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Abstract |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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To study the mechanisms contributing to the recruitment of a selective leukocyte subset in allergic inflammation involving the airways as may occur in asthma, we examined whether allergic exposure induces the
expression of cell adhesion molecules (CAMs) on the bronchial endothelium of passively sensitized human bronchi. Human bronchial tissue obtained from patients undergoing lung cancer surgery was passively sensitized with serum from patients with atopic asthma who were sensitive to house dust mite. We
incubated the tissues for 30, 120, 240, and 480 min in the presence or absence of the dust mite allergen.
The tissues were stained immunohistochemically for intercellular adhesion molecule 1 (ICAM-1), E-selectin, and vascular cell adhesion molecule 1 (VCAM-1). ICAM-1 was constitutively expressed in both the
epithelium and endothelium in all tissues but after allergen stimulation significantly increased at 240 and
480 min. E-selectin expression also existed constitutively and increased significantly at 120 and 240 min with
allergen exposure. The constitutive expression of VCAM-1 was less than that of ICAM-1 and E-selectin.
Following allergen exposure, VCAM-1 expression increased significantly at 30, 120, 240, and 480 min,
and at 480 min reached an almost 3.5-fold increase from baseline expression. The TNF-
level in the supernatants significantly increased at 120 min after allergen stimulation, and the interleukin (IL)-1
level
increased in 4 of 15 samples. We also examined the induction of CAMs by TNF-, IL-1, and IL-4 on human bronchial tissue. TNF- and IL-1 increased the expression of ICAM-1, E-selectin, and VCAM-1,
whereas IL-4 induced only that of VCAM-1. In addition, neutralizing antibody against TNF- and IL-1
partially blocked the upregulation of CAMs on passively sensitized bronchial tissue after allergen exposure. Thus, both an IgE-dependent allergic response and selected cytokines are able to upregulate endothelial CAMs in human bronchial tissue. These observations provide further evidence that leukocyte infiltration into the site of allergic inflammation as occurs in atopic asthma is in part regulated by the expression
of ICAM-1, VCAM-1, and E-selectin.
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Introduction |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Bronchial asthma has been recognized as a disease resulting from chronic airway inflammation characteristically involving tissue eosinophilia (1). However, the mechanisms involved in eosinophil recruitment to the inflamed tissue are not well understood.
Vascular endothelial cell adhesion molecules (CAMs)
are now regarded as important contributors to the migration of leukocytes into inflamed tissue (2). Representative CAMs include intercellular cell adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1),
and E-selectin. ICAM-1 is the first adhesion molecule reported to be involved in the inflammatory response of
asthma (3). It is the ligand for the lymphocyte function-
associated antigen (LFA-1) and Mac-1, which are present on
various types of leukocytes. ICAM-1 is constitutively expressed on endothelial and epithelial cells in subjects with
and without asthma (4). Montefort and coworkers demonstrated that ICAM-1 is upregulated on the bronchial vascular endothelium 6 h after bronchial allergen challenge in
allergen-sensitized patients with asthma (5). VCAM-1 is
the ligand for very late activation antigen (VLA-4). Because VLA-4 is present on eosinophils but not on neutrophils (6, 7), interaction between VCAM-1 and VLA-4 is
thought to be important for selective eosinophil recruitment into the allergic inflammatory site. In some animal
models of asthma, a blocking anti-VLA-4 antibody prevents bronchial hyperreactivity and cellular infiltration (8,
9). Ohkawara and coworkers have demonstrated that
VCAM-1 is markedly upregulated on the human bronchial vascular endothelium of subjects with asthma who
have air flow limitation, when compared with subjects
without asthma (10). E-selectin is recognized to contribute
mainly in the early, "rolling" process of leukocyte adhesion to the endothelium. The glycoprotein, sialyl Lewis X,
expressed on various types of leukocytes, is a ligand for
E-selectin. E-selectin is described to be upregulated 6 h after bronchial allergen challenge (5). The expression of
CAMs is thought to be modulated by cytokines such as interleukin-1 (IL-1), IL-4, tumor necrosis factor (TNF-),
and IL-13 (11, 12).
