Ozone exposure increases respiratory epithelial permeability in humans

Ozone is a respiratory irritant that has been shown to cause an increase in the permeability of the respiratory epithelium in animals. We used inhaled aerosolized 99mTc-labeled diethylene triamine pentacetic acid (99mTc-DTPA) to investigate whether human respiratory epithelial permeability is similarly affected by exposure to ozone. In a randomized, crossover double-blinded study, 8 healthy, nonsmoking young men were exposed for 2 h to purified air and 0.4 ppm ozone while performing intermittent high intensity treadmill exercise (minute ventilation = 66.8 L/min). SRaw and FVC were measured before and at the end of exposures. Seventy-five minutes after the exposures, the pulmonary clearance of 99mTc-DTPA was measured by sequential posterior lung imaging with a computer-assisted gamma camera. Ozone exposure caused respiratory symptoms in all 8 subjects and was associated with a 14 +/- 2.8% (mean +/- SEM) decrement in FVC (p less than 0.001) and a 71 +/- 22% increase in SRaw (p = 0.04). Compared with the air exposure day, 7 of the 8 subjects showed increased 99mTc-DTPA clearance after the ozone exposure, with the mean value increasing from 0.59 +/- 0.08 to 1.75 +/- 0.43%/min (p = 0.03). These data show that ozone exposure sufficient to produce decrements in the pulmonary function of human subjects also causes an increase in 99mTc-DTPA clearance.     

Pulmonary epithelial clearance of 99mTc-DTPA after thrombin-induced pulmonary microembolism

We investigated the effect of thrombin-induced pulmonary microembolism on the pulmonary clearance rate of aerosolized 99mTc diethylenetriamine pentaacetic acid (99mTc-DTPA) in awake, chronically prepared sheep. Chest activity was recorded after administration of a 0.44 micron aerosol of 99mTc-DTPA. Decay-corrected data were fit to an exponential and expressed as percent decrease per min (%/min). Sheep were given alpha-thrombin intravenously (80 U/kg for 10 min) 60 min after the aerosol administration. The clearance rate prior to alpha-thrombin was 0.35 +/- 0.05 %/min (mean +/- SEM). During alpha-thrombin administration, the clearance rate increased to 5.84 +/- 0.70 %/min (p less than 0.001 from baseline), but returned to 0.41 +/- 0.06 %/min within 30 min after the end of the thrombin infusion. The increased clearance rate during alpha-thrombin administration was not due to increased lung volume since alpha-thrombin did not change functional residual capacity. Moreover, the clearance rate was unchanged during gamma-thrombin administration, which does not induce coagulation, or during alpha-thrombin challenge in defibrinogenated animals. alpha-thrombin administration in neutrophil-depleted sheep caused a transient increase in DTPA clearance similar to that in control sheep, suggesting that the increase occurred independently of neutrophils. The results indicate that alpha-thrombin causes a large, transient increase in 99mTc-DTPA clearance, which may be the result of increased epithelial permeability. This response is dependent on the activation of intravascular coagulation.     

Permeability of the bronchial mucosa to 99mTc-DTPA in asthma

Previous investigators, using 99mTc-DTPA aerosol as a marker to assess epithelial permeability in asthma, did not find an increased permeability in this group. However, they either failed to deliver the aerosol to the optimal site (bronchial mucosa, not alveoli) or failed to account for mucociliary clearance in analyzing their results. We studied 10 asthmatics and eight age-matched control subjects using a dosimeter (Spira-Elektra 2) and a carefully controlled breathing pattern to deliver aerosol to the subjects' airways. Two aerosols were delivered on separate days in each patient; 99mTc-DTPA aerosol, and 99mTc-HSA (human serum albumin), using similar breathing patterns to ensure reproducibility of the deposition pattern with the two aerosols. From measurements of retention versus time over a 1-h period, rate constants Ktot and Km were determined for the clearance of 99mTc-DTPA and 99mTc-HSA, respectively. By modelling the airways as a single compartment with two possible routes of clearance, we determined the permeability rate constant, Kp, as Ktot minus Km. There was no significant difference between Ktot in normal subjects and asthmatics; however, because of the slower mucociliary clearance in the asthmatic group, and the relative importance of mucociliary clearance in determining the washout of 99mTc-DTPA aerosol, there was a significant difference in airway permeability between the normal subjects and the asthmatics (t1/2 = 296 min +/- 141 SD and 126 min +/- 58, p less than 0.01, in normal subjects and asthmatics, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ozone-induced accelerated lung clearance of 99mTc-DTPA aerosol in conscious sheep

