/- 0.47 cmH2O.l-1s, P less than 0.001) increased. Cdyn (C 0.100 +/- 0.01 vs. CH 0.082 +/- 0.007 l/cmH2O) and Crs (CH 0.46 +/- 0.003 vs. C 0.59 +/- 0.009 l/cmH2O) were not significantly different. Compared with airways of C calves, airways of CH animals did not exhibit in vivo or in vitro MCh hyperresponsiveness; however, in vitro contractility to KCl of airways from CH animals was significantly increased. Histologically, airways from the CH calves showed increases in airway fibrous tissue and smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of increases in lung volume on clearance of aerosolized solute from human lungs

To study the effect of increases in lung volume on solute uptake, we measured clearance of 99mTc-diethylenetriaminepentaacetic acid (Tc-DTPA) at different lung volumes in 19 healthy humans. Seven subjects inhaled aerosol (1 micron activity median aerodynamic diam) at ambient pressure; clearance and functional residual capacity (FRC) were measured at ambient pressure (control) and at increased lung volume produced by positive pressure [12 cmH2O continuous positive airway pressure (CPAP)] or negative pressure (voluntary breathing). Six different subjects inhaled aerosol at ambient pressure; clearance and FRC were measured at ambient pressure and CPAP of 6, 12, and 18 cmH2O pressure. Six additional subjects inhaled aerosol at ambient pressure or at CPAP of 12 cmH2O; clearance and FRC were determined at CPAP of 12 cmH2O. According to the results, Tc-DTPA clearance from human lungs is accelerated exponentially by increases in lung volume, this effect occurs whether lung volume is increased by positive or negative pressure breathing, and the effect is the same whether lung volume is increased during or after aerosol administration. The effect of lung volume must be recognized when interpreting the results of this method.     

Pulmonary rapidly adapting receptors reflexly increase airway secretion in dogs

We attempted to determine whether stimulation of pulmonary rapidly adapting receptors (RARs) increase tracheal submucosal gland secretion in anesthetized open-chest dogs. Electroneurographic studies of pulmonary afferents established that RARs but not lung C-fibers were stimulated by intermittent lung collapse during deflation, collapse being produced by removing positive end-expiratory pressure (PEEP, 4 cmH2O) or by applying negative end-expiratory pressure (NEEP, -4 cmH2O). We measured tracheal secretion by the "hillocks" method. Removing PEEP or applying NEEP for 1 min increased secretion from a base line of 6.0 +/- 1.1 to 11.8 +/- 1.7 and 22.0 +/- 2.8 hillocks.cm-2.min-1, respectively (P less than 0.005). After PEEP was restored, dynamic lung compliance (Cdyn) was 37% below control, and secretion remained elevated (P less than 0.05). A decrease in Cdyn stimulates RARs but not other pulmonary afferents. Hyperinflation, which restored Cdyn and RAR activity to control, returned secretion rate to base line. Secretory responses to lung collapse were abolished by vagal cooling (6 degrees C), by pulmonary vagal section, or by atropine. We conclude that RAR stimulation reflexly increases airway secretion. We cannot exclude the possibility that reduced input from slowly adapting stretch receptors contributed to the secretory response.     

Evaluation of the mechanism of decreased airway responsiveness in lambs

In this study we investigated three possible mechanisms for the decreased airway responsiveness (AR) found in young lambs. To evaluate aerosol delivery, 6 adult sheep (9 mo-3 yr old) and 12 lambs (4-8 wk old) were challenged with aerosol (aH) and intravenous histamine (ivH). Awake animals were intubated and studied in a plethysmograph, which measured dynamic compliance (Cdyn), resistance of the lung, and functional residual capacity. AR to histamine was measured by administration of increasing concentrations of histamine until a significant change in lung mechanics occurred or until the maximum dose of histamine was given. In all six adult sheep, the response to both aH and iVH was a decrease in Cdyn. In two lambs Cdyn was decreased with both aH and ivH, in five lambs with neither, in three lambs with aH only, and in two lambs with ivH only. To examine the role of beta-adrenergic activity in determining AR, six adult sheep and six lambs received ivH and on a separate day ivH with propranolol pretreatment (p + ivH). The median effective dose of histamine that caused a reduction in Cdyn to 65% of normal saline control (ED65Cdyn) for the adult sheep given ivH was 3.60 (range 0.23-4.85) and 0.70 (range 0.49-8.0) micrograms.kg-1.min-1 for p + ivH (P = NS). The median ED65Cdyn for the six lambs was 8.0 micrograms.kg-1.min-1 for both ivH alone and p + ivH. To evaluate the role of airway smooth muscle (SM), AR to aH was quantitated in six adult sheep and six lambs, and then an open-lung biopsy was performed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung dysfunction after thermal injury in relation to prostanoid and oxygen radical release