Although these CAMs could play important roles in
leukocyte recruitment to the site of allergic inflammation,
the time course and the nature of their expression in relation to the disease are still controversial. Many investigators have studied the expression of adhesion molecules using human umbilical venous endothelial cells (HUVECs),
but the time courses of adhesion molecule expression in
the early events of the allergic response involving human
bronchial vascular endothelium are less well known. In
this study, we have investigated the expression of ICAM-1,
E-selectin, and VCAM-1 together with the release and effects of cytokines, as early events of allergic response in
passively sensitized human bronchus in vitro. We have also
studied the expression of the CAMs on the endothelium in
the human bronchus stimulated directly with TNF-, IL-1, and IL-4.
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Materials and Methods |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Tissue Preparation
Human bronchial tissue was obtained from 29 patients (19 males, 10 females; 18 smokers, 11 nonsmokers) undergoing surgery for lung cancer. They had no history of allergic diseases, including bronchial asthma, and their pulmonary functions (vital capacity and forced expiratory volume in 1 s) were within normal limits. Their ages ranged from 38 to 83 yr (mean age, 65.1 yr). Immediately after the lung or lobe was resected, the tissues were placed in Krebs- Henseleit solution. Airway segments from the third- and fourth-generation bronchi were cut into 5-mm lengths as bronchial rings. All tissues were prepared within 2 h after the resection. To observe the constitutive expression of CAMs, one bronchial ring from each patient was embedded in ornithine carbamyl transferase (O.C.T.) embedding medium (Miles, Elkhart, IN) and snap-frozen in liquid nitrogen immediately after its preparation.
Passive Sensitization
The tissues were sensitized passively according to a previously described method (13). Briefly, after three washes in Krebs-Henseleit solution, the bronchial tissue fragments were incubated for 1 h at 25°C with the serum from patients with atopic asthma whose IgE against house dust mites was strongly positive. After incubation with the serum, the tissues were washed three times in RPMI 1640 medium.
Stimulation of Bronchial Tissue with Allergen
The passively sensitized bronchial tissues were placed in a
24-well tissue culture plate (Becton Dickinson Labware,
Oxnard, CA) and incubated in 1 ml RPMI 1640 supplemented with 250 U/ml penicillin, 250 µg/ml streptomycin,
and 250 µg/ml amphotericin B, containing a final concentration of 0.1% house dust extract allergen (Torii Pharmaceutical, Tokyo) at 37°C under 95% oxygen and 5% carbon dioxide. Because, in a previous study, we could not
find a dose-related bronchial contraction in response to
the added house dust mite extract in passively sensitized
human bronchus, we used a concentration of allergen that
produced a maximal contraction of the smooth muscle
(13). As the control, passively sensitized tissues from each
patient were incubated without allergen. The tissues were
taken out of the culture plate at 30, 120, 240, and 480 min
after the incubation was started. Each tissue was placed in
O.C.T. embedding medium, snap-frozen in liquid nitrogen, and stored at 
80°C until cryostat sectioning.
Measurement of Cytokines in the Supernatants
Two pairs of generation- and size-matched bronchial tissues were obtained from 15 patients. They were passively
sensitized as described previously, and subsequently incubated with or without allergen. The culture supernatants
were collected at 30 and 120 min after the stimulation with
allergen, and were stored at 80°C until use. TNF-, IL-1, and IL-4 measurements of the supernatants were performed by using an enzyme-linked immunosorbent assay
(ELISA; R&D Systems, Minneapolis, MN). Minimum detection levels of TNF-, IL-1, and IL-4 are 4.4, 1.0, and
4.1 pg/ml, respectively.
Stimulation of Bronchial Tissue with Cytokines
After the preparation of the bronchial rings, the tissues
were rinsed three times in RPMI 1640 without passive sensitization. The tissues were then placed in a 24-well tissue
culture plate and incubated at 37°C under 95% oxygen
and 5% carbon dioxide in RPMI 1640 supplemented with
antibiotics as described previously. Each well contained
10, 102, 103, and 104 U/ml recombinant human TNF-
(Genzyme, Cambridge, MA); 0.01, 0.1, 1.0, and 10 ng/ml
recombinant human IL-1 (Genzyme); and 0.1, 1.0, 10, and 100 ng/ml recombinant human IL-4 (R&D Systems). As the control, tissues from each patient were incubated
in parallel in the absence of cytokines. After incubation
for 240 min, the tissues were placed in O.C.T. embedding
medium, snap-frozen in liquid nitrogen, and stored at
80°C until cryostat sectioning. Because the expression of
ICAM-1, E-selectin, and VCAM-1 induced by stimulation
with allergen reached a plateau at 240 min after the addition of the allergen, we chose 240 min as the optimal time
of experiment.