This study was initiated to determine the rate and characteristics of 99mTc-DTPA clearance from the lungs of unanesthetized sheep exposed to varying concentrations of O3 for 4 h in a whole-body exposure chamber. Four sheep exposed to 1 ppm O3 had a monoexponential T50 of 274 +/- 81 min (SD), not significantly different from sham exposures (316 +/- 150); 5 sheep exposed to 2 ppm had a T50 of 234 +/- 101 min, not significantly different from sham exposures (364 +/- 131 min). Five additional unanesthetized sheep exposed to 2 ppm for 4 h via a nasotracheal tube had a T50 of 192 +/- 55 min, significantly different from sham exposures (300 +/- 96 min). The results show that the effect of oxidant pollutants on the permeability of alveolobronchiolar epithelium may be assessed in conscious sheep.     

Lung inflammation in coal miners assessed by uptake of 67Ga-citrate and clearance of inhaled 99mTc-labeled diethylenetriamine pentaacetate aerosol.

We compared the diffuse lung uptake of 67Ga-citrate, an index of inflammatory lung activity, with the lung clearance of inhaled 99mTc-labeled diethylenetriamine pentaacetate (DTPA) aerosol, an index of pulmonary epithelial permeability, in a group of 19 West Virginia coal miners whose pulmonary status was compatible with coal worker's pneumoconiosis. 99mTc-DTPA clearance alone and 67Ga-citrate uptake alone were measured in nine and five additional subjects, respectively. The objective of this study was to determine if increased 99mTc-DTPA lung clearance was caused by inflammation at the lung epithelial surfaces. Subjects inhaled approximately 150 microCi (approximately 5.6 MBq) of 99mTc-DTPA aerosol, and quantitative gamma camera images of the lungs were acquired at 1-min increments for 25 min. Regions of interest (ROI) were selected to include (1) both lungs; (2) each individual lung; and (3) the upper, middle, and lower thirds of each lung. 99mTc-DTPA clearance was determined from the slopes of the respective time-activity plots for the different ROI. Each subject was intravenously administered 50 miCroCk (1.9 MBq)/kg 67Ga-citrate 48 to 72 h before imaging the body between neck and pelvis. The extent of 67Ga-citrate lung uptake was expressed as the gallium index (GI). Mean radioaerosol clearance half-time (T1/2) for the six nonsmoking coal miners (60.6 +/- 16.0 min) was significantly shorter (p less than 0.001) than for the nonsmoking control group (123.8 +/- 28.7 min). T1/2 for the 12 smoking miners (18.4 +/- 10.2 min) was shorter than for the smoking control group (33.1 +/- 17.8 min), but the difference did not attain statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of 99mTc-DTPA and 113mIn-DTPA aerosol clearances in humans. Effects of smoking, hyperinflation, and in vitro oxidation

As an index of permeability of the alveolar epithelium, the clearance of an inhaled aerosol of 99mTc-DTPA is increased in several disease states. However, the usefulness of the test to assess the severity of disease is limited because healthy smokers also have abnormally rapid rates of clearance. Because the stability of the 99mTc-DTPA bond might be a contributory factor, we tested the affinity of 99mTc for DTPA in vitro, and in groups of healthy smokers (n = 13) and nonsmokers (n = 7) we measured the clearances of 99mTc-DTPA and 113mIn-DTPA, which have a similar molecular shape and charge. In vitro, sodium hypochlorite or hydrogen peroxide released as much as 98% of free 99mTc from the 99mTc-DTPA complex. When incubated with human neutrophils stimulated with phorbol myristate acetate, between 4 and 7% of free 99mTc-DTPA was released after 30 min, and 12% was released after 60 min. In vivo, the clearances of both 99mTc-DTPA and 113mIn-DTPA in the smokers (n = 13) were faster than in the nonsmokers (n = 7) (p less than 0.05). Within the smokers, the mean 99mTc-DTPA clearance (T1/2 25 +/- 4 min) was faster than the mean 113mIn-DTPA clearance (34 +/- 6 min), (p less than 0.05). For nonsmokers, the difference was smaller (T1/2 99mTc-DTPA, 56 +/- 6; T1/2 113mIn-DTPA, 62 +/- 6) and not significant. During hyperinflation, smokers (n = 8) and nonsmokers (n = 8) both demonstrated an increase in 113mIn-DTPA clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of pattern of aerosol inhalation on clearance of technetium-99m-labeled diethylenetriamine pentaacetic acid from the lungs of normal humans.

