1 Institut National de la Santé et de la Recherche Médicale U416, Institut Pasteur de Lille, 59019 Lille; 2 EA2689, Institut Fédératif de Recherche 22, Université de Lille II, 59024 Lille; 3 Service d'Anatomie et de Cytologie Pathologiques, Hôpital Saint-Louis, 75010 Paris, France; and 4 Departments of Anesthesia and Perioperative Care and Surgery, University of California-San Francisco, San Francisco, California 94143
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ABSTRACT |
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Bronchial inflammation
in allergic asthma is associated with active exudation from the
bronchial tree into the interstitial space of both mucosa and
submucosa. The aim of this study was to evaluate epithelial and
endothelial permeability as well as alveolar fluid movement in a model
of chronic allergic inflammation in Brown-Norway rats sensitized and
challenged with ovalbumin (OA). Control groups were challenged with
saline solution (C), and rats were immunized by OA but not challenged
(Se). Lung sections showed a marked inflammatory infiltrate associated
with perivascular and peribronchiolar edema in OA. To measure alveolar
liquid clearance, a 5% bovine albumin solution with 1 µCi of
125I-labeled human albumin was instilled into the air
spaces. Alveolar-capillary barrier permeability was evaluated by
intravascular injection of 1 µCi of 131I-labeled albumin.
Endothelial permeability was significantly increased in OA, from
0.08 ± 0.01 in the C group to 0.19 ± 0.03 in OA group
(P < 0.05). Final-to-initial protein ratio was also statistically higher in OA (1.6 ± 0.05) compared with C
(1.38 ± 0.03, P = 0.01) and Se groups (1.42 ± 0.03, P = 0.04). Administration of anti-tumor
necrosis factor- antibodies within the instillate significantly
decreased this ratio (1.32 ± 0.08, P = 0.003 vs. OA). To conclude, we demonstrated a tumor necrosis factor-
-dependent increase in alveolar fluid movement in a model of severe bronchial allergic inflammation associated with endothelial and epithelial leakage.
asthma; allergy; alveolar clearance; permeability
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INTRODUCTION |
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BRONCHIAL INFLAMMATION in allergic asthma is associated with active exudation from the bronchial tree into the interstitial space of both mucosa and submucosa (5, 21, 29, 47). This exudate is constituted of proteins and mediators susceptible to amplify bronchoconstriction and bronchial wall thickness. In severe asthma, edema is present in alveolar spaces and can impair gas exchange; moreover, mucous plugs obstruct the bronchial lumen and increase airway resistance (46, 48).
Several studies have established active sodium transport as the
primary mechanism driving alveolar liquid clearance (ALC) in the normal
lung (11, 12, 35). Sodium transport is regulated through
amiloride-sensitive sodium channels on alveolar type II cells on the
apical surface and the Na-K-ATPase on the basolateral surface. The
functionality of this transport is critical for the resolution of
alveolar edema in humans (22). In hydrostatic edema and
acute respiratory distress syndrome, preservation of alveolar fluid
clearance is associated with better oxygenation and a lower hospital
mortality (43, 44). Restoration or enhancement of alveolar
fluid clearance was described in various pathological conditions, such
as septic and hemorrhagic shock (20, 32) or lung bacterial
infections (32, 40). However, to our knowledge, this
parameter has not yet been assessed in asthma. As severe asthma
associates alveolar edema and distal airway dysfunction, the aim of
this study was to evaluate epithelial and endothelial permeability as
well as alveolar fluid movement in a model of chronic allergic
inflammation in Brown-Norway rats sensitized to ovalbumin (OA). To do
so, 1) we decided to study alveolar fluid movement and
permeability in a chronic allergic bronchial inflammation model; and
2) to focus on the potential mechanisms hypothesizing that
either a tumor necrosis factor (TNF)- or a catecholamine factor
could be involved in the increase of alveolar fluid movements, we,
therefore, used anti-TNF-
antibodies and propranolol. Our results show the crucial role of TNF-
in lung fluid balance after allergic challenge.
