Airway responsiveness to inhaled and intravenous carbachol in sheep: effect of airway mucus

Excessive airway mucus can alter both the mass and site of aerosol deposition, which, in turn, may affect airway responsiveness to inhaled materials. In six prone sheep, we therefore measured pulmonary airflow resistance (RL) and cumulative aerosol deposition during five standard breaths (AD5) at base line and 3 min after inhalation challenge with 2% carbachol in buffered saline (10 breaths, tidal volume = 500 ml) or after an intravenous loading dose of carbachol (3 micrograms/kg) followed by a constant infusion of 0.3 micrograms.kg-1.min-1 with and without instillation of 20 ml of a mucus simulant (MS) into the distal end of each of the main bronchi or 30 ml of MS into the right main bronchus only by means of a flexible fiber-optic bronchoscope. Before carbachol challenge, RL did not change with MS into either both lungs or one lung only. AD5 increased from 36 +/- 2% (SE) before to 42 +/- 2% after MS instillation into both lungs (P less than 0.05) but remained unchanged after MS into one lung. After carbachol inhalation, RL increased significantly by 154 +/- 20 before and 126 +/- 25% after MS into both lungs and 162 +/- 24 before and 178 +/- 31% after MS into one lung (P less than 0.05). When the percent increase in RL was normalized for total aerosol deposition (% delta RL/AD5), the normalized values were lower after MS (3.0 +/- 0.5) than before MS (4.4 +/- 0.3) into both lungs (P less than 0.05) but were not significantly different before and after MS into the right lung only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung edema formation following inhalation injury: role of the bronchial blood flow

We investigated the contribution of the bronchial blood flow to the lung lymph flow (QL) and lung edema formation after inhalation injury in sheep (n = 18). The animals were equally divided into three groups and chronically prepared by implantation of cardiopulmonary catheters and a flow probe on the common bronchial artery. Groups 1 and 2 sheep were insufflated with 48 breaths of cotton smoke while group 3 received only room air. Just before injury, the bronchial artery of group 2 animals was occluded. The occlusion was maintained for the duration of the 24-h study period. At the end of the investigation, samples of lung were taken for determination of blood-free wet weight-to-dry weight ratio (W/D). Inhalation injury induced a sevenfold increase in QL in group 1 (7 +/- 1 to 50 +/- 9 ml/h; P less than 0.05) but only a threefold increase in group 2 (10 +/- 2 to 28 +/- 7 ml/h; P less than 0.05). The mean W/D value of group 1 animals was 23% higher than that of group 2 (5.1 +/- 0.4 vs. 3.9 +/- 0.2; P less than 0.05). Our data suggest that the bronchial circulation contributes to edema formation in the lung that is often seen after the acute lung injury with smoke inhalation.     

Flow limitation, cough, and patterns of aerosol deposition in humans

We studied deposition of radioactive monodisperse 1.5-micron aerosol in humans following inhalation during quiet breathing. Two groups were studied: normal, defined by tidal loops below the maximum expiratory flow-volume (MEFV) envelope [forced expiratory volume at 1 s at percent of forced vital capacity (FEV1%) 62-78]; and flow-limited, with tidal loops superimposed on MEFV relationship (FEV1% 21-57) and flow-limiting segments (FLS) known to exist in central airways. During simultaneous imaging with a gamma camera, fraction of inhaled aerosol deposited in the lung (DF) was determined by right-angle light scattering. With regions of interest defined by an equilibrium image of 133Xe, regional deposition was normalized for area and lung thickness and expressed as a central-to-peripheral (C/P) ratio. Deposition was uniform throughout the lung in normal subjects [C/P 1.02 +/- 0.07 (SD), n = 6]. In flow-limited group, central deposition predominated (C/P 1.98 +/- 0.64, n = 6, P less than 0.05). Tidal volume and inspiratory flow, forces thought to influence deposition during inspiration, were not different between groups. Spontaneous cough occurred in five flow-limited subjects during aerosol inhalation, with further increase in central deposition when compared with quiet breathing (C/P 1.85 +/- 0.60 to 2.69 +/- 0.600, P less than 0.01). During cough, tidal volume (ml) was reduced significantly (576 +/- 151 to 364 +/- 117, P less than 0.01) with no change in inspiratory flow (l/s) (1.37 +/- 0.23 to 1.38 +/- 0.40, P = NS). DF, however, was unaffected by cough (0.34 +/- 0.13 to 0.61 +/- 0.12, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchial airway deposition and retention of particles in inhaled boluses: effect of anatomic dead space

