(Chest. 2002;121:354-360.)
© 2002
American College of Chest Physicians
Up-regulation of L-Selectin and E-Selectin in Hypersensitivity Pneumonitis*
Carmen Navarro, MD;
Felipe Mendoza, MSc;
Lourdes Barrera, MSc;
Lourdes Segura-Valdez, PhD;
Miguel Gaxiola, MD;
Ignacio Páramo, MSc and
Moisés Selman, MD, FCCP
*
From the Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, México DF, México.
Correspondence to: Moisés Selman, MD, FCCP, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502; Col. Sección XVI, México DF, CP 14080, México; e-mail: mselman{at}conacyt.mx
 |
Abstract
|
|---|
Background: Selectins are adhesion molecules that
contribute to leukocyte recruitment into the tissue after an injury.
Hypersensitivity pneumonitis (HP) is a lymphocytic alveolitis, and we
hypothesized that the overexpression of selectins could play a role in
this process.
Patients and measurements: We studied 16
patients with HP and 7 healthy control subjects (HCs). Sera and BAL
selectins and tumor necrosis factor-
were determined by
enzyme-linked immunosorbent assay, and cellular lung localization was
determined by immunohistochemistry. Additionally, BAL L-selectin, and
L-selectin-bearing T-lymphocytes analyzed by flow cytometry were
evaluated in HP patients and in exposed but asymptomatic subjects
(EAS).
Setting: Tertiary referral center and
immunohistochemistry laboratory.
Results: Raised
levels of E-selectin (mean [± SD], 178.9 ± 30.5 vs 59.4 ± 4.7
ng/mL, respectively; p < 0.001) and P-selectin (mean,
232.6 ± 29.9 vs 67.6 ± 14.2 ng/mL, respectively; p < 0.001)
were detected in HP patient sera compared to control subjects, while
L-selectin levels showed no differences between groups.
Conversely, HP patients displayed a significant increase in levels of
L-selectin found in BAL fluid compared with both HCs and EAS
(11.0 ± 1.7 vs 6.9 ± 0.43 and 3.1 ± 0.5 ng/mL, respectively;
p < 0.05). The levels of E-selectin found in BAL fluid were similar
in patients from both groups, and P-selectin was not detected.
Percentage of CD3+CD62 L+ lymphocytes was lower in HP patients compared
with EAS (2.33 ± 0.8 vs 4.31 ± 2.4, respectively; p = 0.05). By
immunohistochemistry, L-selectin was detected in interstitial
macrophages and polymorphonuclear cells, and E-selectin was detected in
endothelial cells.
Conclusion: These findings
demonstrate that L-selectin and E-selectin are up-regulated during the
development of HP, suggesting that they may contribute to the increased
traffic of lung inflammatory cells.
Key Words: allergic alveolitis • hypersensitivity pneumonitis • L-selectin • lymphocytes • selectin gene family • selectins
|
Introduction
|
|---|
The
recruitment of inflammatory cells at the target site is mediated by
interactions between leukocytes and endothelial cells through a group
of cell-surface proteins known as adhesion molecules. So far, the
following three families of adhesion molecules have been described that
share a number of structural, functional, and genetic properties:
the selectin gene family; the Ig supergene family; and the
integrin gene family.1
2
Each group is involved in
different steps of the leukocyte-endothelial cell rolling, tight
adhesion, and migration stages. The most important role of the
selectin family is the rolling of leukocytes along the vessel wall and
the initial adhesion to endothelial cells. These molecules also are
involved in the regulation of cell function.3
Members of
this family include L-selectin expressed on leukocytes, P-selectin
expressed on platelets and endothelial cells, and E-selectin expressed
on endothelial cells. Each of these proteins recognizes and binds to
their carbohydrate ligands. Enzymatic cleavage from the membrane
surface results in the presence of soluble forms in the
circulation.4
Hypersensitivity pneumonitis (HP) represents a group of granulomatous
interstitial lung disorders that are provoked by exposure to a variety
of organic particles.5
The disease is characterized by a
marked influx and accumulation of inflammatory cells, primarily
T-lymphocytes, which play a pivotal pathogenic role.6
However, the mechanisms implicated in the inflammatory cell
recruitment and traffic throughout the lungs in patients with HP are
still unclear. Some chemokines, such as interleukin (IL)-8, and
macrophage inflammatory protein (MIP)- have been shown to be
increased in HP patients.7
8
Several investigators have
found an up-regulation of intercellular adhesion molecule-1, a cell
surface glycoprotein that pertains to the Ig supergene family, on
alveolar macrophages of patients with HP.9
Also, increased
levels of soluble intercellular adhesion molecule-1 in the sera of
these patients have been reported.10
The possible role of the selectin family in HP has not been explored.