We studied whether changes in lung function after burns (1- to 12-h period) were due to changes in lung water or airways resistance and the relationship of the changes to prostanoid and O2 radical activity (measured as lipid peroxidation). Twenty-five anesthetized mechanically ventilated adult sheep were given a 40% of body surface scald burn and resuscitated to restore and maintain base-line filling pressures. Dynamic lung compliance (Cdyn) decreased by 40% from 38 +/- 5 to 24 +/- 4 ml/cmH2O at 12 h. Venous thromboxane B2 transiently increased from 210 +/- 40 to 1,100 +/- 210 pg/ml, and the value in lung lymph increased from 180 +/- 80 to 520 +/- 80 pg/ml. Prostacyclin levels in lung lymph and plasma remained at base line. Protein-poor lung lymph flow increased two- to threefold, but postmortem lung analysis revealed no increase in lung water from the control of 3.5 +/- 0.3 g H2O/g dry wt. No increase in protein permeability was seen. However, the lipid peroxidation of lung tissue measured as malondialdehyde was significantly increased from the control value of 56 +/- 4 nmol/g lung to a value of 69 +/- 6. Ibuprofen pretreatment (12.5 mg/kg) markedly attenuated the decrease in Cdyn, with the value at 12 h being 90% of base line. Ibuprofen also decreased the amount of lung lipid peroxidation but did not decrease the lung lymph response. We conclude that the decrease in Cdyn seen early postburn is not due to increased lung water, but, rather, is due to a mediator-induced bronchoconstriction, attenuated by ibuprofen; the mediator being either thromboxane or a byproduct of O2 radicals as evidenced by increased lipid peroxide production in lung tissue.     

Respiratory effects of a patent ductus arteriosus in premature newborn lambs

We examined the respiratory effects of a patent ductus arteriosus in 29 premature lambs (131-135 days gestational age) after infiltrating the ductal wall with formaldehyde solution (Formalin) and placing a snare around the ductus to regulate its patency. The lambs were given sheep surfactant, paralyzed, and mechanically ventilated at birth. We first compared 8 lambs with open ductus and 13 lambs with closed ductus during the 12 h after birth. Although lambs with open ductus had greater pulmonary blood flow (301 +/- 36 vs. 188 +/- 11 ml.min-1.kg-1, mean +/- SE, at 12 h of age) and mean pulmonary arterial (44 +/- 3 vs. 33 +/- 2 mmHg) and left ventricular end-diastolic (6 +/- 0.6 vs 4 +/- 0.7 mmHg) pressures, we found no differences in dynamic respiratory compliance (Cdyn = 0.55 +/- 0.07 vs. 0.55 +/- 0.03 ml.cmH2O-1.kg-1), midtidal volume resistance (62 +/- 5 X 10(-3) vs. 62 +/- 7 X 10(-3) cmH2O.ml-1.s), or functional residual capacity (FRC = 27 +/- 3 vs. 26 +/- 2 ml.kg-1). Alveolar-arterial PO2 difference was lower in the lambs with open ductus (238 +/- 65 vs. 362 +/- 37 Torr). Next, we challenged eight lambs with two separate saline infusions (50 ml.kg-1 over 3 min), each given with the ductus alternately closed or open. When the ductus was closed, FRC was unchanged, but Cdyn increased by 18% immediately after the infusion. When the ductus was open, FRC decreased by 16% and Cdyn decreased by 12%. We conclude that the premature lamb is surprisingly resistant to changes in respiratory function from ductal patency during the immediate neonatal period.     