The fractionaldeposition of particles in boluses delivered to shallow lung depths andtheir subsequent retention in the airways may depend on the relativevolume and size of an individual's airways. To evaluate the effect ofvariable anatomic dead space (ADS) on aerosol bolus delivery we hadhealthy subjects inhale radiolabeled, monodisperse aerosol(^99mTc-iron oxide, 3.5 µm meanmondispersed aerosol diameter) boluses (40 ml) to a volumetric frontdepth of 70 ml into the lung at a lung volume of 70% total lungcapacity end inhalation. By using filter techniques, aerosolphotometry, and gamma camera analysis, we estimated the fraction of theinhaled boluses deposited in intrathoracic airways (IDF). ADS bysingle-breath N₂ washout was alsomeasured from 70% total lung capacity. Results showed that among allsubjects IDF was variable (range = 0.04-0.43, coefficient ofvariation = 0.54) and increased with decreasing ADS(r = 0.76, P = 0.001, n = 16). We found significantlygreater deposition in the left (L) vs. right (R) lungs; mean L/R (ratioof deposition in L lung to R lung, normalized to ratio of L-to-R lungvolume) was 1.58 ± 0.42 (SD; P < 0.001 for comparison with 1.0). Retention of deposited particles at 2 hwas independent of ADS or IDF. There was significant retention ofparticles at 24 h postdeposition (0.27 ± 0.05) andslow clearance of these particles continued through 48 hpostdeposition. Finally, analysis of central-to-peripheral ratios ofinitial deposition and 24-h-retention gamma-camera images suggestsignificant retention of insoluble particles in large bronchial airwaysat 24 h postdeposition (i.e., 24 h central-to-peripheral ratio = 1.40 ± 0.44 and 1.82 ± 0.54 in the R and L lung, respectively; P < 0.02 for comparison with 1.0).These data may prove useful for 1)designing aerosol delivery techniques to target bronchial airways and2) understanding airway retention ofinhaled particles.

     

Methodology for the measurement of mucociliary function in the mouse by scintigraphy.

The objective of the study was to develop a scintigraphic method for measurement of airway mucociliary clearance in small laboratory rodents such as the mouse. Previous investigations have characterized the secretory cell types present in the mouse airway, but analysis of the mucus transport system has been limited to in vitro examination of tissue explants or invasive in vivo measures of a single airway, the trachea. Three methods were used to deposit insoluble, radioisotopic colloidal particles: oropharyngeal aspiration, intratracheal instillation, and nose-only aerosol inhalation. The initial distribution of particles within the lower respiratory tract was visualized by gamma-camera, and clearance of particles was followed intermittently over 6 h and at the conclusion, 24 h postdelivery. Subsets of mice underwent lavage for evidence of tissue inflammation, and others were restudied for reproducibility of the methods. The aspiration and instillation methods of delivery led to greater distributions of deposited activity within the lungs, i.e., approximately 60--80% of the total respiratory tract radioactivity, whereas the nose-only aerosol technique attained a distribution of 32% to the lungs. However, the aerosol technique maximized the fraction of particles that cleared the airway over a 24-h period, i.e, deposited onto airway epithelial surfaces and cleared by mucociliary function such that lung retention at 24 h averaged 57% for delivery by aerosol inhalation and > or =80% for the aspiration or intratracheal instillation techniques. Particle delivery methods did not cause lung inflammation/injury with use of inflammatory cells and chemoattractant cytokines as criteria. Scintigraphy can discern particle deposition and clearance from the lower respiratory tract in the mouse, is noninvasive and reproducible, and includes the capability for restudy and lung lavage when time course or chronic treatments are being considered.     

JNK activation is responsible for mucus overproduction in smoke inhalation injury

Background

Increased mucus secretion is one of the important characteristics of the response to smoke inhalation injuries. We hypothesized that gel-forming mucins may contribute to the increased mucus production in a smoke inhalation injury. We investigated the role of c-Jun N-terminal kinase (JNK) in modulating smoke-induced mucus secretion.

