Obesity induced bronchopulmonary hyperresponsiveness in Tunisian women.

OBJECTIVE: The specific objective of this investigation was to determine whether bronchopulmonary responsiveness (BPR) to methacholine (MCH) was associated with the body mass index (BMI) of Tunisian women. SUBJECTS: In all, 160 healthy nonsmoker women (52 lean, 45 overweight and 63 obese) were recruited and examined in the Clinical Laboratory of Physiology located in the Medical School of Sousse. The average ages (+/-s.e.) of the three categories of lean, overweight and obese subjects were 27.7+/-1.1, 33.2+/-1.7 and 37.5+/-1.3 years, respectively. Their corresponding mean BMIs (+/-s.e.) were 21.9+/-0.3, 27.7+/-0.2 and 36.5+/-0.8 kg m(-2), respectively. MEASUREMENTS: Before their inclusion into the study, subjects were screened for their lung status by measuring their pulmonary function testing parameters using a whole body plethysmograph. BPR was assessed, using a cumulative concentration response curve technique, by measuring with a spirometer the decrease in forced expiratory volume in 1 s (FEV(1)) in response to a cumulative dose of MCH. RESULTS: After adjusting for age, significant differences in both FEV(1) and forced vital capacity (VC) were found between the obese and lean groups (P<0.01), as well as between the obese and overweight groups (P<0.01). In addition, forced expiratory flow between 25 and 75% of VC was significantly different between the obese and lean groups (P<0.001), as well as between the lean and overweight groups (P=0.015). The mean maximum fall of FEV(1) in response to MCH challenge was significantly higher for the obese group (12.0%) than for the overweight (9.8%) or the lean (6.6%) group (P<0.01). Furthermore, the efficacy of the MCH agonist promoting the maximal response (E(max)) and its potency or effective dose producing 50% of the maximal response (ED(50)) were both associated with BMI (the higher the BMI, the higher the E(max) and the lower the ED(50)). CONCLUSION: Our data clearly show that obesity affects pulmonary function performance in Tunisian women by potentially promoting their bronchial hyperreactivity as suggested by the significant correlation between their BMI and the efficacy of the MCH, as well as its potency.

Obesity-induced impairment of endothelium-dependent vasodilation in Tunisian women.

OBJECTIVE: It is now well recognized that obesity is a major public health concern, and its prevalence has tremendously increased worldwide over the last decades, including Tunisia. As obesity is associated with cardiovascular diseases, the purpose of this study was to investigate the effect of obesity on forearm skin blood flow (FSBF) response to acetylcholine (Ach), an endothelium-dependent vasodilator, in Tunisian women over a wide range of body mass indices (BMIs). SUBJECTS: One hundred and eighty healthy women with an average age of 34+/-6 years, an average height of 162+/-7 cm and an average weight of 78+/-19 kg participated in this investigation. The mean BMIs of the 60 lean, 50 overweight and 70 obese subjects were 22.1+/-0.3, 27.7+/-0.2 and 38.4+/-0.7 kg m(-2), respectively. MEASUREMENTS: The FSBF was measured non-invasively using a laser Doppler flowmeter in response to local infusion of a cumulative dose of Ach. RESULTS: After adjusting for age, the mean response of FSBF to Ach was significantly greater in lean (1168%+/-78) than in overweight (643%+/-38) and obese subjects (323%+/-18) (P=0.002; P<0.0001, respectively), suggesting a reduction of the endothelium-dependent nitric oxide (NO) release by obesity. Our regression analysis also revealed that the maximum FSBF response to Ach (that is, its efficacy) was inversely correlated with BMI, waist and hip circumferences (r=-0.994, P=0.002; r=-0.2, P<0.0001, and r=-0.321, P=0.001, respectively). CONCLUSION: Our data demonstrate a reduction of skin vasodilatory reserve in obese patients and suggest a defect of both endothelial-dependent relaxation and wall compliance associated with obesity.

Large porous particles for pulmonary drug delivery.

A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.

Effect of passive sensitization on the mechanical activity of human isolated bronchial smooth muscle induced by substance P, neurokinin A and VIP.