Immunohistochemical Staining
The frozen tissues were cut 6 µm thick and five serial sections were placed on microscope slides. The slides were air-dried for 1 h, fixed in cold acetone for 10 min, and then air-dried again for 1 h. Endogenous peroxidase was blocked using a solution of 0.1% sodium azide and 0.3% hydrogen peroxide, and the slides were rinsed three times in phosphate-buffered saline (PBS). PBS containing 10% normal goat serum was applied to block nonspecific reactions, followed by a primary antibody. The slides were then incubated at room temperature for 1 h. The primary antibodies used and their sources of origin are shown in Table 1. After rinsing the sections, peroxidase-conjugated anti-mouse IgG (Biodesign, Kennebunk, MA) or peroxidase-conjugated anti-rabbit IgG (Biodesign) was applied for 1 h. After another rinsing in PBS, 3,3'-diaminobenzidine (Dojin, Kumamoto, Japan) was used as a substrate to develop a peroxidase-dependent brown color reaction. The slides were counterstained with Mayer's hematoxylin.
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Microscopic Assessment and Quantification of Immunostaining
The stained sections were examined with a VANOX AHBS3 microscope (Olympus, Tokyo). Counting of stained sections was initially undertaken by an observer who did not have prior knowledge of either the stimulus or the time of incubation. The number of positively stained vessels for each antibody against ICAM-1, E-selectin, or VCAM-1 in the lamina propria was counted. To quantify the expression of CAMs on the endothelium, we have used a modified technique of Montefort and coworkers (5). Briefly, blood vessels were stained with an antibody specific to the von Willebrand factor (A082) that is contained in vascular endothelial cells. The number of vessels present in the section stained with A082 was taken as the full complement of vessels in this section. The number of vessels on the serial section that positively stained for specific adhesion molecules was expressed as a percentage of the total vessel population. Because ICAM-1-positive staining was observed not only on vascular components, but also on mononuclear cells in the lamina propria and the bronchial epithelium, we counted the vessels positively stained for ICAM-1 on the basis of their morphology.
In nonsensitized bronchial tissue, the house dust mite extract did not itself induce increased CAM expression (data not shown).
Effect of Neutralizing Antibodies against Cytokines on CAM Upregulation after Allergen Stimulation
To study the roles of cytokines in inducing CAM expression in the allergic reaction, we examined the effect of
neutralizing antibodies against cytokines on CAM expression induced by allergic stimulation. The passively sensitized bronchial tissues were incubated with neutralizing
polyclonal antibodies against human TNF-, IL-1, and/or
IL-4 (Genzyme), or normal rabbit immunoglobulin (as
control), for 180 min. Because we could not know the optimal concentration of each antibody for tissue culture, we
used the highest doses we could prepare (2% as final concentration for all antibodies). After adding house dust extract allergen to the tissues, we further incubated the tissues for 240 min. In parallel, we also incubated tissues
without any of the antibodies in the absence of allergen to
observe the baseline expression of CAMs. Because the expression of ICAM-1, E-selectin, and VCAM-1 induced by
stimulation with allergen reached their plateaus at 240 min
after the addition of the allergen, we chose 240 min as the
optimal time. Immunohistochemical staining for CAMs
and quantification were performed as described previously.
Statistical Analysis
Data are expressed as mean ± SEM. A paired t test was used to analyze statistical differences. P < 0.05 was taken to be significant.
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Results |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Levels of Cytokines in the Supernatants
At 30 min after allergen stimulation, none of the chosen
cytokines was detected in any supernatant. At 120 min after allergen stimulation, TNF- increased in 13 of 15 supernatants, and for the group the increase was significant
when compared with the control (93.5 ± 15.1 versus 48.7 ± 7.86 pg/ml, P = 0.002; Figure 1). At 120 min after allergen
stimulation, supernatant levels of IL-1 increased in 4 of
15 supernatants, but the increase failed to achieve significance when compared with the control (0.750 ± 0.357 versus 0 ± 0 pg/ml, P = 0.054; Figure 1). IL-4 was not detected in any of the samples.