Methods

We intubated mice and exposed them to smoke from burning cotton for 15 min. Their lungs were then isolated 4 and 24 h after inhalation injury. Three groups of mice were subjected to the smoke inhalation injury: (1) wild-type (WT) mice, (2) mice lacking JNK1 (JNK1-/- mice), and (3) WT mice administered a JNK inhibitor. The JNK inhibitor (SP-600125) was injected into the mice 1 h after injury.

Results

Smoke exposure caused an increase in the production of mucus in the airway epithelium of the mice along with an increase in MUC5AC gene and protein expression, while the expression of MUC5B was not increased compared with control. We found increased MUC5AC protein expression in the airway epithelium of the WT mice groups both 4 and 24 h after smoke inhalation injury. However, overproduction of mucus and increased MUC5AC protein expression induced by smoke inhalation was suppressed in the JNK inhibitor-treated mice and the JNK1 knockout mice. Smoke exposure did not alter the expression of MUC1 and MUC4 proteins in all 3 groups compared with control.

Conclusion

An increase in epithelial MUC5AC protein expression is associated with the overproduction of mucus in smoke inhalation injury, and that its expression is related on JNK1 signaling.     

Enantioselective disposition of oral amlodipine in healthy volunteers

Plasma concentrations of (R)- and (S)-amlodipine were measured after single oral administrations to 18 healthy volunteers of 20 mg amlodipine racemate. The contribution of the pharmacologically active (S)-enantiomer to the concentrations of total amlodipine (sum of enantiomers) was significantly higher than that of the inactive (R)-enantiomer, with mean values of 47% R to 53% S for the C_max and 41% R to 59% S for the AUC (range between 24% R:76% S and 50% R:50% S). The oral clearance of the active (S)-form was subject to much less intersubject variation (25% CV) than that of the inactive (R)-form (52% CV). (R)-Amlodipine was more rapidly eliminated from plasma than (S)-amlodipine, with mean terminal half-lives of 34.9 h (R) and 49.6 h (S). The terminal half-lives of total amlodipine (mean 44.2 h) were strongly correlated with—and thus highly predictive for—the half-lives of the (S)-enantiomer. It is proposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers. © 1994 Wiley-Liss, Inc.     

Determining deposition sites of inhaled lung particles and their effect on clearance

An essential component of lung defense is clearance of particulates and infectious vectors from the mucus membrane of the tracheobronchial tree and the alveolar regions of the lung. To partition clearance between these areas we determined the bronchial branching pattern, the anatomical sites of particle deposition, and subsequent clearance in the same animal. Using a 2.85-microns particle tagged with 57Co for inhalation and deposition in the sheep lung, we followed clearance via a series of computer-stored gamma-scintillation lung images. The same sheep was reinhaled, and the particle distributions for both inhalations were compared. After the animals were killed, the bronchial branching pattern and length of the bronchial tree were documented. The number of particles depositing in all bronchi down to 1 mm diam was determined by scintillation counting, and the number in respiratory bronchioles and alveoli was microscopically counted. We conclude that particles deposited in bronchi greater than or equal to 1 mm diam clear in 2-4 h postdeposition. Bronchi distal to 1-mm-diam bronchi and alveoli clear evenly over 72 h, and the number of particles equal to the tracheobronchial deposition cleared after 45 h.     

The determinants of Canadian children's personal exposures to magnetic fields

Study of the health effects of magnetic fields often depends on identifying determinants and hence indicators of personal exposure. This study identified determinants of children's exposure to magnetic fields and constructed a prediction model for them. For 632 children participating in a case-control study of childhood leukemia, we made direct measures of exposure over 48 h using a portable device, together with observations on candidate determinants. A child's age and sex, the proportion of time spent in the home, and their parents' education or income were very weak predictors of (logged) mean 48 h magnetic field (R(2) < 1%). More important were province (R(2) = 8.0%) and type of residence (R(2) = 11.3%). Low temperatures at the time of measurement were associated with high fields (about 20% increase for each 10 degrees C below 14, R(2) = 4.9%). Several visible attributes of wiring around residences predicted exposure, mostly captured in the Wertheimer-Leeper wire code (R(2) = 13.5%). Stationary 24 h measurement in the bedroom (R(2) = 63.3%) and spot measurements outside the house (R(2) = 40.7%) predicted personal exposures best. Adding other minor predictors increased only slightly variance explained by 24 h stationary (R(2) = 66.2%) and spot (R(2) = 46.8%) measurements. Without spot or stationary measurements, the best model was much less powerful (R(2) = 29.0%). We conclude that spot measurements outside the residence provide a moderately effective basis for estimating exposure for children living there, but do not perform as well as 24 h stationary measurements in the child's bedroom. Although several other easily-observed variables were associated with personal exposure, they were weak determinants, either individually or in combination.     