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MATERIALS AND METHODS |
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Animals
Specific pathogen-free male Brown-Norway rats (250-320 g) were purchased from IFFA CREDO, France. Rats were housed in the Lille Pasteur Institute Animal Care Facility and allowed food and water ad libitum. All experiments were performed with the approval of the Lille Institutional Animal Care and Use Committee. Fifty-eight rats were used for all of the experiments.Immunization
Rats were actively immunized to OA. On the first and the fifteenth days, rats were injected intraperitoneally with 10 µg of OA dissolved in sterile isotonic saline. Simultaneously, an adjuvant was injected (0.5 ml of 1.5 × 1010 heat-killed bordetella pertussis organisms and 1 mg of Al2O3, Vaxicoq absorbé; Institut Mérieux, Lyon, France) (18). Control (C) animals were injected on days 1 and 15 with 0.5 ml of sterile isotonic saline.OA solution was prepared with endotoxin-free PBS buffer and then detoxified by passage through a detoxi-gel column (Pierce). This concentrated solution was used for both immunization and nebulization. Endotoxin contamination was checked by using the Limulus amoebocyte lysate test (E-Toxate, Sigma Chemical). No endotoxin was detected in the detoxified OA solution.
Exposure to OA
Animals were exposed to aerosolized OA or sterile saline in an inhalation chamber. The concentration of OA was 1% (weight for volume). The aerosol was generated into the chamber with an ultrasonic nebulizer (Pariboy, Starnberg, Germany). According to its characteristics, the nebulizer produced particles with a diameter from 5 to 0.5 µm. The output of the nebulizer was 2.7 ml/min. The aerosol was generated over a period of 20 min (18). Rats were exposed to aerosolized OA for the first time at day 21 (6 days after the last OA intraperitoneal injection). They received a total of six OA nebulizations (or sterile saline for C animals) (on days 21, 25, 29, 33, 37, and 41).Measurement of OA-specific IgE
An RIA assay with murine monoclonal anti-rat IgE antibodies was used. Anti-rat IgE antibodies were coupled to a solid phase. The solid phase (sepharose-anti-IgE) was washed with the RIA buffer and diluted to a concentration of 1 mg/ml. Of this diluted sepharose-anti-IgE, 500 µl were added to a test tube, and 50 µl of the serum dilution were added, followed by 50 µl of 125I-labeled OA solution. Tubes were incubated for 12 h and washed, and finally sepharose-bound remaining radioactivity was counted. Results are expressed in nanograms of OA bound to IgE per milliliter of fluid.Histopathology
Lung and bronchial samples from each group were analyzed. The sample was fixed in formaldehyde and embedded in paraffin. Paraffin sections were stained with hematoxylin and eosin for analysis of inflammatory cells. Cells were counted (eosinophils, neutrophils, and mononuclear cells) by two independent observers and expressed by high-power field (×100). Four fields, preferentially selected on peribronchial, peribronchiolar, and perivascular areas, were evaluated for each section.In Vivo Measurement of ALC
Lung barrier function studies.
surgical preparation and ventilation.
Rats were anesthetized with pentobarbital (Sanofi, Libourne, France). A
catheter (PE-50) was inserted into the left carotid artery to monitor
systemic arterial pressure and obtain blood samples. Pancuronium
bromide (0.3 mg · kg1 · h
1
iv) was given to achieve neuromuscular blockade. An endotracheal tube
(PE-220) was inserted through a tracheostomy. The rats were ventilated
with a constant-volume pump (Harvard Apparatus, South Natick, MA) with
an inspired O2 fraction of 1.0, peak airway pressures of
8-12 cmH2O, and a positive end-expiratory pressure of
2 cmH2O.
General protocol. For all experiments, the following general protocol was used (24, 40). After the surgical preparation, heart rate and blood pressure were allowed to stabilize for 1 h. The rat was then placed in the left lateral decubitus position (to facilitate liquid deposition into the left lung).