1. The effect of passive sensitization on the mechanical activity of human isolated bronchial smooth muscle induced by the following neuropeptides substance P (SP), neurokinin A (NKA) and vasoactive intestinal peptide (VIP) was studied both in the absence and in the presence of the neutral endopeptidase (NEP) inhibitor, phosphoramidon. 2. Cumulative concentration-response curves (CCRC) to these neuropeptides were constructed in human passively sensitized isolated bronchial rings and compared to those in paired controls. Passively sensitized human isolated bronchial rings were tissues incubated overnight in serum from asthmatic patients atopic to Dermatophagoides pteronyssinus and paired controls were tissues originating from the same lung specimens but incubated overnight in serum from healthy donors. 3. In the absence of phosphoramidon, passive sensitization significantly increased the amplitude of the contractile responses to SP and NKA including that to the maximal concentration given from 50 +/- 5% to 76 +/- 6% (n = 5, P < 0.05) and from 70 +/- 7% to 101 +/- 6% (n = 5, P < 0.05) of the maximal response to acetylcholine, respectively. Passive sensitization significantly shifted to the left the CCRC for both tachykinins as measured by the geometric means dose-ratios which were 8.5 (95% confidence limits (CL): 3.1-13.9) and 7.3 (95% CL: 4.2-10.3) for SP and NKA, respectively. 4. In the presence of phosphoramidon (10 microM), passive sensitization still increased significantly the amplitude of the contractile responses to SP and NKA including that to the maximal concentration given from 74 +/- 4% to 115 +/- 7% (n = 5, P<0.05) and from 104 +/- 9% to 146 +/- 16% (n = 5, P<0.05)of the maximal response to acetylcholine, respectively. Passive sensitization still significantly shifted to the left the CCRC for both tachykinins as measured by the dose-ratios which were 9.0 (95% CL:4.3-13.6) and 5.4 (95% CL: 2.9-7.9) for SP and NKA, respectively.5. The relaxant response to the maximal concentration of VIP given in tissues precontracted with histamine (0.5 mM) was significantly reduced by passive sensitization from 41 +/- 4% to 25 +/- 3% (n = 5,P <0.05) of the amplitude of the precontraction in the absence of phosphoramidon and from 72 +/- 1%to 49 +/- 4% (n = 5, P<0.05) in the presence of phosphoramidon (10 microM). Passive sensitization significantly shifted to the right the CCRC for VIP as measured by the dose-ratios which were 10.4(95% CL: 6.6-14.1) and 6.4 (95% CL: 3.0-9.8) in the absence and in the presence of phosphoramidon,respectively.6. We conclude that passive sensitization enhances the mechanical response to neuropeptides which contract human isolated bronchial smooth muscle and reduces that to a neuropeptide which relaxes it.The mechanism of passive sensitization-induced changes in the mechanical activity appears to be independent of a decrease in NEP activity since these changes persist in the presence of the NEP inhibitor, phosphoramidon.

Effect of dry warm air on respiratory water loss in children with exercise-induced asthma.

The variation in respiratory water loss (RWL) over time, expressed as the mass of water vapor lost per liter (body temperature and pressure, saturated) of ventilation (MH2O), was investigated in two groups: (1) children with exercise-induced asthma; and (2) healthy children. Children were matched for age and sex and went without medication for at least 12 hours before each experiment. The children breathed dry warm air (TI = 28.4 degrees C +/- 0.3 degree C) for 15 minutes while bicycling at constant and moderate work load (50 W). The MH2O was measured by collecting and weighing the expired water vapor (1) at rest breathing in warm conditions of inspired gas (control values), (2) every five minutes during exercise while breathing dry warm air, and (3) four minutes after the end of exercise. Pulmonary function tests were performed before and six minutes after exercise. The results were abnormal only in children with exercise-induced asthma. During exercise, RWL significantly fell (compared to control value) at the tenth and 15th minute in both groups. Whereas normal subjects recovered their initial values for MH2O four minutes after stopping exercise, asthmatic children still had a reduction in respiratory water loss. During exercise, MH2O decreased a little more in healthy than in asthmatic children. The decrease in MH2O in both groups suggests that the means to fully humidify expired gas are overwhelmed by thermal stress. The lack of increase in MH2O in asthmatic children on stopping exercise suggests that the airway mucosa is unable to produce enough water vapor and is thus dehydrated and probably hyperosmotic.