Effect of ozone on the postnatal development of lamb mucociliary apparatus

We determined whether exposure to O3 early in the postnatal period impairs the normal development of the mucociliary apparatus in lambs and whether such changes lead to prolonged abnormalities in mucociliary function. Lambs were exposed to air (controls) or to 1 ppm O3 for 4 h/day for 5 days during the 1st wk of life. Tracheal mucus velocity (TMV), a marker of lung mucociliary clearance, was measured in vivo at birth (0 wk) and up to 24 wk later, and tracheal secretory function was measured (in vitro) and the morphology of the tracheal mucosa was determined at 0 and 2 wk in both groups. In the control group, TMV increased 94% from 0 to 2 wk (P less than 0.05), continued to increase until reaching a plateau at 8 wk, and then remained constant from 8 to 24 wk. In contrast, O3-exposed lambs showed a 24% decrease in TMV from 0 to 2 wk (P less than 0.05 vs. control), and throughout the remaining time TMV remained below (P less than 0.05) that observed in control lambs. O3 exposure partially prevented the age-dependent decrease in basal secretion of tracheal macromolecules normally observed between 0 and 2 wk. These changes in secretory function were associated with a significant increase in tissue conductance (37%, P less than 0.05 vs. 0 wk), predominantly the result of active chloride secretion. The functional changes induced by O3 were associated with a retardation of the normal morphological development of the tracheal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clearance of mucus by simulated cough

We examined the relationship between mucus rheology, depth of mucus layer, and clearance by simulated cough. A model trachea was constructed of rigid Plexiglas of rectangular cross section (1 X 2 X 35 cm). The bottom of the trachea was lined with mucus simulants, gels prepared from locust bean gum cross-linked with sodium borate. Cough was simulated by opening a solenoid valve connecting the model trachea to a pressurized tank. An upstream flow-constrictive element was used to shape the flow profile of the simulated cough to approximate the pattern seen in a normal adult. Clearance of mucus was quantitated by observing the movement of contrasting marker particles floating in the mucus layer. The median particle displacement per cough maneuver was defined as the clearance index (CI). We found that CI for any initial depth of mucus increased with the driving pressure in the tank. For a given driving pressure, CI increased linearly with increasing mucus depth. For a given driving pressure and depth, CI decreased with increasing mucus cross-link density. For mucus samples with comparable levels of dynamic viscosity, samples with higher elasticity cleared less well. Mucus clearance was associated with transient wave formation in the lining layer.     

The role of mucus sol phase in clearance by simulated cough

Using a simulated cough machine, we analyzed the effect of adding tensio-active liquids as sol phase simulant on the clearance of gel mucus simulant by cough. Polysaccharides crosslinked with sodium tetraborate were used at different concentration as gel mucus simulant. A drop of gel mucus simulant was deposited either directly on the model trachea or on a sol phase layer simulant (2% sodium dodecyl sulfate in water). The clearance of the mucus simulants was quantified by observing the movement of marker particles in the gel layer. The viscoelastic properties of gel mucus simulants were determined by using a viscoelastometer (SEFAM). The adhesive properties were analyzed by means of the platinum ring technique. The wettability of the mucus simulants was quantified by the automatic measurement of the contact angle of the drop of gel on the model trachea. We found that the addition of a sol phase significantly decreased by about 50% the adhesivity and wettability of the gel mucus simulants. This decrease was associated with a marked enhancement of cough clearance, whatever the viscoelastic properties of the gel mucus simulants. These results suggest that the sol phase is essential in bronchial respiratory mucus clearance by the cough mechanism.     