To calculate the flux of plasma protein into the lung interstitium, a vascular tracer, 1 µCi of 131I-labeled human albumin, was injected into the bloodstream. 131I-labeled human serum albumin was prepared in our institution according to a standardized technique (16). To calculate the flux of protein from the air spaces into the circulating plasma, 3 ml/kg of the 5% bovine albumin solution with 1 µCi of 125I-albumin were instilled 30 min later into the left lung over a 2-min period by using a 1-ml syringe and polypropylene tube (0.5 mm ID). One hour after the beginning of the alveolar instillation, the abdomen was opened, and the rat was exsanguinated. Urine was sampled for radioactivity counts. The lungs were removed through a sternotomy. Fluid from the distal air spaces was obtained by passing a propylene tube (0.5 mm ID) into a wedged position in the left lower lobe, and total protein concentration and radioactivity of the liquid sampled were measured. Right and left lungs were homogenized separately for water-to-dry weight ratio measurements and radioactivity counts.Measurements. hemodynamics, pulmonary gas exchange, and protein concentration. Systemic arterial pressure and airway pressures were monitored continuously. Arterial blood gases were measured at 1-h intervals. The arterial PO2 was used to quantify the oxygenation deficit (25, 31). Samples from instillated protein solution, from final distal air space fluid, and from initial and final blood were collected to measure total protein concentration with an automated analyzer (Hitachi 917).
ALBUMIN FLUX ACROSS ENDOTHELIAL AND EPITHELIAL BARRIERS. Two different methods were used to measure the flux of albumin across the lung endothelial and epithelial barriers. The first method measures residual 125I-albumin (alveolar protein tracer) in the lungs and accumulation of 125I-albumin in plasma. The second method measures 131I-albumin (vascular protein tracer) in the lung extravascular spaces (24, 40). The first method requires measurement of the total quantity of 125I-albumin (alveolar protein tracer) instilled into the lung. This value was determined by measuring duplicate samples of the instilled solution for total radioactivity counts (counts · minExperimental Protocols
The following experimental groups were studied (6). Group C rats received an intraperitoneal injection of sterile saline (as a control for OA immunization), were challenged by sterile saline, and were analyzed on day 43 (n = 5). Group Se rats were immunized with OA, challenged with sterile saline, and analyzed on day 43 (n = 5). Group OA rats were immunized and challenged with OA and analyzed on day 43 (n = 6). Group TOA rats were immunized and challenged with OA and analyzed on day 43, with inhibition test by anti-TNF-In vivo studies to evaluate lung fluid transport and permeability of the alveolocapillary barrier to proteins were performed on each of the six described groups. These measurements were obtained 24 h after the last nebulization in the four groups. Pathological analysis and bronchoalveolar lavage were obtained with the same timing.
Statistical Analysis
Results are presented as means ± SE. Data were analyzed by using the Kruskal-Wallis test and the Mann-Whitney test. P values < 0.05 were regarded as statistically significant. ![]() |
RESULTS |
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The Sensitization Protocol Increases Specific IgE Levels in the OA Group
No OA-specific IgE was detected in the C group. In the Se group, only small amounts of specific IgE were detected (12.6 ± 4.2 ng OA bound/ml). In the OA group, the level was 170.6 ± 35.8 ng OA bound/ml, thus demonstrating that these rats were actively sensitized to OA.Histological Findings Confirm the Inflammatory Process
Lung histology showed an infiltrate of eosinophils, neutrophils, and mononuclear cells in the OA group. Inflammatory cells were preferentially located in perivascular, peribronchial, and peribronchiolar areas; a similar infiltrate was observed in distal airways.A marked edema in the interstitial tissue was preferentially located in
peribronchial, peribronchiolar, and perivascular areas; this
observation was consistent with the increase of lung wet-to-dry weight
ratio that we report in the next section (Fig.
1). Increased airway wall thickness was
also observed in the OA group. No significant change was observed in
the Se group compared with the C group (Table
1).