The clearance rate of inhaled aerosols of technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) from the lungs provides a rapid, clinically useful, noninvasive index of pulmonary epithelial permeability. In order to identify a method that minimizes intrasubject and intersubject variability and thereby provides a reliable means to identify patients with abnormal values, we administered a submicronic aerosol of 99mTc-DTPA to 10 healthy, nonsmoking male subjects with either tidal breathing (Vtidal) or multiple vital capacity maneuvers (VVC). Subjects then spontaneously breathed room air while counting continued for 30 min. Monoexponential clearance rates over 7, 15, and 30 min were compared with a two-compartment, biexponential analysis over 30 min. Intrasubject reproducibility was evaluated by repeating clearance 2 to 156 days later. Monoexponential clearance following VVC at 30 min equaled 1.36 +/- 0.55%/min compared with 0.83 +/- 0.25%/min for Vtidal (p less than 0.025). VVC inhalations resulted in a larger fast compartment of 16 +/- 12% compared with 3 +/- 2% with tidal breathing (p less than 0.01). The least intrasubject variability with coefficient of variation (CV) of +/- 18% was obtained with monoexponential analyses after Vtidal during 15 min of scanning and with either breathing maneuver over 30 min. Monoexponential clearance for 30 min with Vtidal gave the least scatter between subjects, with CV of +/- 30%. These data show that simple tidal inhalations of 99mTc-DTPA followed by a monoexponential analysis of the 30-min time-activity curve from both lungs minimize the degree of variability between and among subjects and provide a predicted normal value of clearance of 0.83 +/- 0.25%/min. The development of a more rapid curvilinear clearance followed by delivery VVC suggests that several deep breaths transiently increase epithelial permeability or reduce the volume of liquid in the alveolar subphase in some regions. Resting for 20 min prior to inhaling the aerosol of 99mTc-DTPA is recommended to avoid alterations in clearance rates from deep breathing.     

Pulmonary clearance of 99mTC-DTPA aerosol in patients with silicosis]

99mTc-DTPA clearance was studied in 11 healthy nonsmokers, 20 patients with simple or complicated silicosis (5 of simple, 15 of complicated). The results indicated that both the patients with simple silicosis (T1/2 32.8 +/- 14.4min) and complicated silicosis (T1/2 26.6 +/- 8.5min) showed faster clearance of inhaled 99mTc-DTPA than observed in healthy nonsmokers (77.9 +/- 11.7min, p < 0.01). Regional clearance apico-basal difference was found in patients with silicosis. This study presents evidence of increased pulmonary epithelial permeability and regional distribution of pulmonary epithelial permeability in silicosis.     

Fibrinogen depletion and control of permeability in oleic acid lung injury

To determine if the biphasic pulmonary clearance of aerosolized 99mTc diethylene penta acetate (99mTc-DTPA) observed in oleic acid lung injury represents acute epithelial damage followed by sealing as a result of intra-alveolar fibrin deposition, we examined the effect of fibrinogen depletion. 99mTc-DTPA clearance was assessed in three groups of rabbits: Group 1, normal fibrinogen + oleic acid injury; Group 2, fibrinogen-depleted + oleic acid injury; Group 3, fibrinogen-depleted with no oleic acid injury. In Group 3 animals with no lung injury, the 99mTc-DTPA clearance rate, expressed as k, the percent decrease in thoracic radioactivity, was similar to that previously reported for healthy rabbits (k = 1.16 +/- 0.57%/min, mean +/- SD). Oleic acid administration to Groups 1 and 2 resulted in significantly faster clearance rates, with identical biphasic curves in all animals, irrespective of fibrinogen status. There were no significant differences between either the initial fast phase (k, Group 1 = 5.26 +/- 1.83%/min, Group 2 = 5.70 +/- 1.77%/min) or the subsequent slow phase (k, Group 1 = 1.67 +/- 0.63%/min, Group 2 = 1.57 +/- 0.55%/min, p greater than 0.05). On histologic examination, Groups 1 and 2 showed greater cellular interstitial infiltrate, alveolar edema, and hemorrhage than did Group 3. Fibrinogen depletion plus oleic acid injury resulted in greater alveolar cellular exudate, edema, and hemorrhage than did either oleic acid or fibrinogen depletion alone. We conclude that fibrinogen is not necessary to produce biphasic 99mTc-DTPA clearance in oleic acid lung injury.     