Effect of exercise on deposition and subsequent retention of inhaled particles

To investigate the effect of exercise and its associated increase in ventilation on the deposition and subsequent retention of inhaled particles, we measured the fractional and regional lung deposition of a radioactively tagged (99mTc) monodisperse aerosol (2.6 microns mass median aerodynamic diam) in normal human subjects at rest and while exercising on a bicycle ergometer. Breath-by-breath deposition fraction (DF) was measured throughout the aerosol exposures by Tyndallometry. Following each exposure gamma camera analysis was used to 1) determine the regional distribution of deposited particles and 2) monitor lung retention for 2.5 h and again at 24 h. We found that DF was unchanged between ventilation at rest (6-10 l/min) and exercise (32-46 l/min). Even though mouth deposition was enhanced with exercise, it was not large enough to produce a significant difference in the deposition fraction of the lung (DFL) between resting and exercise exposures. The central-to-peripheral distribution of deposited aerosol was larger for the exercise vs. resting exposure, reflecting a shift of particle deposition to more central bronchial airways. Apical-to-basal distribution was not different for the two exposures. Retention at 2.5 h and 24 h (R24) was reduced following the exercise vs. the resting exposure, consistent with greater bronchial deposition during exercise. The product of DFL and R24 gave a measure of fractional burden at 24 h (B24), i.e., the fraction of inhaled aerosol residing in the lungs 24 h after exposure. B24 was not significantly different between rest and exercise exposures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of relaxin on facilitation of parturition in dairy heifers

Purified pig relaxin (3000 U/mg) was injected i.m. into pregnant Holstein dairy heifers on Day 276 or 277 to determine its effect on parturition and sequential measurements of the pelvic area, cervical dilatation, and peripheral blood-plasma concentrations of progesterone and relaxin. Treatments included phosphate-buffer saline (2 ml, Group C, N = 7), relaxin once (1 mg, Group 1R, N = 7), and twice (2 mg, 12 h apart; Group 2R, N = 7). Intervals (mean +/- s.e.) between the first injection of relaxin or PBS and calving were 64 +/- 17, 80 +/- 19 and 125 +/- 34 h for Groups 2R, 1R and C, respectively. The calving intervals were reduced in Groups 2R (P less than 0.01) and 1R (P less than 0.05) compared with Group C. The incidence of dystocia was 29% (2 of 7) in Group 2R and 43% (3 of 7) in Group 1R compared with 57% (4 of 7) in Group C (P less than 0.01). Body weights and ratios of males to females of the calves were similar (P greater than 0.05) between groups. Progesterone plasma concentrations decreased (P less than 0.01) earlier in Groups 1R and 2R compared with Group C, and this acute decrease began within 6 h of treatment. At 24 h after relaxin or PBS injection, progesterone concentrations were 2.7 +/- 1.1 ng/ml for Group 2R, 3.5 +/- 0.9 ng/ml for Group 1R, and 6.0 +/- 0.1 ng/ml for Group C. Relaxin reached peak blood-plasma levels of 19 +/- 2.2 ng/ml 1 h after injection of relaxin, but remained unchanged, 0.3 +/- 0.01 ng/ml, in Group C. Pelvic area was increased 26%, 22% and 14% and cervical dilatation was increased 109%, 76% and 53% 48 h after injection in Groups 2R, 1R and C, respectively, but these responses were similar among groups at the time of parturition. We conclude that two i.m. injections of relaxin facilitated earlier calving, acutely decreased progesterone secretion, increased cervical dilatation and pelvic area expansion, and decreased the incidence of dystocia in dairy heifers.     

Plasma fibronectin therapy and lung protein clearance with bacteremia after surgery