High frequency jet ventilation and upper tracheal stenosis: a model study.

A chest-lung model, consisting of a human laryngo-tracheo-bronchial tree cast (4 or 5 bronchial generations) tightly enclosed in a 100 l rigid box was used to assess the potential efficiency of high frequency jet ventilation in patients with upper tracheal stenosis. The elasticity of the air in the box stimulated normal adult chest-lung compliance. Diaphragms (0.5 or 1.5 cm thick) were inserted into the upper trachea to simulate stenoses of 0.7, 1, 1.5 and 1.75 cm inner diameter. A rigid injector-catheter (5 mm outside diameter) was directed in the axis of the trachea with its tip 2.5 cm beneath the stenosis. The end inspiratory alveolar pressure (PA), the end expiratory pressure (PEEP) and the tidal volume (VT) were measured at a rate of 100/min and 30% inspiratory to total periods ratio. Entrained flow, Vem, measured at the start of air insufflation, was compared to that calculated (Vec) from a simple model. For a given setting of the ventilator, PEEP, PA--PEEP and VT were approximately linearly related to the difference in diameters of stenosis and injector. While PEEP decreased, both PA--PEEP and VT increased with increasing diameter of stenosis. When the diameter of the stenosis was higher than 1.5 cm no changes in PA--PEEP and VT were observed, owing to the narrowest section of the larynx. Vec was always higher than Vem. The thickness of the stenosis did not affect the results, and the diameter of the stenosis appeared to be the main factor affecting the ventilatory parameters under our experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent advances in pulmonary drug delivery using large, porous inhaled particles.

The ability to deliver proteins and peptides to the systemic circulation by inhalation has contributed to a rise in the number of inhalation therapies under investigation. For most of these therapies, aerosols are designed to comprise small spherical droplets or particles of mass density near 1 g/cm3 and mean geometric diameter between approximately 1 and 3 micron, suitable for particle penetration into the airways or lung periphery. Studies performed primarily with liquid aerosols have shown that these characteristics of inhaled aerosols lead to optimal therapeutic effect, both for local and systemic therapeutic delivery. Inefficient drug delivery can still arise, owing to excessive particle aggregation in an inhaler, deposition in the mouth and throat, and overly rapid particle removal from the lungs by mucocilliary or phagocytic clearance mechanisms. To address these problems, particle surface chemistry and surface roughness are traditionally manipulated. Recent data indicate that major improvements in aerosol particle performance may also be achieved by lowering particle mass density and increasing particle size, since large, porous particles display less tendency to agglomerate than (conventional) small and nonporous particles. Also, large, porous particles inhaled into the lungs can potentially release therapeutic substances for long periods of time by escaping phagocytic clearance from the lung periphery, thus enabling therapeutic action for periods ranging from hours to many days.

Longitudinal distribution of ozone absorption in the lung: effects of respiratory flow.

In our previous work, we developed a bolus inhalation apparatus and measured the longitudinal distribution of ozone (O3) uptake in intact human lungs at a quiet respiratory flow of 250 ml/min. The objective of the present study was to determine the effect of alternative respiratory flows between 150 and 1,000 ml/s. Uptake was expressed as the O3 absorbed during a single breath relative to the amount of O3 in the inhaled bolus (lambda). Measurements of lambda were correlated with the penetration volume of the bolus into the respiratory tract (Vp). Vp in the range of 20-70 ml was considered to indicate upper airways (UA), the Vp interval of 70-180 ml was identified as lower conducting airways (CA), and Vp > 180 ml was associated with the respiratory air spaces (RA). During quiet oral breathing at 250 ml/s, lambda increased smoothly as Vp increased, with 50% of the inhaled O3 absorbed in the UAs and the remainder absorbed within the CAs such that no O3 reached the RAs. The effect of increasing the respiratory flow was to shift the lambda-Vp distribution distally such that significantly less O3 was absorbed in the UAs and CAs and some O3 reached the RAs. For example, at 1,000 ml/s, only 10% of the inhaled O3 was absorbed in UAs and 65% was absorbed in the CAs such that 25% reached the RAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Longitudinal distribution of ozone absorption in the lung: quiet respiration in healthy subjects.