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Alveolar-Capillary Barrier Permeability Is Increased After OA Sensitization
Evaluation of epithelial as well as endothelial barrier permeability showed a statistically significant increase of these two parameters. Endothelial permeability was assessed with the leak of the vascular tracer 131I-radiolabeled albumin, expressed as the ratio of radioactivity obtained in the lung aspirate compared with the plasma activity. OA sensitization increased this ratio from 0.08 ± 0.01 in the C group to 0.19 ± 0.03 in the OA group. Similarly, the leak of the alveolar marker, 125I-radiolabeled albumin, was also increased in the OA group compared with the C group, which is consistent with an increase in the epithelial permeability. These results are shown in Fig. 2. Alveolar barrier permeability was not improved after anti-TNF-
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Lung Fluid Movements Are Increased After OA Sensitization Compared
with C Groups by a TNF--dependent Mechanism
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DISCUSSION |
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To date, the analysis of allergic bronchial inflammation has
mainly been focused on cellular events and cytokine release; our
results on permeability and lung fluid movement provide an opportunity
to observe another chain of events in the allergic reaction in rats
sensitized to OA. Consistent with previous studies, histological
findings evidence an infiltration with inflammatory cells and a marked
interstitial edema. In these animals, sensitized and challenged with
OA, there is an increase in alveolar fluid movement with an increased
vascular and epithelial permeability. The mechanism of increased
alveolar fluid movement was mediated by a TNF--dependent mechanism
and was independent of endogenous catecholamine release. These changes
may represent an adaptive response of the lung to such an injury, which
may be, as we will discuss, beneficial as well as deleterious.
Brown Norway rats sensitized to OA are a well-recognized model for the study of early and late allergic inflammatory response (5, 28, 33, 38). This model of chronic allergic inflammation mimics severe asthma (18); in fact, repeated OA challenges, compared with a single exposition, are associated with a marked increase in the inflammatory cell infiltrate (eosinophils and neutrophils). In the present study, the experimental protocol was performed within 24 h after the last challenge, consistent with the fact that the late phase after antigen challenge starts at 4 h and ends by the 24th h (1). In our work, we evaluated the chronic inflammation rather than the effect of an isolated challenge. We observed an increase in plasma-specific IgE. Consistent with those systemic markers of an allergic process, lung pathological analysis confirmed that this protocol of repeated allergen challenge induced a marked eosinophil and neutrophil recruitment, mainly on peribronchiolar and perivascular areas. From these elements establishing the adequacy of the model, we decided to focus our study on alveolar capillary barrier permeability and lung fluid movements.
Mediators derived from neuronal, humoral, or cellular sources implicated in the endothelial and epithelial permeability increase in asthma are numerous: histamine, cysteinyl leukotrienes, and eosinophil products (7, 23, 27). Our results show an increase in both epithelial and endothelial permeability assessed by the leak of both radiolabeled markers and suggest an involvement of the alveoli in asthmatic disease. Although asthma is usually considered a bronchial disease, it was recently shown that distal airways and parenchyma were also involved, particularly in severe and nocturnal asthma (3, 4, 19); functional tests also showed a contribution of distal lung units (42, 45). Transbronchial biopsies performed in asthmatic patients showed inflammation of alveolar tissues associated with an influx of eosinophils and macrophages. The presence of distal lung inflammation contributes to the increase of peripheral tissue resistance, particularly implicated in nocturnal asthma (19). Hamid et al. (15) reported the presence of a more severe inflammatory process in peripheral compared with central airways of patients with asthma, showing that small airways are a major site of obstruction. Our group and others have also demonstrated an activation of alveolar macrophages in upper and lower airways (13, 14, 41). All of these events could, therefore, be responsible for the increase in permeability observed in our study. Associated with this alteration of the alveoli-capillary barrier, major changes in lung fluid movements were also observed.