Plasma fibronectin modulates macrophage phagocytic function and can also incorporate into the insoluble tissue pool of fibronectin where it influences endothelial cell adhesion and tissue integrity. We studied the effect of postoperative bacteremia on lung protein clearance in relation to plasma fibronectin levels using the unanesthetized sheep lung lymph fistula model and the effect of infusion of purified human plasma fibronectin on lung protein clearance. Sheep received live Pseudomonas aeruginosa (5 X 10(8) iv) at a time of normal plasma fibronectin (590 +/- 37 micrograms/ml) or 5 days later at a time corresponding to elevation of plasma fibronectin (921 +/- 114 micrograms/ml). After the first bacterial challenge, there was a 22% decrease (P less than 0.05) in plasma fibronectin. Lung lymph flow (QL) initially increased 308% (P less than 0.05) by 2 h (0 h = 4.7 +/- 1.1 ml/h; 2 h = 14.4 +/- 3.5 ml/h), and the total protein lymph-to-plasma concentration ratio (L/P) declined. This was followed by a sustained second phase response over 3-12 h which was characterized by a 202-393% elevation in QL (P less than 0.05), an increase in the L/P ratio, and a 240-480% (P less than 0.05) increase in lung transvascular protein clearance (TVPC = QL X L/P). Sheep with elevated fibronectin levels also manifested the early (2 h) elevation in QL (P less than 0.05) coupled with a decline in L/P ratio after the second bacterial challenge, but the second-phase increase in TVPC was markedly attenuated. Intravenous infusion of 500 mg of human plasma fibronectin into normal sheep to elevate the fibronectin level comparable to that in the hyperfibronectinemic sheep also attenuated (P less than 0.05) the second-phase (3-12 h) increase in lung protein clearance with sepsis. Thus elevation of plasma fibronectin during postoperative Gram-negative bacteremia may protect the lung vascular barrier. This response may be mediated by either fibronectin's opsonic support of phagocytic function or its influence on lung endothelial cell adhesion.     

气道高反应动物模型的建立与指标检测

目的 通过重新评价卵蛋白致小鼠哮喘模型,寻找一种简便易行的气道高反应动物模型和相应的检测指标,为研发治疗本类疾病药物和研究气道高反应发病机制提供新的实验手段.方法 小鼠采用卵白蛋白（OVA）致敏;致敏后（15～21）d给予10% OVA雾化吸入激发哮喘,在末次激发24 h内测量小鼠辣椒素引咳的半数有效浓度,处死小鼠取肺组织测定匀浆中NO、IL-13、ET-1的含量.结果 卵蛋白致敏模型小鼠随辣椒素浓度的升高其咳嗽反应阳性率、咳嗽次数明显增加（与对照组相比较P〈0.01）.模型组辣椒素引咳的半数有效浓度为89.39 μmol/L,对照组、地塞米松组分别为204.84、220.02 μmol/L;小鼠肺匀浆NO、ET-1、IL-13含量均明显增加,地塞米松可明显抑制NO的升高（与对照组相比较P〈0.01）.结论小鼠经卵蛋白致敏并连续激发7 d与临床气道高反应性（AHR）的多种特征相似,操作简便易行,稳定性高,故可作为气道高反应性的模型.辣椒素引咳阈值的测定、动物肺组织中NO、IL-13、ET-1含量的变化,可作为评价模型严重程度的指标.     

Site of deposition and factors affecting clearance of aerosolized solute from canine lungs

We determined the influence of several factors on lung solute clearance using aerosolized 99mTc-diethylenetriaminepentaacetate. We used a jet nebulizer-plate separator-balloon system to generate particles with an activity median aerodynamic diameter of 1.1 micron, administered the aerosol in a standard fashion, and determined clearance half times (t1/2) with a gamma-scintillation camera. The following serial studies were performed in five anesthetized, paralyzed, intubated, mechanically ventilated dogs: 1) control, with ventilatory frequency (f) = 15 breaths/min and tidal volume (VT) = 15 ml/kg during solute clearance; 2) repeat control, for reproducibility; 3) increased frequency, with f = 25 breaths/min and VT = 10 ml/kg; 4) positive end-expiratory pressure (PEEP) of 10 cmH2O; 5) unilateral pulmonary arterial occlusion (PAO); and 6) bronchial arterial occlusion (BAO). Control t1/2 was 25 +/- 5 min and did not change in the repeat control, increased frequency, or BAO experiments. PEEP markedly decreased t1/2 to 13 +/- 3 min (P less than 0.01), and PAO increased it to 37 +/- 6 min (P less than 0.05). We conclude that clearance from the lungs by our method is uninfluenced by increased frequency, increases markedly with PEEP, and depends on pulmonary, not bronchial, blood flow.     