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Constitutive Expression of ICAM-1, E-Selectin, and VCAM-1
Immunostaining of the untreated human bronchus revealed constitutive expression of ICAM-1 and E-selectin on microvessels in the lamina propria. ICAM-1 expression was also observed on submucosal mononuclear cells and the bronchial epithelia, predominantly on the basal layer. Expression of E-selectin and VCAM-1 was not observed on the extravascular cells. Constitutive VCAM-1 expression was also observed on the microvessels, but it was less than that of either ICAM-1 or E-selectin. The percentages of vessels positively stained for the presence of ICAM-1, E-selectin, and VCAM-1 in the lamina propria were 56.4 ± 5.4%, 19.7 ± 2.9%, and 10.4 ± 7.9%, respectively (Figures 2a, 2b and 2c).
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ICAM-1 Expression after Stimulation with Allergen
Stimulation of the tissues with allergen significantly increased ICAM-1 expression on the vessels at 240 and 480 min after exposure when compared with the control (Figures 2 and 3).
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E-Selectin Expression after Stimulation with Allergen
Stimulation of the tissues with allergen significantly increased E-selectin expression on the vessels at 120 and 240 min after exposure when compared with the control (Figures 2 and 4). E-selectin expression peaked at 240 min, then decreased close to that of the control at 480 min.
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VCAM-1 Expression after Stimulation with Allergen
Stimulation of the tissues with allergen significantly increased VCAM-1 expression on the vessels at 30, 120, 240, and 480 min after exposure when compared with the control (Figures 2 and 5). VCAM-1 expression increased rapidly during the first 120 min, then more gradually. By 480 min, postchallenge VCAM-1 reached an almost 3.5-fold increase over the control level of expression in the control explants.
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ICAM-1, E-Selectin, and VCAM-1 Expression Induced
by TNF-, IL-1, and IL-4
Immunostaining for ICAM-1 and E-selectin on the vessels
was significantly induced by recombinant TNF- and IL-1 in a dose-dependent manner, but not by IL-4 at any
concentration used (Figures 6 and 7). VCAM-1 expression
on the vessels was induced by recombinant TNF-, IL-1,
and IL-4 in a dose-dependent manner (Figure 8). Thus,
TNF- and IL-1 induced the expression of ICAM-1,
E-selectin, and VCAM-1, whereas IL-4 induced the expression only of VCAM-1 on the bronchial endothelium.
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Inhibition of CAM Expression by Neutralizing Antibody against Cytokines
In the tissues incubated with normal rabbit immunoglobulin, expression of ICAM-1, E-selectin, and VCAM-1 increased after allergen stimulation when compared with
baseline (data not shown). This increase from the baseline
expression was taken as 100% in each experiment. Antibodies against human IL-1 (anti-IL-1) significantly reduced ICAM-1, E-selectin, and VCAM-1 upregulation induced by allergen exposure (Figures 9-11). Anti-TNF-
significantly reduced ICAM-1 upregulation after allergen
stimulation. Anti-IL-4 reduced VCAM-1 upregulation
(73% of control increase), but this was not statistically significant (P = 0.059).
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Discussion |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The passively sensitized human bronchus has often been used as a model of bronchoconstriction in atopic asthma (13). In this study, we have employed this model to investigate the initial event of allergic inflammation immediately after allergen exposure by observing the time course of adhesion molecule expression.
In the present study, we have found that an allergic tissue response involving IgE induced expression of adhesion molecules ICAM-1, E-selectin, and VCAM-1 in bronchial vessels in the passively sensitized human bronchus.
We also found that TNF- increased in the supernatant of
the bronchial tissues after allergen stimulation and that
IL-1 increased in 4 of 15 supernatants. In addition, adhesion molecule upregulation induced by allergen was
in part blocked by neutralizing antibodies against TNF-
and IL-1. Furthermore, we have shown that recombinant
TNF- and IL-1 induced the vascular expression of
ICAM-1, E-selectin, and VCAM-1, whereas for IL-4 this
was restricted to VCAM-1 alone.