Changes in lung mechanics and reactivity with age after viral bronchiolitis in beagle puppies

We measured changes with growth in lung function and airway reactivity after acute canine parainfluenza virus type 2 (CPI2, n = 5), canine adenovirus type 2 (CAV2, n = 7), and sequential CAV2-CPI2 (n = 6) infections or no infection (controls, n = 6) in beagle puppies (age approximately 79 days). In the CPI2 and CAV2 groups, a lower respiratory illness developed by day 3 postinfection with clinical recovery by day 14. In the CAV2-CPI2 group, puppies were inoculated initially with CAV2 and 12 days later with CPI2. In this group, illness persisted until day 14 after infection with CPI2. Lung resistance (RL), dynamic (Cdyn) and static (Cst) lung compliance, functional residual capacity (FRC), and responsiveness to aerosolized histamine were measured before infection and at periodic intervals until 239 +/- 43 days of age. Lung function data were analyzed using a longitudinal random effects model. In all groups, FRC, Cst, and Cdyn increased with age. In all infected groups, the regression slopes for Cdyn were steeper than in controls. RL decreased linearly with age without group slope differences. Histamine reactivity increased with age, but there were no differences in slope among groups. Lung pathological studies showed areas of obliterative bronchiolitis and chronic small airways inflammation particularly in the CAV2 and CAV2-CPI2 groups. Thus, viral bronchiolitis produces chronic small airways inflammation in beagle puppies and alters the changes in lung function occurring with growth. Histamine reactivity increases with age and is not modified by viral infection.     

Neonatal capsaicin treatment alters basal pulmonary mechanics and response to methacholine in F344 rats.

Full methacholine dose-response curves were performed on anesthetized tracheostomized Fischer 344 adult rats treated neonatally with capsaicin (50 mg/kg) or with vehicle alone. Capsaicin, the hot extract of pepper, releases substance P (SP) from nonmyelinated sensory nerve endings and causes acute bronchoconstriction and airway microvascular leakiness. Chronic treatment with capsaicin leads to depletion of SP and other tachykinins from afferent C-fibers and can therefore be used as a tool to investigate the contribution of SP innervation to airway responses. The rats (9 controls and 6 treated with capsaicin) were paralyzed with succinylcholine and mechanically ventilated at a constant tidal volume and frequency. Airway resistance (RL) and dynamic compliance (Cdyn) were determined at each dose of methacholine from measurements of volume, flow, and transpulmonary pressure. Capsaicin-treated rats were found to have a significantly reduced baseline RL [0.150 +/- 0.039 (SD) vs. 0.225 +/- 0.050 cmH2O.ml-1.s, P = 0.009] and a correspondingly significantly elevated Cdyn (0.371 +/- 0.084 vs. 0.268 +/- 0.053 ml/cmH2O, P = 0.012). There was no significant difference in sensitivity to methacholine, but the maximal response to methacholine was significantly greater in the capsaicin-treated rats. In terms of RL, the maximal response for capsaicin-treated rats was 6.03 x baseline +/- 0.98 vs. 4.30 x baseline +/- 1.80 (P = 0.05) for controls, and for Cdyn changes the maximal decrease was 5.75 x baseline +/- 1.22 vs. 3.83 +/- 0.69 (P = 0.002). The observed differences in RL and Cdyn coupled with the differences in maximal responses can be attributed to the selective destruction of a subpopulation of pulmonary afferent C-fibers.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of atropine in ponies with recurrent airway obstruction

The effects of atropine on lung function and airway reactivity in two groups of ponies were measured. Principal ponies had a history of recurrent airway obstruction when housed in a barn and fed hay; control ponies had no history of airway obstruction. Principal and control ponies were paired, and measurements were made when principal ponies were in clinical remission (period A) and during an acute attack of airway obstruction (period B). Atropine did not alter pulmonary resistance (RL), dynamic compliance (Cdyn), or airway responsiveness in either group of ponies at period A or in the controls at period B. In principal ponies at period B, atropine did not alter Cdyn or the concentration of aerosol histamine required to decrease Cdyn to 65% of base line (ED65Cdyn) but reduced RL and the change in RL induced by 0.1 mg/ml histamine (delta RL0.1). It is likely that the latter observation was due to geometric changes in the airways, because the change in RL and in delta RL0.1 were significantly correlated. The results of this study show little resting bronchomotor tone in normal ponies, but a major portion of the increase in RL in principals at period B is mediated via muscarinic receptors. Little evidence exists for muscarinic receptor involvement in the response to aerosol histamine in either principal or control ponies.     