Comparison of three tracers for detecting lung epithelial injury in anesthetized sheep

We compared the ability of three aerosolized tracers to discriminate among control, lung inflation with a positive end expired pressure of 10 cmH2O, lung vascular hypertension and edema without lung injury, and lung edema with lung injury due to intravenous oleic acid. The tracers were 99mTc-diethylenetriaminepentaacetate (99mTc-DTPA, mol wt 492), 99mTc-human serum albumin (99mTc-ALB, mol wt 69,000), and 99mTc-aggregated albumin (99mTc-AGG ALB, mol wt 383,000). 99mTc-DTPA clearance measurements were not able to discriminate lung injury from lung inflation. The 99mTc-AGG ALB clearance rate was unchanged by lung inflation and increased slightly with lung injury. The 99mTc-ALB clearance rate (0.06 +/- 0.02%/min) was unchanged by lung inflation (0.09 +/- 0.02%/min, P greater than 0.05) or 4 h of hypertension without injury (0.09 +/- 0.04%/min, P greater than 0.05). Deposition of 99mTc-ALB within 15 min of the administration of the oleic acid increased the clearance rate to 0.19 +/- 0.06%/min, which correlated well with the postmortem lung water volume (r = 0.92, P less than 0.01). This did not occur when there was a 60-min delay in the deposition of 99mTc-ALB. We conclude that 99mTc-ALB is the best indicator for studying the effects of lung epithelial injury on protein and fluid transport into and out of the air spaces of the lungs in a minimally invasive manner.     

Stochastic Modeling Predictions for the Clearance of Insoluble Particles from the Tracheobronchial Tree of the Human Lung

Bronchial clearance of deposited particles was simulated using a stochastic model of the tracheobronchial tree. The clearance model introduced in this study considers (1) a continuous decrease of the mucus thickness from the trachea to the terminal bronchioles according to a linear or an exponential function, (2) the possibility of mucus discontinuities, which are mainly found in intermediate and distal airways of the tracheobronchial compartment, (3) mucus production in proximal airways, (4) a slow bronchial clearance phase due to the capture of a defined particle fraction f _s in the periciliary sol phase, and (5) an eventual delay of the mucociliary transport at carinal ridges of airway bifurcations. Based on the concept of mucus volume conservation in single bifurcations, a reduction of the thickness of the mucus blanket from proximal to distal airways causes a significant increase of the mucus velocities in small ciliated airways compared to other stochastic modeling predictions assuming a constant thickness of the mucus layer throughout the conducting airways. This effect is further enhanced by the consideration of mucus discontinuities. In contrast, the ability of bronchial airways to produce a certain volume of mucus has a decreasing effect on the mucus velocities. In all generated clearance velocity models, mucociliary clearance is completely terminated within 24 h after exposure, consistent with the experimental evidence. Implementation of a slow bronchial clearance phase predicts a long-term retention fraction, which is fully cleared from the lung after several weeks. For 1-μm MMAD particles, 24-h retention varies between 0.42 and 0.52, in line with the suggestions of the ICRP. Mucus delay at carinal ridges only affects short-term clearance by increasing the retained particle fraction at a given time, while long-term retention is not influenced.     

Effect of increased surface tension and assisted ventilation on 99mTc-DTPA clearance

Experiments were performed to determine the effects of conventional mechanical ventilation (CMV) and high-frequency oscillation (HFO) on the clearance of technetium-99m-labeled diethylenetriamine pentaacetate (99mTc-DTPA) from lungs with altered surface tension properties. A submicronic aerosol of 99mTc-DTPA was insufflated into the lungs of anesthetized, tracheotomized rabbits before and 1 h after the administration of the aerosolized detergent dioctyl sodium sulfosuccinate (OT). Rabbits were ventilated by one of four methods: 1) spontaneous breathing; 2) CMV at 12 cmH2O mean airway pressure (MAP); 3) HFO at 12 cmH2O MAP; 4) HFO at 16 cmH2O MAP. Administration of OT resulted in decreased arterial PO2 (PaO2), increased lung wet-to-dry weight ratios, and abnormal lung pressure-volume relationships, compatible with increased surface tension. 99mTc-DTPA clearance was accelerated after OT in all groups. The post-OT rate of clearance (k) was significantly faster (P less than 0.05) in the CMV at 12 cmH2O MAP [k = 7.57 +/- 0.71%/min (SE)] and HFO at 16 cmH2O MAP (k = 6.92 +/- 0.61%/min) groups than in the spontaneously breathing (k = 4.32 +/- 0.55%/min) and HFO at 12 cmH2O MAP (4.68 +/- 0.63%/min) groups. The clearance curves were biexponential in the former two groups. We conclude that pulmonary clearance of 99mTc-DTPA is accelerated in high surface tension pulmonary edema, and this effect is enhanced by both conventional ventilation and HFO at high mean airway pressure.