Solute movement across the alveolar-capillary membrane after intratracheally administered bleomycin in rats

The rate of absorption across the alveolar-capillary membrane of inhaled 99mTc-DTPA and the concentration of albumin in the bronchoalveolar lavage (BAL) fluid were characterized in a rat model of bleomycin-induced pulmonary fibrosis. Adult male Lewis rats were studied from 1 h to 120 days after a single intratracheal instillation of bleomycin (0.5 to 0.6 U/100 g body weight). The retention of 99mTc-DTPA in the lungs, expressed as a percentage of the baseline radioactivity, was determined at 15 min (%R15) after delivery of the tracer. The %R15 was 83.7 +/- 6.0 for normal untreated rats and 84.3 +/- 3.7 for saline-treated animals. The rate of absorption of 99mTc-DTPA began to increase 24 h after bleomycin, reaching a maximum at Day 7, with %R15 = 56.0 +/- 6.5 (p less than 0.0001). Resolution to control values occurred by Day 34 after bleomycin. At Day 45 after bleomycin, the rate of absorption of 99mTc-DTPA was slower than sham (control), with %R15 = 89.2 +/- 1.9 (p less than 0.5). However, from Day 63 onwards, removal was not different from control. The concentration of albumin in the BAL fluid began to increase 48 h after bleomycin, was 10-fold greater than control by Day 7 (150 +/- 38 versus 16 +/- 3 micrograms/ml), and returned to control values by Day 28. The percentage of neutrophils in the BAL increased at 12 h, reached a plateau of 33 +/- 9% between 4 and 7 days, and then returned to control values by Day 14.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased airway mucosal permeability of smokers. Relationship to airway reactivity

We studied pulmonary epithelial permeability and bronchial reactivity in 10 smoking and 8 nonsmoking adults. Permeability was measured as the disappearance half-life (T 1/2) of aerosolized 99mTc-DTPA from the lungs, and a permeability index (PI) calculated that reflected the appearance of the tracer in the blood. Smokers had increased permeability with a T 1/2 of 44.6 +/- 12.2 min and PI values at 10, 25, and 60 min of 27.3 +/- 13.2, 32.5 +/- 10.2, and 34.3 +/- 9.9, compared with those in nonsmokers with a T 1/2 of 110.0 +/- 62.7 min and PI values of 9.4 +/- 5.7, 14.9 +/- 8.3, and 23.1 +/- 9.0. Bronchial reactivity to histamine was measured with and without prior exposure to aerosolized propranolol (to achieve beta-blockade of airway smooth muscle). Reactivity increased significantly (p less than 0.001) in both groups after beta-blockade, but no difference was found between smokers and nonsmokers. Despite the increased permeability in smokers, there was no evidence of increased reactivity.     

Influence of Pneumocystis carinii pneumonia on serum and tissue concentrations of pentamidine administered to rats by tracheal injections.

Pentamidine isethionate was administered by the tracheal route to control rats and immunodepressed rats with Pneumocystis carinii pneumonia (PCP). The serum concentration of pentamidine base 20 min after the administration was higher in the PCP rats (309 +/- 165 ng/ml) than in the control animals (71 +/- 36 mg/ml; p less than 0.001); 90 min after the injection the proportion of the pentamidine administered was lower in the right lung of the PCP rats (29 +/- 15%) than in the control rats (57 +/- 23%; p = 0.038); the proportion of pentamidine in the left kidney was higher in the PCP rats (14 +/- 4%) than in the control animals (4 +/- 2%; p less than 0.001). Respiratory clearance of 99mTc-DTPA, an index of the permeability of the respiratory epithelium, was higher in the PCP rats (1.84 +/- 0.42 %/min) than in the controls (0.44 +/- 0.11 %/min; p less than 0.001). We conclude that the more rapid diffusion of pentamidine from the alveolar lumen to the pulmonary circulation is explained by the increased alveolocapillary permeability as a result of pneumocystosis.     