The objective of this research was to develop a bolus-response method for the noninvasive determination of O3 distribution in the human lung. A previously developed O3 analyzer and bolus generator were incorporated in a computer-controlled inhalation system, and measurements of O3 absorption from inhaled 10-ml boluses with a peak O3 concentration of 4 ppm were carried out on nine previously unexposed healthy male subjects engaged in quiet oral breathing. The fraction of O3 absorbed during a single breath was measured over a range of airway penetrations from 20 to 200 ml, with inspiratory and expiratory flows fixed at a nominal value of 250 ml/s. The resulting data indicated that 50% of the inhaled O3 was absorbed at a penetration of 70 ml, which roughly corresponds to the upper airways, and essentially complete absorption occurred at a penetration of 180 ml, which roughly corresponds to the 16th airway generation, the beginning of the proximal alveolar region. This compares favorably with the results of direct-sampling methods, which indicated that 40.4% of continuously inhaled O3 is removed by the extrathoracic airways (Gerrity et al. J. Appl. Physiol. 65: 393-400, 1988). The computation of an absorption rate constant, Ka, revealed that the efficiency of O3 uptake increased with longitudinal position throughout most of the conducting airways but began to fall off at a penetration of 160 ml.

Longitudinal distribution of ozone absorption in the lung: comparison of nasal and oral quiet breathing.

Employing a bolus inhalation system, we noninvasively measured the fraction of inhaled ozone (O3) that is absorbed during a single breath (lambda) as a function of bolus penetration volume into the respiratory tract (Vp). During nasal breathing at a constant respiratory flow of 250 ml/s, lambda increased smoothly as Vp increased with 80% of the inhaled O3 absorbed in the upper airways and 90% absorbed at the distal end of the trachea. Oral breathing caused a distal shift of the lambda-Vp distribution to the extent that absorption in the upper airways was reduced to 50% and inhaled O3 was 90% absorbed only after a bolus reached the 13th bronchial generation. Therefore, an exercise-induced change from nasal to oral breathing can render the distal lung more susceptible to O3 damage because of an elevation in O3 dose. We also found that changing the peak inhaled bolus concentration over a 10-fold range of 0.4-4 ppm O3 did not affect the lambda-Vp distribution. This finding implies that the diffusion and chemical reaction dynamics that dictate O3 absorption are linear processes.

Longitudinal distribution of O3 absorption in the lung: gender differences and intersubject variability.

Because the National Ambient Air Quality Standard for ozone (O3) is intended to protect the most sensitive individuals in the general population, it is necessary to identify sources of intersubject variation in the exposure-dose-response cascade. We hypothesize that differences in lung anatomy can modulate exposure-dose relationships between individuals, and this results in differences between their responsiveness to O3 at a fixed exposure condition. During quiet breathing, the conducting airways remove the majority of inhaled O3, so the volume of this region should have an important impact on O3 dose distribution. Employing the bolus inhalation method, we measured the distribution of O3 absorption with respect to penetration volume (Vp), and using the Fowler single-breath N2 washout method, we determined the dead space volume (VD) in the lungs of 10 men and 10 women at a fixed respiratory flow of 250 ml/s. On average, the women absorbed O3 at smaller Vp than the men, and the women had smaller VD than the men. When expressed in terms of Vp/VD, the absorption distribution of the men and women was indistinguishable. Moreover, an interpretation of the O3 distribution in terms of an intrinsic mass transfer parameter (Ka) indicated that differences between the O3 dosimetry in all subjects, whether men or women, could be explained by a unique correlation with anatomic dead space: Ka (in s-1) = 610 VD-105 (in ml). Application of this result to measurements of O3 exposure response indicated that previously reported gender differences may be due to a failure in properly accounting for tissue surface within the conducting airways.

Ozone uptake in the intact human respiratory tract: relationship between inhaled dose and actual dose.