The constitutive expression of CAMs in this study was similar to that reported in other studies (5, 14). ICAM-1 is known to be expressed on several types of cells, including macrophages, fibroblasts, epithelial cells, lymphocytes, and follicular reticulum dendritic cells (15, 16). Because constitutive ICAM-1 was expressed in the extravascular components, we evaluated the expression of ICAM-1 on the bronchial vessels as a proportion of the total vessel complement identified by immunostaining for von Willebrand factor.
ICAM-1 expression significantly increased at 240 and 480 min after stimulation with allergen when compared with the control. This upregulation in vitro was induced more rapidly than reported previously in patients who received bronchial biopsy at 6 h after endobronchial allergen challenge (5). E-selectin expression significantly increased at 120 and 240 min after stimulation with allergen when compared with the control. This expression increased rapidly during the first 120 min, reached a plateau at 240 min, and then decreased slightly at 480 min. A previous study shows that upregulation of E-selectin is rapid but transient in HUVECs stimulated by IL-1 (12), a view supported by our own findings in bronchial blood vessels when exposed to allergen.
VCAM-1 expression increased rapidly over the first 120 min, and gradually thereafter until 480 min after stimulation with allergen, reaching an almost 3.5-fold increase over the baseline expression. VCAM-1 is markedly upregulated in the bronchial tissue of asthmatic patients with an air flow limitation (10), and in nasal tissue 24 h after allergen challenge in patients with allergic rhinitis (17). Our results add to these findings. Because VLA-4, the counterligand for VCAM-1, is present on eosinophils but not on neutrophils (6, 7), VCAM-1 is thought to be important for eosinophil recruitment into the site of allergic inflammations such as asthma. Thus, we suggest that, after bronchial blood vessels are stimulated by substances released from mast cells by the allergic response, E-selectin is expressed first, followed by VCAM-1 and finally ICAM-1.
There are discrepancies among the studies of the expression of CAMs in the bronchus in asthmatics. For example, Montefort and coworkers demonstrated that, in
the bronchi of patients with mild asthma at 5 to 6 h after
bronchial allergen challenge, expression of ICAM-1 and
E-selection, but not VCAM-1, was upregulated (5). In
contrast, Fukuda and coworkers showed that the expression of VCAM-1 was upregulated but those of ICAM-1
and E-selectin were not in patients with asthma who received oral or inhaled stimulant and/or theophylline
(18). Ohkawara and coworkers demonstrated that expression of ICAM-1, E-selectin, and VCAM-1 was upregulated in basically corticosteroid-dependent patients with
asthma (10). Taken together, we speculate that a graded
response may exist, in which patients with severe, chronic
asthma as reported by Ohkawara and coworkers express
ICAM-1, E-selectin, and VCAM-1; patients with moderate, chronic asthma as reported by Fukuda and coworkers express only VCAM-1; and patients with mild and acutely
induced asthma as reported by Montefort and coworkers
express ICAM-1 and E-selectin. In our study, allergic response caused the expression of ICAM-1, E-selectin, and
VCAM-1. Because the concentration of allergen used in
this study causes bronchial smooth muscle contraction as
potent as that induced by 10
3 M acetylcholine, i.e., maximal contraction (13), the chemical mediators and cytokines released from mast cells will have reached a maximum, suggesting that stimulation of endothelium may also be maximal. Therefore, we speculate that the discrepancies among studies of CAM expression in the bronchi of
patients with asthma may be due to differences in the intensity of stimulation and/or in the production of cytokines or mediators.
The expression of ICAM-1, E-selectin, and VCAM-1 is
known to be induced by cytokines such as TNF-, IL-1,
IL-4, and IL-13 on HUVECs (11, 12). In the present study,
a significant increase in TNF- was observed in tissue supernatants after stimulation with allergen for 120 min. In
addition, an increase in IL-1 was observed in 4 of 15 supernatants, although this increase was not significant. Because all of the basal IL-1 levels were below the minimum
detection level, we believe that any observed increase in
IL-1 is relevant as a constituent of mediator pool.