E-selectin and L-selectin actively participate in leukocyte/endothelial
cell interactions. The members of the selectin family and the 4
integrins have been shown to mediate the initial contact between
free-flowing leukocytes and the endothelium in
vivo.11
12
Likewise, P-selectin seems to play an
important role for targeting neutrophil migration at endothelial
borders.13
However, the rolling of leukocytes on the
endothelial selectins is not restricted to neutrophils, but it also has
been demonstrated for bovine and human T cells.14
Moreover, it has been demonstrated that the inefficient accumulation of
T lymphocytes in an artificial site of inflammation is related to a
lack of expression of the E-selectin ligand and
L-selectin.15
Since T lymphocytes are a major component of the pulmonary inflammatory
process in patients with HP, the present study was designed to evaluate
the expression of the three members of the selectin family in this
disease. Levels of the soluble forms of selectins were determined in
BAL fluid and serum by enzyme-linked immunosorbent assay (ELISA).
L-selectin-bearing T lymphocytes were evaluated by flow cytometry, and
lung tissue localization was performed by immunohistochemistry. In
addition, we measured levels of tumor necrosis factor (TNF)-, a
cytokine that plays a pivotal role in the expression of specific
endothelial cell adhesion molecules and in the induction of the
transendothelial migration of T lymphocytes.16
|
Materials and Methods
|
|---|
Study Population
Sixteen nonsmoking female patients with subacute/chronic HP
induced by avian antigens (ie, pigeon breeder’s disease),
aged 20 to 54 years (mean [± SD] age, 39.7 ± 2.4 years) were
investigated. The diagnosis was based on a history of antigen exposure,
the typical clinical manifestations of HP, chest radiograph, CT scans,
pulmonary function tests, and BAL fluid features. All patients revealed
positive specific serum antibodies, and the diagnosis was confirmed by
histologic examination.17
As control subjects, we studied
seven healthy volunteers who were nonsmokers (three men and four women;
mean age, 31.1 ± 8.8 years). They were sequentially enrolled,
unrelated, healthy blood donors from the National Institute of
Respiratory Diseases. The Transfusion Department of that
institute serves the geographic area from which the HP patients were
recruited.
For BAL fluid and sera L-selectin measurements, we also included five
asymptomatic subjects who had been exposed (EAS) to avian antigens (two
men and three women; mean age, 25.4 ± 8.4 years). Serum samples were
taken simultaneously from 9 of 16 patients with pigeon breeder’s
disease and the control groups. The study was approved by the Ethics
Committee of the institute, and informed consent was obtained
from each subject.
BAL
BAL samples were obtained by the modification of a previously
described technique.18
One of the subsegmental bronchi of
the middle lobe was lavaged with six 50-mL aliquots of sterile saline
solution. The recovered fluid was measured, strained through a surgical
gauze to remove mucus and debris, and centrifuged at 400g
for 10 min at 4°C. The cell pellet was resuspended in
phosphate-buffered saline solution (PBS) in order to determine total
cell counts and viability by trypan blue exclusion, followed by
Wright-Giemsa staining for differential cell counts. The supernatants
were stored at -70°C until use.
Flow Cytometric Analysis of Surface L-Selectin on BAL Cells
BAL cells (3 x 105) were incubated in
50 µL staining buffer (ie, PBS containing 1% bovine serum
albumin and 0.1% sodium azide) with fluorescein
isothiocyanate-conjugated anti-CD3 monoclonal antibody (Becton
Dickinson; San José, CA) and phycoerythrin-conjugated
anti-L-selectin monoclonal antibody (CD62 L; Becton Dickinson) for 30
min at 4°C. Mouse IgG antibodies of the same isotype and
concentration were used for detection of the nonspecific binding of
antibodies. After two washes, all cells were fixed in 1%
paraformaldehyde. Flow cytometric analysis of cell-surface markers was
performed using a flow cytometer (FACScan; Becton Dickinson) with
CellQuest software (Becton Dickinson).