Inhaled concentration (C), minute volume (MV), and exposure duration (T) are factors that may affect the uptake of ozone (O(3)) within the respiratory tract. Ten healthy adult nonsmokers participated in four sessions, inhaling 0.2 or 0.4 ppm O(3) through an oral mask while exercising continuously to elicit a MV of 20 l/min for 60 min or 40 l/min for 30 min. In each session, fractional absorption (FA) was determined on a breath-by-breath basis as the ratio of O(3) uptake to the inhaled O(3) dose. The mean +/- SD value of FA for all breaths was 0.86 +/- 0.06. Although C, MV, and T all had statistically significant effects on FA (P < 0.0001, P = 0.004, and P = 0.026, respectively), the magnitudes of these effects were small compared with intersubject variability. For an average subject, a 0. 05 change in FA would require that C change by 1.3 ppm, MV change by 46 l/min, or T change by 1.7 h. It is concluded that inhaled dose is a reasonable surrogate for the actual dose delivered to a particular subject during O(3) exposures of <2 h, but it is not a reasonable surrogate when comparisons are made between individuals.

Ozone absorption in the human nose during unidirectional airflow.

This study addresses the effect of gas flow rate and ozone (O(3)) concentration on the uptake of this air pollutant in the nose. A nasal exposure system was developed in which a constant flow of humidified air (V) containing a constant concentration of O(3) (C(inlet)) entered one nostril and then exited the other nostril while a subject closed the velopharyngeal aperture. Experiments were conducted on 10 healthy nonsmokers for whom O(3) concentration was measured at the inlet nostril and the outlet nostril to determine the fraction of inhaled O(3) that was absorbed into the nasal mucosa (Lambda(nose)). Lambda(nose) decreased from 0.80 +/- 0.02 to 0.33 +/- 0.02 (SE) when V was increased from 3 to 15 l/min and C(inlet) was fixed at 0.4 ppm. Analysis of these data with a mathematical model indicated that O(3) uptake was limited by diffusion reaction through mucus, rather than by convective diffusion through the respired gas. A small decrease in Lambda(nose) from 0.36 +/- 0.02 to 0.32 +/- 0.01 was also observed when C(inlet) was increased from 0.1 to 0.4 ppm at a fixed V of 15 l/min. This may have been due to nonlinear reaction kinetics between O(3) and reactive substrates in mucus or an active response by a physiological process such as mucus secretion or transepithelial water influx.

A mechanical approach to the longitudinal dispersion of gas flowing in human airways.

The aim of this work is to contribute to elucidating the mechanism underlying gas mixing in the human pulmonary airways. For this purpose, a particular attempt is made to analyse the fluid mechanical aspects of gaseous dispersion using bolus response methods. The experiments were performed on five normal subjects by injection of 10 cm3 bolus of He, Ar and SF6 into the latter part of the inspired airstream, in such a way that the whole bolus entered the inspiratory flow and was recovered during the following expiration. The results, presented in a logarithmic plot of dimensionless variance (dispersion of the output bolus) against the Peclet number, show that gaseous dispersion is only slightly dependent on the nature of the tracer gas but is strongly related to flow velocity. This is in agreement with the theory of turbulent or disturbed dispersion; however, it seems that Taylor laminar dispersion does not play a significant role in the airways.

Noninvasive determination of respiratory ozone absorption: development of a fast-responding ozone analyzer.