Pulmonary antigen challenge in rats passively sensitized with a monoclonal IgE antibody induces immediate but not late changes in airway mechanics

Pulmonary antigen challenge in sensitized individuals results in isolated immediate, isolated late, or dual reactions consisting of both an immediate and late change in airway function. The immediate response appears to be dependent on the presence of IgE antibody and mast cell mediator release. Although the late phase of dual responses is considered to be related to or a continuum of the immediate hypersensitivity response, its precise pathogenesis remains to be determined. To increase both the sensitivity and specificity of analyzing the pathogenesis of IgE-dependent pulmonary responses, we have used a Sprague-Dawley rat model system in which rats are passively sensitized with a murine monoclonal IgE anti-dinitrophenol (DNP) antibody prior to challenge with DNP-bovine serum albumin (DNP-BSA). Pathogen-free rats were injected with IgE or saline in a randomized blinded protocol, and in 24 to 48 h were anesthetized with urethane (1.2 g/kg intraperitoneally) and instrumented to measure lung resistance (RL) and dynamic compliance (Cdyn). Rats were then challenged with aerosolized DNP-BSA (10 mg/ml), and RL and Cdyn monitored through 7 h after challenge. Both RL (0.30 +/- 0.10 versus 0.13 +/- 0.02 cm H2O/ml.sec-1) and Cdyn (0.41 +/- 0.10 versus 0.25 +/- 0.08 ml/cm H2O) were significantly different (p less than 0.05) in sensitized rats compared to control rats immediately after challenge. No late changes were observed in either the treated or control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of pulmonary epithelial permeability in interstitial lung diseases]

The pulmonary epithelial permeability of 99mTc-DTPA (diethylene triamine penta acetate) was assessed in patients with interstitial lung diseases including radiation pneumonitis, idiopathic interstitial pneumonia/pulmonary fibrosis, sarcoidosis, unclassified interstitial pneumonia, and in healthy subjects. Pulmonary epithelial permeability was estimated by the rate constant (kep) of inhaled 99mTc-DTPA clearance from the lungs. Healthy nonsmokers had a mean kep value of 0.82 +/- 0.26% min, and their kep values were constant irrespective of age or sex. Of healthy smokers, 53% showed an increase in kep. This increase correlated with their cigarette consumption per day, but was reversible after cessation of smoking. The provocative concentration of histamine to decrease FEV 1.0 by more than 20% caused an increase in epithelial permeability. However, its effect on permeability was transient, limited, and not dose-dependent. During lung inflation by continuous external negative pressure or by positive end-expiratory pressure, pulmonary 99mTc-DTPA clearance was increased, suggesting changes in epithelial permeability. The patients with diffuse interstitial lung diseases also showed increased permeability compared with healthy nonsmokers. In the patients with pre-existing radiation pneumonitis, the mean kep value obtained from the area with infiltration on chest X-ray films was significantly higher than that from the opposite lung. In the prospective study, 3 of 11 patients developed radiation pneumonitis during the course of radiation therapy. The mean kep value obtained in the 3 patients who developed radiation pneumonitis increased just before onset, and further increased when the disease manifested clinically. We believe that 99mTc-DTPA aerosol inhalation is a sensitive test for the detection of inflammatory changes in the bronchioalveolar epithelium.     

Hyperthermic pretreatment decreases microvascular protein leakage and attenuates hypotension in anaphylactic shock in rats