Parenchymal stress affects interstitial and pleural pressures in in situ lung.

After resecting the intercostal muscles and thinning the endothoracic fascia, we micropunctured the lung tissue through the intact pleural space at functional residual capacity (FRC) and at volumes above FRC to evaluate the effect of increasing parenchymal stresses on pulmonary interstitial pressure (Pip). Pip was measured at a depth of approximately 230 microns from the pleural surface, at 50% lung height, in 12 anesthetized paralyzed rabbits oxygenated via a tracheal tube with 50% humidified O2. Pip was -10 +/- 1.5 cmH2O at FRC. At alveolar pressure of 5 and 10 cmH2O, lung volume increased by 8.5 and 19 ml and Pip decreased to -12.4 +/- 1.6 and -12.3 +/- 5 cmH2O, respectively. For the same lung volumes held by decreasing pleural surface pressure to about -5 and -8.5 cmH2O, Pip decreased to -17.4 +/- 1.6 and -23.8 +/- 5 cmH2O, respectively. Because Pip is more negative than pleural pressure, the data suggest that in intact pulmonary interstitium the pressure of the liquid phase is primarily set by the mechanisms controlling interstitial fluid turnover.     

Effects of granulocyte depletion on pulmonary responsiveness to aerosol histamine

The effects of granulocyte depletion with hydroxyurea on pulmonary responsiveness to aerosol histamine were studied in 10 chronically instrumented unanesthetized sheep. Sheep were studied when granulocyte counts were normal (B), after 3 days of hydroxyurea but before granulocyte counts had dropped below 700 cells/mm3 (H), and after granulocyte counts had fallen below 200 cells/mm3 (D). Hydroxyurea itself had no effect on aerosol histamine responsiveness and the results were unaffected by the order of experimentation. All 10 sheep were less responsive (P less than 0.05) to aerosol histamine when granulocyte depleted effective dose of histamine that caused a reduction to 65% of control dynamic compliance (ED65Cdyn = 23.98 +/- 4.70 mg/ml) compared with base line (ED65Cdyn = 7.06 +/- 1.86 mg/ml). Those sheep initially most responsive to aerosol histamine had the greatest attenuation in their airway responsiveness to aerosol histamine (P less than 0.05). There was a significant negative correlation between absolute granulocyte counts in peripheral blood and pulmonary responsiveness to aerosol histamine during base-line (B) condition (r = -0.74, P less than 0.05) and for the data as a whole [r = -0.69, P less than 0.05 (B + H + D)]. Circulating granulocytes and/or pulmonary inflammation may contribute to pulmonary responsiveness to bronchial challenge.     

Inspiratory muscles during exercise: a problem of supply and demand

The capacity of inspiratory muscles to generate esophageal pressure at several lung volumes from functional residual capacity (FRC) to total lung capacity (TLC) and several flow rates from zero to maximal flow was measured in five normal subjects. Static capacity was 126 +/- 14.6 cmH2O at FRC, remained unchanged between 30 and 55% TLC, and decreased to 40 +/- 6.8 cmH2O at TLC. Dynamic capacity declined by a further 5.0 +/- 0.35% from the static pressure at any given lung volume for every liter per second increase in inspiratory flow. The subjects underwent progressive incremental exercise to maximum power and achieved 1,800 +/- 45 kpm/min and maximum O2 uptake of 3,518 +/- 222 ml/min. During exercise peak esophageal pressure increased from 9.4 +/- 1.81 to 38.2 +/- 5.70 cmH2O and end-inspiratory esophageal pressure increased from 7.8 +/- 0.52 to 22.5 +/- 2.03 cmH2O from rest to maximum exercise. Because the estimated capacity available to meet these demands is critically dependent on end-inspiratory lung volume, the changes in lung volume during exercise were measured in three of the subjects using He dilution. End-expiratory volume was 52.3 +/- 2.42% TLC at rest and 38.5 +/- 0.79% TLC at maximum exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Augmentation of parasympathetic contraction in tracheal and bronchial airways by PGF2 alpha in situ