We developed a chemiluminescent ozone analyzer and constructed an ozone bolus generator with the eventual goal of using a bolus-response method to measure noninvasively the longitudinal distribution of ozone absorption in human lungs. Because the analyzer will be used to sample gases within a single breath, it must have a sufficiently rapid response to monitor changes in ozone concentration during a four-second breathing period, yet its sampling flow must be small enough that it does not interfere with quiet respiratory flows of 300 mL/sec. Our analyzer, which is based on the chemiluminescent reaction between 2-methyl-2-butene and ozone, has favorable performance characteristics: a 90 percent step-response time of 110 msec; a linear calibration from 0.03 to 10 parts per million (ppm)2 with a sensitivity of 2.3 nA/ppm; a signal-to-noise ratio of 30 evaluated at 0.5 ppm; and a minimum detection limit of 0.017 ppm. At an airflow corresponding to quiet breathing, the ozone generator is capable of producing single boluses with a peak ozone fraction as high as 4 ppm, but containing only 0.35 micrograms of ozone dispersed over a small volume of 19 mL. To test the combination of ozone analyzer and bolus generator, we performed bolus-response experiments at steady airflows of 50 to 200 mL/sec in excised pig and sheep tracheas. In spite of the small surface area available for radial diffusion, we found that 25 to 50 percent of the ozone introduced into the trachea was absorbed. By comparing the mathematical moments of the bolus input and the response curves to the predictions of a diffusion theory, we computed an absorption coefficient (K). The values of K increased with increasing airflow, implying that ozone absorption is limited by diffusion processes in the airway lumen as well as in the surrounding tissue.

Noninvasive determination of respiratory ozone absorption: the bolus-response method.

Morphometric studies in animals exposed to ozone (O3), and mathematical simulations of O3 transport in human lungs indicate that O3 toxicity is focal in nature, causing tissue damage that is more pronounced in the proximal alveolar region (the proximal end of the respiratory airspaces in our compartment models) than in other airways. These findings suggest that the internal distribution of O3 uptake must be known in order to assess health risk reliably. In previous work (Ultman and Ben-Jebria 1990), we developed a fast-responding chemiluminescent O3 analyzer and a small-scale O3 generator, both of which are suitable for respiratory measurements. The objective of the current research was to integrate these instruments into a bolus inhalation system capable of noninvasively measuring the longitudinal distribution of O3 absorption in intact human lungs. With this system we aimed to carry out baseline experiments in healthy men during quiet oral breathing at a respiratory flow rate of 250 mL/sec, determine the effect of alternative respiratory flow rates between 150 and 1,000 mL/sec, compare the absorption distribution during quiet oral breathing with that during quiet nasal breathing, and ascertain the influence of a peak inspired concentration between 0.3 and 4.0 parts per million (ppm). Ozone uptake (lambda) was expressed as the amount of O3 absorbed during a single breath relative to the amount in the inhaled bolus. Measurements of lambda were correlated with the penetration volume (VP) of the bolus into the respiratory tract. Values of VP less than 70 mL were considered to be associated with the upper airways, values between 70 and 180 mL were associated with the lower conducting airways, and values greater than 180 mL were associated with the respiratory airspaces. During quiet oral breathing, lambda increased smoothly with VP, with 50% of the inhaled O3 absorbed in the upper airways and the balance absorbed within the lower conducting airways. This compares favorably with the results of direct-sampling methods, which have indicated that 40.4% of continuously inhaled O3 is removed by the extrathoracic airways (Gerrity et al. 1988). The effect of increasing the respiratory flow, which occurs when people exercise, was to shift the lambda-VP distribution distally so that significantly less O3 was absorbed in the upper airways and more reached the respiratory airspaces. Compared with oral breathing, nasal breathing caused a proximal shift in the lambda-VP distribution to the extent that absorption in the upper airways increased from 50% to 80%.(ABSTRACT TRUNCATED AT 400 WORDS)

Improvement of a respiratory ozone analyzer.

The breath-to-breath measurement of total respiratory ozone (O3) uptake requires monitoring O3 concentration at the airway opening with an instrument that responds rapidly relative to the breathing frequency. Our original chemiluminescent analyzer, using 2-methyl-2-butene as the reactant gas, had a 10% to 90% step-response time of 110 msec and a minimal detectable concentration of 0.018 parts per million (ppm) O3 (Ben-Jebria et al. 1990). This instrument was suitable for respiratory O3 monitoring during quiet breathing and light exercise. For this study, we constructed a more self-contained analyzer with a faster response time using ethylene as the reactant gas. When the analyzer was operated at a reaction chamber pressure of 350 torr, an ethylene-to-sample flow ratio of 4:1, and a sampling flow of 0.6 liters per minute (Lpm), it had a 10% to 90% step-response time of 70 msec and a minimal detectable concentration of 0.006 ppm. These specifications make respiratory O3 monitoring possible during moderate-to-heavy exercise. In addition, the nonlinear calibration and the carbon dioxide (CO2) interference exhibited by the original analyzer were eliminated. In breath-to-breath measurements in two healthy men, the fractional uptake of O3 during one minute of quiet breathing was comparable to the results obtained by using a slowly responding commercial analyzer with a quasi-steady material balance method (Wiester et al. 1996). In fact, fractional uptake was about 0.8 regardless of O3 exposure concentration (0.11 to 0.43 ppm) or ventilation rate (4 to 41 Lpm/m2).