Systemic anaphylaxis is a life-threatening allergic reaction and its pathologic conditions, such as edema, bronchospasm, and hypotension, have been attributed to release of vasoactive mediators. Heat shock protein (HSP) is known to play a protective role in living cells under various stresses. In these studies, we investigated the protective role of heat shock response in anaphylactic shock, focusing on changes of blood pressure (BP) and vascular permeability. Adult sensitized rats were injected intravenously with Evans blue (EB) and challenged with bovine serum albumin (BSA). The rats were treated with whole-body hyperthermia at 41.5 +/- 0.5 degrees for 15 min 24 h before BSA challenge. Vascular protein leakage in tissues was analyzed with the EB technique. The results showed that BSA challenge induced EB extravasation in all sensitized rats. EB values (EB/tissue; microg/g) in heart and lung (112.3 +/- 41 and 244.4 +/- 90.6; mean +/- SD; n = 6) in the nonheated rats were significantly higher than those (33.4 +/- 23.3 and 103.4 +/- 63.9; n = 9) in the heated rats (P < 0.05). The results showed that BSA challenge caused BP to fall drastically in the sensitized rats. BP in the heated rats was significantly higher than BP in the nonheated rats from 4 to 15 min during anaphylactic shock (P < 0.001). Inducible HSP72 appeared overexpressed in heart, lung, and liver tissue in the heated rats tested by Western immunoblotting. The results indicate that reduction of increased protein leakage and attenuation of hypotension may result from induction of HSP by whole-body hyperthermia.     

Comparison of 99mTc-DTPA and urea for measuring cefepime concentrations in epithelial lining fluid.

The efficacy of antimicrobial agents against pulmonary infections depends on their local concentrations in the lung. The aims of the present study were to: 1) compare technetium-99m diethylenetriaminepenta-acetic acid (99mTc-DTPA) and urea as markers of epithelial lining fluid (ELF) dilution for measuring ELF concentrations of pharmaceuticals; 2) quantify ELF cefepime concentrations in normal and injured lung; and 3) measure the increase in permeability to cefepime following oleic acid-induced acute lung injury. A modified bronchoalveolar lavage technique, based on equilibration of infused 99mTc-DTPA, was used to measure ELF volume. Cefepime was administered intravenously at steady plasma levels. Six serial bronchoalveolar lavages were performed 5 h after the beginning of infusion. ELF to plasma cefepime concentration ratios were 95 +/- 17 and 100 +/- 14.5% in normal and injured lung respectively. When urea was used as marker, cefepime concentration ratios were underestimated at 16.4 +/- 2.7 and 73.9 +/- 8.4% respectively. Cefepime blood/ airspace clearance increased from 3.8 +/- 0.7 micro x min(-1) in controls to 39.8 +/- 4.9 microL x min(-1) in acute lung injury. It was concluded that: 1) cefepime concentrations in epithelial lining fluid were in equilibrium with those in plasma in both normal and injured lung after 5 h at steady plasma concentrations; 2) epithelial lining fluid cefepime concentration by the urea method was much less underestimated in injured versus normal lung; and 3) acute lung injury induces a 10-fold elevation of cefepime blood/airspace clearance.     

Assessment of alveolar epithelial permeability in progressive systemic sclerosis (PSS) using 99mTc-DTPA (diethylene triamine penta acetate) aerosol inhalation]

To evaluate alveolar epithelial damage in PSS, we studied pulmonary epithelial permeability by measuring the clearance of inhaled 99mTc-DTPA aerosol and performing thin slice CT scan, pulmonary function tests and right heart catheterization in 28 patients with PSS. The 99mTc-DTPA clearance rate (kep value) in PSS was greater than in 11 non-smoking normal subjects (18.2 +/- 7.63 x 10(-3)/min vs. 9.12 +/- 0.77 x 10(-3)/min, p less than 0.01). In PSS, the kep value did not correlate with age, sex, duration of illness, dermal lesions, % vital capacity, or PaO2. In contrast, the kep value showed significant correlations with %DLco (diffusing capacity for carbon monoxide), extent of interstitial lesions evaluated by CT scan (CT score), and mean pulmonary artery pressure. On the other hand, the kep value was high in some patients with normal CT scan and normal %DLco. These findings indicate that pulmonary interstitial lesions in PSS are accompanied by alveolar epithelial damage, and that the clearance of 99mTc-DTPA may be an early predictor of interstitial change.     

Aerosolized lipopolysaccharide increases pulmonary clearance of 99mTc-DTPA in rabbits.