In the present study, TNF- and IL-1 induced ICAM-1,
E-selectin, and VCAM-1 expression in human bronchial
vessels, whereas for IL-4 this was restricted to VCAM-1
alone. Allergic stimulation induced ICAM-1, E-selectin,
and VCAM-1 expression and in parallel the release of
TNF- and IL-1. In addition, we showed that neutralizing antibody against TNF- and IL-1 partially blocked
the upregulation of CAMs induced by allergen exposure
in the passively sensitized bronchial vessels. Thus, in the
allergic response described in this model, TNF- and IL-1 may be responsible in large part for CAM expression.
T lymphocytes, mast cells, and macrophages are the
source of these cytokines, such as TNF-, IL-1, and IL-4.
T lymphocytes and mast cells increase in number at allergic inflammatory sites (5). Because the bronchial tissues
that we used did not contain lymphocytes sensitized with
house dust mite allergen, the passively sensitized mast
cells are likely to be the main effectors of CAM upregulation. Bradding and coworkers reported that mast cells release IL-4, IL-5, IL-6, and TNF-, cytokines associated
with allergy-related diseases such as asthma (19). Fukuda
and coworkers demonstrated that VCAM-1 expression increased in bronchial biopsies from patients with asthma
whose IL-4 was detectable in bronchoalveolar lavage fluid
(18). In the present study, we have confirmed that IL-4 induces only VCAM-1. Although we could not find a detectable level of IL-4 in the supernatants of the bronchial tissues stimulated by allergen, a local in situ existence of IL-4
(and/or IL-13) cannot be excluded because of the notable
induction of VCAM-1 that was shown in this study. Anti-IL-4 reduced VCAM-1 upregulation after allergen exposure to 70% of the control, but this was not significant. Because VLA-4, a counterligand for VCAM-1, is present on
eosinophils but not on neutrophils, this increase in
VCAM-1 appears to be consistent with a mechanism for
eosinophil recruitment into the inflamed tissue, and as
others have suggested, may be important for the constitution of allergic inflammation.
In summary, in passively sensitized human bronchial
tissue, an IgE-triggered allergic response induced by allergen upregulated the expression of endothelial adhesion
molecules ICAM-1, E-selectin, and VCAM-1 on the blood
vessels associated with the release of TNF- and, in some
samples, IL-1. This increase in CAM expression was partially blocked by anti-TNF- and anti-IL-1 neutralizing antibodies. In addition, we have shown that recombinant
TNF- and IL-1 induce the increased expression of
ICAM-1, E-selectin, and VCAM-1, whereas IL-4 induces
VCAM-1 expression alone. Although the relationship between CAM expression and the infiltration of leukocytes
cannot be examined in this model, our findings indicate that allergic inflammation in human airways may be modulated by targeting adhesion molecule upregulation.
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Footnotes |
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Address correspondence to: Hirotsugu Kohrogi, M.D., First Department of Internal Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860, Japan.
(Received in original form July 8, 1996 and in revised form April 7, 1997).
Acknowledgments: For their kind cooperation in providing human lung tissues, the authors thank Drs. Yamaguchi, Gotoh, and Ogawa of the Second Department of Surgery, Kumamoto University School of Medicine, Drs. Kiyama and Fujino of Kumamoto Chuoh Hospital, Dr. Yasuo of Kumamoto Minami National Hospital, and Dr. Baba of Kumamoto City Hospital, as well as the entire staff of their department. They also thank Mr. Alan D. Rosen of Kumamoto University for reading the manuscript. Presented in part at the 1996 American Lung Association/American Thoracic Society International Conference. Supported by Scientific Grant-in-Aid for Scientific Research (C) 02670343 and 06670622 from the Ministry of Education, Science and Culture of Japan.
Abbreviations
CAMs, cell adhesion molecules;
HUVECs, human umbilical venous
endothelial cells;
ICAM-1, intercellular cell adhesion molecule 1;
IL-1, interleukin-1;
IL-4, interleukin-4;
IL-13, interleukin-13;
PBS, phosphate-buffered saline;
TNF-, tumor necrosis factor ;
VCAM-1, vascular cell adhesion molecule 1;
VLA-4, very late activation antigen.
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References |
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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