Determination of L-selectin, P-selectin, E-selectin, and TNF-
Sera and BAL fluid quantification of soluble L-selectin,
P-selectin, E-selectin, and TNF- was performed by using a sensitive
and specific commercial ELISA, following the instructions of the
manufacturer (R&D Systems; Minneapolis, MN).
Immunohistochemistry
Lung tissues obtained by open lung biopsy were formalin-fixed
and paraffin-embedded for conventional light microscopy. Lung sections
from all patients were immunostained for L-selectin, P-selectin, and
E-selectin, as previously described,19
by a
biotin/streptavidin complex technique using a commercial kit
(Vectastain Universal Quick Kit; Vector Laboratories, Inc; Burlingame,
CA). In brief, sections were deparaffinized and hydrated through
xylenes and graded alcohol series, were washed in PBS, and were
incubated in blocking serum for 10 min. Prior to the immune reaction,
antigen retrieval with 0.1 M citrate buffer (pH, 6.0) was performed.
The serum was drained, and sections were incubated with the polyclonal
antibody anti-human E-selectin (R&D Systems) or with monoclonal
antibodies anti-human L-selectin or P-selectin (Zymed Laboratory, Inc;
San Francisco, CA) overnight at 4°C. After three 5-min washes in PBS,
the slides were incubated with biotinylated universal secondary
antibody for 10 min, were washed in PBS, and were incubated with
streptavidin/peroxidase complex for 5 min. Sections were washed in PBS
and were incubated with peroxidase substrate solution until staining
developed. Slides were counterstained with hematoxylin, cleared, and
mounted. Three macroscopic and microscopic healthy lung specimens that
were obtained from lobectomies were used as controls.
Statistical Analysis
All data are expressed as the mean ± SD. Comparisons were made
using a Student’s t test for paired observations. Values of
p < 0.05 were considered to be statistically significant. The
relationships among L-selectin from BAL fluid, TNF- from BAL fluid,
and L-selectin from BAL with BAL lymphocytes were assessed using
Spearman’s correlation coefficient.
|
Results
|
|---|
The baseline characteristics of patients with HP are summarized in
Table 1
. All patients showed clinical and functional evidence of interstitial
lung disease, with variable degrees of dyspnea, reduced lung
capacities, and hypoxemia at rest that worsened during exercise. The
differential cell count in BAL fluid was characterized by a marked
lymphocytosis, usually > 50%, which was significantly higher when
compared with both control groups (Table 2
). Patients were defined as having subacute/chronic HP when they
complained of at least 3 months of persistent symptoms, primarily
progressive dyspnea on exercise. The patients exhibited predominant
ground-glass attenuation on CT scans and a noteworthy increase in BAL
fluid lymphocytes, supporting the presence of active disease. In
addition, a lung biopsy showed diffuse lung inflammation with poorly
formed granulomas that were located mainly in terminal and respiratory
bronchioles, but also in the alveolar walls.
Soluble Selectins in Serum
Figure 1
illustrates E-selectin and P-selectin sera findings. The level of
soluble E-selectin (Fig 1, A)
was measured in the serum of 9
of 16 HP patients and in 7 healthy control subjects (HCs). The HP
patient group displayed a significant increase in serum levels of
E-selectin compared to control subjects (178.9 ± 30.5 vs
59.4 ± 4.7 ng/mL, respectively; p < 0.001). Likewise, serum
levels of soluble P-selectin (Fig 1, B) were significantly
higher in HP patients than in those found in healthy subjects
(232.6 ± 29.9 vs 67.6 ± 14.2 ng/mL; p < 0.001). By contrast,
the level of soluble L-selectin in the HP patient group showed no
significant difference from the control group (1,315.3 ± 160 vs
1,563.6 ± 29.27 ng/mL, respectively). There was no correlation
between serum levels of E-selectin and P-selectin and the number or
type of inflammatory cells found in BAL fluid.