We studied the effect of exogenous prostaglandin F2 alpha (PGF2 alpha) on airway smooth muscle contraction caused by parasympathetic stimulation in 22 mongrel dogs in situ. Voltage (0-30 V, constant 20 Hz) and frequency-response (0-25 Hz, 25 V) curves were generated by stimulating the cut ends of both cervical vagus nerves. Airway response was measured isometrically as active tension (AT) in a segment of cervical trachea and as change in airway resistance (RL) and dynamic compliance (Cdyn) in bronchial airways. One hour after 5 mg/kg iv indomethacin, a cumulative frequency-response curve was generated in nine animals by electrical stimulation of the vagus nerves at 15-s intervals. Reproducibility was demonstrated by generating a second curve 7 min later. A third frequency-response curve was generated during active contraction of the airway caused by continuous intravenous infusion of 10 micrograms X kg-1 X min-1PPGF2 alpha. Additional frequency-response studies were generated 15 and 30 min after PGF2 alpha, when airway contractile response (delta RL = +2.8 +/- 0.65 cmH2O X 1(-1) X s; delta Cdyn = -0.0259 +/- 0.007 1/cmH2O) returned to base line. Substantial augmentation of AT, RL, and Cdyn responses was demonstrated in every animal studied (P less than 0.01 for all points greater than 8 Hz) 15 min after PGF2 alpha. At 30 min, response did not differ from initial base-line control. In four animals receiving sham infusion, all frequency-response curves were identical. We demonstrate that PGF2 alpha augments the response to vagus nerve stimulation in tracheal and bronchial airways. Augmentation does not depend on PGF2 alpha-induced active tone.     

Relationship of end-expiratory pressure, lung volume, and 99mTc-DTPA clearance

We investigated the dose-response effect of positive end-expiratory pressure (PEEP) and increased lung volume on the pulmonary clearance rate of aerosolized technetium-99m-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA). Clearance of lung radioactivity was expressed as percent decrease per minute. Base-line clearance was measured while anesthetized sheep (n = 20) were ventilated with 0 cmH2O end-expiratory pressure. Clearance was remeasured during ventilation at 2.5, 5, 10, 15, or 20 cmH2O PEEP. Further studies showed stepwise increases in functional residual capacity (FRC) (P less than 0.05) measured at 0, 2.5, 5, 10, 15, and 20 cmH2O PEEP. At 2.5 cmH2O PEEP, the clearance rate was not different from that at base line (P less than 0.05), although FRC was increased from base line. Clearance rate increased progressively with increasing PEEP at 5, 10, and 15 cmH2O (P less than 0.05). Between 15 and 20 cmH2O PEEP, clearance rate was again unchanged, despite an increase in FRC. The pulmonary clearance of aerosolized 99mTc-DTPA shows a sigmoidal response to increasing FRC and PEEP, having both threshold and maximal effects. This relationship is most consistent with the hypothesis that alveolar epithelial permeability is increased by lung inflation.     

Mechanical properties of the passive pharynx in Vietnamese pot-bellied pigs. I. Statics.

The static mechanical properties of the passive pharynx were investigated in Vietnamese pot-bellied pigs by using an isolated upper airway preparation. During general anesthesia and neuromuscular blockade, cross-sectional area (A) of the pharynx was measured while airway pressure (Paw) was held at various pressures in the absence of airflow. The static A-Paw relationship was measured during application of 0, 1, and 2 cm of caudal tracheal displacement. Relative to humans, closing pressures (Pclose) of the pig pharynx were very low (-15 to -35 cmH(2)O). Tracheal displacement significantly decreased compliance of the hypopharynx (from 0.074 +/- 0.02 cm(2)/cmH(2)O with no displacement to 0.052 +/- 0.01 cm(2)/cmH(2)O with 2 cm of displacement) and decreased Pclose of the oropharynx (from -18.2 +/- 9.9 cmH(2)O to -24.1 +/- 10.5 and -28.7 +/- 12.3 cmH(2)O with 1 and 2 cm of displacement, respectively). Tracheal displacement did not affect A of the pharyngeal segments. In conclusion, tracheal displacement decreased collapsibility of the passive pharynx. The pharynx of the pot-bellied pig is structurally more resistant to collapse than the human pharynx.     