Bacterial endotoxins alter the permeability of endothelium, but little is known of their effect on epithelium. We exposed specific pathogen-free rabbits to aerosolized Pseudomonas aeruginosa LPS or saline and performed serial measurements of RL, Cdyn, BP, WBC count and differential, and platelet counts. Pulmonary 99mTc-DTPA half-life was measured 4, 6, or 8 h after exposure. The animals were sacrificed and BAL performed. Background and PMA-stimulated superoxide production was measured from individual AM using electrooptical determination of reduction of NBT. Lung tissue was processed for light microscopy and ratio of wet to dry weight. 99mTc-DTPA half-life was significantly shorter in LPS-exposed animals at 6 h (p < 0.05) and 8 h (p < 0.001). There were no differences in Cdyn, RL, BP, WBC, differential, platelet, or BAL cell count at any time between groups. No histologic changes or differences in lung wet to dry weight ratios were found. PMA-stimulated AM superoxide production was significantly increased (p < 0.01) in LPS-exposed animals. This effect was time dependent and could be duplicated in AM from control animals following a 4-h incubation with LPS, lavage fluid from LPS-exposed animals, or recombinant murine TNF. These results demonstrate that aerosolized Pseudomonas LPS increases pulmonary epithelial permeability and primes AM superoxide production.     

Modulation by pentobarbital of neutrophil responses to inhaled E. coli endotoxin in sheep: role of lung epithelium.

Neutrophils (PMNs) are implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). The role of the epithelium in the modulation of PMN migration within the lungs was examined. Epithelial integrity and PMN concentrations in the lung air spaces and lymph were measured in sheep anaesthetized with either halothane (1-2.5%) or intravenous pentobarbital (12+/-4 mg x kg(-1) x h(-1)). Ventilation with an aerosol containing 25 mg Escherichia Coli endotoxin (lipopolysaccharide; LPS) effected neutrophil recruitment to the air spaces. Lymphatic clearance of aerosolized 99mTc-DTPA provided an index of epithelial integrity. Three hours after the deposition of LPS, the lung lining fluid of sheep anaesthetized with halothane (n=7) had 4.9+/-3.2x10(6) PMN.mL(-1), but the lung lymph had almost no PMNs (3+/-8%). Sheep anaesthetized with pentobarbital (n=6) had fewer PMNs in the air spaces (2.4+/-1.2X10(6) mL(-1)) and more PMNs in the lung lymph (30+/-20%). Control sheep (n=5) that received no LPS had almost no PMNs in the airspaces or lung lymph, regardless of the anaesthesia. Three additional sheep that remained awake after receiving LPS also had no PMNs in the lung lymph. The PMN fraction in the lung lymph correlated well with the extra-alveolar epithelial permeability measured by lymphatic clearance of aerosolized diethylenetriamine penta-acetic acid (r=0.81, p<0.001). Aerosolized lipopolysaccharide recruits neutrophils into the lungs of sheep, but they appear to remain in the airspaces unless extra-alveolar permeability is increased by agents such as pentobarbital.     

Differential renal function during angiotensin converting enzyme inhibition in renovascular hypertension

Renal function was measured sequentially in 32 patients with proven renovascular hypertension who were treated with the oral angiotensin converting enzyme inhibitor captopril. Renal function was assessed by serial measurement of serum creatinine. Six patients showed acute rises in serum creatinine concentration compatible with acute renal failure. Acute renal failure was confined to those patients with stenosis to a solitary kidney (transplant or native, occurring in 3 of 8 patients) or bilateral renal artery stenosis (occurring in 3 of 13 patients). No rise in serum creatinine concentration was observed in 11 patients with unilateral renal artery stenosis during long-term angiotensin converting enzyme inhibitor therapy. Acute renal failure during angiotensin converting enzyme inhibitor therapy was not related to the degree of blood pressure fall or the plasma angiotensin II level. Eleven patients with renovascular hypertension were followed prospectively with estimation of renal function by 99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance (determined by computer analysis of scintillation camera renography). In six patients with unilateral renal artery stenosis, total 99mTc-DTPA clearance and serum creatinine level remained constant following angiotensin converting enzyme inhibitor therapy, while in five patients with bilateral renal artery stenosis 99mTc-DTPA clearance fell from 40 +/- 9 to 27 +/- 5 ml/min (p less than 0.05). Split renal function studies revealed that 99mTc-DTPA clearance fell in most kidneys with stenosed arteries during angiotensin converting enzyme inhibition, including the stenosed kidney from patients with unilateral renal artery stenosis (16 stenosed kidneys studied; change in Tc-DTPA clearance, -7.5 +/- 2.7 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)