View larger version (12K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1.. Serum levels of soluble E-selectin
(A) and P-selectin (B) in nine HP
patients and seven HCs, measured by ELISA as described in the
"Materials and Methods" section. Values are expressed as the mean
± SD.
|
|
L-Selectin, E-Selectin, and P-Selectin in BAL Fluid
The levels of selectins in BAL fluid were determined in HP
patients, HCs, and EAS subjects. Soluble L-selectin was detected
in the BAL fluid of all 16 HP patients, and the levels were
significantly higher than those in both control groups of EAS
individuals (11.0 ± 1.7 ng/mL vs 6.9 ± 0.43 and 3.1 ± 0.46
ng/mL, respectively; p < 0.05; Fig 2
). By contrast, the levels of soluble E-selectin displayed no
significant differences (data not shown), and soluble P-selectin was
not detected in the BAL fluid of either control group or in the HP
patient group.
View larger version (29K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2.. An increased concentration of soluble L-selectin
was found in the BAL fluid obtained from HP patients compared with HCs
and EAS individuals. The data represent the mean ± SD.
|
|
Additionally, TNF- was only revealed in the BAL fluid of HP patients
(mean level, 1.6 ± 1.4 pg/mL). Although a tendency for correlation
between L-selectin and TNF- levels was suspected because there were
two higher coincident points for both molecules, no significant
correlation was revealed (r = 0.47; p = 0.06).
Flow Cytometric Analysis of Surface L-Selectin in Cells in BAL
Fluid
In addition to soluble L-selectin in BAL fluid, we examined the
expression of this adhesion molecule on the surface of lymphocytes from
BAL fluid in eight HP patients and the five EAS individuals. A marginal
but significant decrease in the percentage of CD3+CD62 L+ lymphocytes
was observed in the HP patients compare to control subjects
(2.33 ± 0.8 vs 4.31 ± 2.4, respectively; p = 0.05). Figure 3
illustrates a representative comparison between a single HP patient and
a single EAS.
View larger version (21K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3.. Flow cytometry dot plots of lymphocytes in BAL
fluid from a representative patient (left) and an EAS
control subject (right). The number in each upper right
quadrant denotes the percentage of CD3+ lymphocytes that were positive
for L-selectin.
|
|
Immunohistochemistry
Tissue from HP patients showed positive signals for E-selectin and
L-selectin, whereas P-selectin was not detected. L-selectin was found
mainly on the surface of interstitial mononuclear cells (Fig 4
, A), primarily macrophages (Fig 4, B
[upper
inset]), and in some polymorphonuclear cells (Fig 4, B
[bottom inset]). E-selectin was expressed in the lungs of HP patients
by endothelial cells primarily from small blood vessels (Fig 4, C)
. Healthy lungs were usually negative for both
selectins, as exemplified for L-selectin in Figure 4, D
.
Control samples incubated with nonimmune sera were negative (Fig 4, E)
.
View larger version (132K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4.. L-selectin and E-selectin immunolocalization in
the lungs of HP patients and HCs. A and
B: lungs of HP patients exhibiting inflammatory cells
immunolabeled for L-selectin (A, original x20;
B, original x40). B: upper
inset, macrophage (original x100); bottom
inset, polymorphonuclear cell (original x100).
C: E-selectin immunoreactive endothelial cells in the
lung of an HP patient (original x20). D: healthy lungs
were usually negative for L-selectin (original x10) and E-selectin
(not shown). E: negative control omitting the primary
antibody (original x20).