Effects of lung volume on maximal methacholine-induced bronchoconstriction in normal humans

We examined the effects of lung volume on the bronchoconstriction induced by inhaled aerosolized methacholine (MCh) in seven normal subjects. We constructed dose-response curves to MCh, using measurements of inspiratory pulmonary resistance (RL) during tidal breathing at functional residual capacity (FRC) and after a change in end-expiratory lung volume (EEV) to either FRC -0.5 liter (n = 5) or FRC +0.5 liter (n = 2). Aerosols of MCh were generated using a nebulizer with an output of 0.12 ml/min and administered for 2 min in progressively doubling concentrations from 1 to 256 mg/ml. After MCh, RL rose from a base-line value of 2.1 +/- 0.3 cmH2O. 1-1 X s (mean +/- SE; n = 7) to a maximum of 13.9 +/- 1.8. In five of the seven subjects a plateau response to MCh was obtained at FRC. There was no correlation between the concentration of MCh required to double RL and the maximum value of RL. The dose-response relationship to MCh was markedly altered by changing lung volume. The bronchoconstrictor response was enhanced at FRC - 0.5 liter; RL reached a maximum of 39.0 +/- 4.0 cmH2O X 1-1 X s. Conversely, at FRC + 0.5 liter the maximum value of RL was reduced in both subjects from 8.2 and 16.6 to 6.0 and 7.7 cmH2O X 1-1 X s, respectively. We conclude that lung volume is a major determinant of the bronchoconstrictor response to MCh in normal subjects. We suggest that changes in lung volume act to alter the forces of interdependence between airways and parenchyma that oppose airway smooth muscle contraction.     

Effects of ozone on lung mechanics and cyclooxygenase metabolites in dogs.

To determine if acute exposure to ozone can cause changes in the production of cyclooxygenase metabolites of arachidonic acid (AA) in the lung which are associated with changes in lung mechanics, we exposed mongrel dogs to 0.5 ppm ozone for two hours. We measured pulmonary resistance (RL) and dynamic compliance (Cdyn) and obtained methacholine dose response curves and bronchoalveolar lavagate (BAL) before and after the exposures. We calculated the provocative dose of methacholine necessary to increase RL 50% (PD50) and analyzed the BAL for four cyclooxygenase metabolites of AA: a stable hydrolysis product of prostacyclin, 6-keto-prostaglandin F1 alpha (6-keto-PgF1 alpha); prostaglandin E2 (PgE2); a stable hydrolysis product of thromboxane A2, thromboxane B2 (TxB2); and prostaglandin F2 alpha (PgF2 alpha). Following ozone exposure, RL increased from 4.75 +/- 1.06 to 6.08 +/- 1.3 cm H2O/L/sec (SEM) (p less than 0.05), Cdyn decreased from 0.0348 +/- 0.0109 TO .0217 +/- .0101 L/cm H2O (p less than 0.05), and PD50 decreased from 4.32 +/- 2.41 to 0.81 +/- 0.49 mg/cc (p less than 0.05). The baseline metabolite levels were as follows: 6-keto PgF1 alpha: 96.1 +/- 28.8 pg/ml; PgE2: 395.8 +/- 67.1 pg/ml; TxB2: 48.5 +/- 11.1 pg/ml; PgF2 alpha: 101.5 +/- 22.6 pg/ml. Ozone had no effect on any of these prostanoids. These studies quantify the magnitude of cyclooxygenase products of AA metabolism in BAL from dog lungs and demonstrate that changes in their levels are not prerequisites for ozone-induced changes in lung mechanics or airway reactivity.