Several studies have established active sodium transport as the primary
mechanism driving ALC in the normal lung (12, 35). The
maintenance of this active transport is critical for the resolution of
alveolar edema in humans (22). In hydrostatic edema and
acute lung injury, preservation of alveolar fluid clearance is
associated with better oxygenation and lower hospital mortality
(39, 44). Alveolar type II cells are responsible for net
vectorial sodium transport from the alveolar to the interstitial side
of the alveolar epithelial barrier (10-12). In our
study, the increase in F/I of alveolar protein in the OA group compared
with the C group represents a good argument to suggest that alveolar
spaces, and particularly alveolar type II cells, are involved in the
bronchial allergic inflammation. Alveolar fluid clearance is regulated
by catecholamine-dependent and -independent mechanisms (17,
32). Endogenous catecholamines stimulate the resorption of fetal
lung fluid from the air spaces of the lung (8, 26). In the
present work, we tried to determine whether the observed increase in
ALC was related to an increase in endogenous catecholamine production.
To test this hypothesis, we administered locally, within the
instillate, propranolol, a -antagonist. Coadministration of
propranolol did not inhibit the increase in alveolar fluid movement;
F/I remained unchanged. From these results, we conclude that
catecholamine-independent mechanisms may be responsible for this
increase. Some mediators, such as growth factors (epidermal growth
factor, transforming growth factor, keratinocyte growth factor)
(9, 43) or TNF-
(2, 34), have the potency
to modulate alveolar fluid movement. TNF-
is a key mediator and,
therefore, a good candidate in the inflammatory process. We looked for
a potential role of TNF-
in our model; to do so, we used specific
neutralizing antibodies added in the instillate. We observed a decrease
in alveolar fluid movement, confirming, in our model, a
TNF-
-dependent mechanism. As previously reported by Escott et al.
(6), using the same model of allergic inflammation in
Brown Norway rats, TNF-
is released in the alveoli after an allergen
challenge. In humans, previous results reported an increase in alveolar
macrophage TNF release after IgE stimulation (13, 14). In
status asthmaticus, it has also been shown that the proinflammatory
activity of the bronchial lavage could be related to an increase in
TNF-
detected at a high level in bronchial lavage (37).
In this study, we show the association of a permeability and an alveolar fluid movement increase in sensitized animals. In asthma, plasma protein leakage occurs during both phases of the inflammatory response to antigen (28) and could, therefore, compromise epithelium integrity (30). Accumulation of plasma proteins mixed with mucus and inflammatory and epithelial cells may also promote viscid luminal plug formation of exudate. The presence of viscid luminal plugs is implicated in severe asthma and was described in necropsic studies of patients dead from status asthmaticus (3). We can, therefore, speculate that, in the context of an increased permeability of the barrier to proteins, the increase in alveolar fluid movement may promote the formation of the plugs. This hypothesis needs, however, to be further investigated.
In conclusion, in our model, we observed an increase in both epithelial
and endothelial barrier permeability to proteins. Besides these
changes, alveolar liquid movement is increased by a TNF--dependent
mechanism. These changes in lung fluid movement in OA rats in a model
of chronic allergic inflammation could be responsible for a modulation
of airway obstruction. Further investigations are necessary to identify
the clinical and functional consequences of these experiments,
particularly if it seems adequate to improve fluid resolution during
severe asthma.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Michael Matthay and Johan Kips for all of the help and support provided in the elaboration of this work. We are also very grateful to Xavier Marchandise, Madelaine Tassin, Pascal Briche, and Nathalie Zenani for daily encouragement. Claude Chopin and the EA2689 team allowed us to manage and improve our studies. Patrice Fialdes and Thierry Prangère helped with the radioactive tracers.
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. P. Guery, Service de Réanimation Médicale et Maladies Infectieuses, Soins intensifs de Cardiologie, Centre Hospitalier de Tourcoing, 135 Rue du Pdt Coty, 59208 Tourcoing, France (E-mail: bguery{at}invivo.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
August 9, 2002;10.1152/ajplung.00147.2002
Received 13 May 2002; accepted in final form 3 August 2002.
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