Inhalation of estradiol for sustained systemic delivery.

Large porous estradiol particles were formulated by spray drying estradiol in combination with various U.S. Food and Drug Administration (FDA)-approved or endogenous excipients. The powders were characterized in terms of their geometrical size, mass density, and aerosolization properties. Small nonporous particles were also prepared using the same excipients and were physically characterized to insure that they possessed a similar mean aerodynamic size as the large porous particles. The two powders were aerosolized into the lungs of rats via an endotracheal tube or subcutaneously injected as a control to assess relative bioavailability. Two different large porous particle formulations were found to produce elevated systemic estradiol concentrations upon inhalation for approximately 5 days, with relative bioavailabilities of 59.7% and 86.0%. Systemic estradiol concentrations following inhalation of two different small nonporous particle powders remained elevated for only approximately 1 day, with relative bioavailabilities of 18.3% and 38.7%. Bronchoalveolar lavage was performed up to 96 hours after inhalation of porous and nonporous estradiol powders. Small changes in neutrophil and macrophage populations were observed following inhalation of both the porous and nonporous powders.

Gas mixing in lung model ventilated by high frequency oscillation: effect of tidal volume, frequency and molecular diffusivity.

The efficiency of gas mixing during sinusoidal oscillatory flow in a model of human lung cast was assessed by using a multibreath carbon dioxide washout manoeuvre. The experiments were performed at high frequencies (5, 10, 15 and 20 Hz) and low tidal volumes (50, 90 and 120 cm3). A particular effort was made to analyse the influence of flow oscillation conditions (f and VT) as well as the effect of resident alveolar gas density (molecular diffusion) on the effective diffusion coefficient (Deff). This longitudinal mixing parameter was found to be strongly dependent on the tidal volume (approximately proportional to VT1.4) and weakly dependent on the frequency (approximately proportional to f0.5). However, molecular diffusion was not, in general, a limiting factor in the gas transport process during high-frequency oscillation (HFO).

Epithelium-linked smooth muscle hyperresponsiveness in ferret tracheae exposed to acrolein.

The effects of acrolein exposure on tissue uptake and airway responses to substance P (SP) and nitroprusside (NIP) were determined in excised ferret tracheae exposed for 60 min to a constant flow of air or 0.3 and 3.5 ppm acrolein-air mixtures. Histological examination indicated that whereas the epithelium of an air-exposed trachea was intact with no apparent injury, acrolein-induced epithelium damage was more pronounced at 3.5 than at 0.3 ppm vapor concentration. The fractional uptake of acrolein into the tracheal tissue continually decreased during the 1 h of exposure and was found to be significantly concentration dependent at the 60 min measurement point. This suggests that the uptake process of acrolein in the mucosal layer is not linear and is dominated by irreversible reaction. In the absence of the neutral endopeptidase inhibitor, phosphoramidon, acrolein significantly increased the maximal response to SP. Pretreatment with phosphoramidon abolished the differential effect of acrolein on airway smooth muscle response to SP. Nitroprusside relaxed acrolein-exposed tracheal rings precontracted with carbachol to their baseline tone, but it induced relaxation of air-exposed tracheal rings below their initial resting tension, indicating the presence of endogenous as well as induced tone. Pretreatment with NIP also abolished the differential effect of acrolein on airway response to carbachol and modified the potency of this agonist. We conclude that acrolein-induced hyperresponsiveness of the underlying airway smooth muscle is linked to inactivation of neutral endopeptidase synthesis as well as to loss of epithelium-derived relaxation factor.