|
|
|
Discussion
|
|---|
HP represents a form of T-cell alveolitis provoked by exposure to
a variety of organic particles. Thus, lung histology and the BAL fluid
cell profile typically exhibit increased numbers of activated
lymphocytes with a dominance of CD8+ T cells at the onset of
disease.20
21
However, the mechanisms accounting for the
accumulation of lymphocytes and other inflammatory cells in the lung
parenchyma have not been elucidated. Two different mechanisms appear to
be implicated in this process. A polyclonal and oligoclonal local
T-cell expansion in the pulmonary microenvironment, probably mediated
by the IL-2 system, has been proposed.22
The detection of
the compartmentalization of T cells bearing discrete Vß gene products
in the lungs of HP patients suggests that the proliferation of specific
T-cell subsets probably occurs as a result of local triggering by a
specific antigen.23
Alternatively, increased traffic and the migration of
lymphocytes from the blood to the lung could account for the intense
alveolitis observed in these patients. Usually, this cellular influx to
an injured site is mediated by the production of a number of
chemotactic agents and by the expression of adhesion molecules in
endothelial and inflammatory cells. There is evidence of increased
synthesis of the chemokines IL-8 and MIP-1 in the lungs of HP
patients, which may be implicated in neutrophil chemoattraction and in
macrophage activation.7
Also, MIP-1 appears to attract
CD8+ T lymphocytes, which are pivotal cells in the pathogenesis of
HP.24
The migration of these cells into lung tissue in
response to the stimuli depends on the expression of a variety of
adhesion molecules. Studies of this process in HP are scanty.
The recruitment of inflammatory cells from the bloodstream is a very
rapid process, and selectins represent a class of cell adhesion
molecules that are specialized for this purpose.4
We
hypothesize that these selectins, particularly up-regulated L-selectin,
act as a lymphocyte-homing receptor and play a critical role in the
entry of these cells into inflamed tissues. The results of a recent
study25
suggested that the inhibition of selectin binding
to ligands suppressed the inflammatory response and consequently
reduced the number of lymphocytes in the lung interstitium in
experimental HP induced by Saccaropolyspora rectivirgula. To
date, there are no studies in the human disease.
Our results confirmed an increase of soluble L-selectin in BAL
fluid and an up-regulation in lung tissue in patients with HP. This
selectin is expressed mainly by macrophages but also by
polymorphonuclear cells. Additionally, a low percentage of
L-selectin-bearing T lymphocytes in the BAL fluid of HP patients
compared with EAS HCs was found.
Similar findings recently have been reported26
in
active pulmonary sarcoidosis, which is also a T-lymphocyte
granulomatous alveolitis. Kaseda et al26
showed raised
levels of soluble L-selectin in the BAL fluid of sarcoidosis patients
compared with those in idiopathic pulmonary fibrosis patients and
healthy subjects. However, a lower percentage of L-selectin-positive T
lymphocytes in BAL fluid also was observed, suggesting that the
shedding of L-selectin occurs when T lymphocytes migrate from the
circulation into the lungs of sarcoidosis patients.26
In HP patients, we found that E-selectin and P-selectin in BAL
fluid displayed no differences with the levels found in HCs. The
absence of expression of lung endothelial P-selectin may be due at
least partially to the chronic state of disease in the patients
we studied. P-selectin plays a major role in the early inflammatory
response and is primarily responsible for targeting neutrophil
transmigration at the endothelial borders.13
This member
of the selectin family might be up-regulated in acute cases of HP in
which there is also a noteworthy increase in the number of
neutrophils.27
A small but significant increase in the
number of neutrophils is also observed in patients with
subacute/chronic HP.18
L-selectin also has been implicated
in leukocyte sequestration throughout lung capillaries.28
Conversely, the levels of P-selectin and E-selectin were increased in
the serum of patients with subacute/chronic HP, while L-selectin showed
no increase. These increases in the levels of P-selectin and E-selectin
may reflect endothelial activation. E-selectin was found in the
endothelial cells of small vessels from the tissue of HP patients,
suggesting that E-selectin also may participate in the recruitment of
inflammatory cells from the bloodstream. L-selectin is lost rapidly
from the surface of normal leukocytes after cellular activation,
yielding a soluble fragment. Soluble L-selectin can be detected in the
serum of healthy individuals at high concentrations and may
increase or decrease in certain disease states.4
The
physiologic significance of shedding remains unclear but may be a
mechanism of down-regulating adhesion following firm attachment to the
endothelium,4
or L-selectin may regulate the leukocyte
rolling velocity.29
Finally, although a tendency for correlations among the levels of
soluble L-selectin, the levels of TNF-, and the percentage of
lymphocytes in BAL fluid was observed, the results did not reach
significance, perhaps because of the small number of patients. It is
known that TNF- promotes the adhesion, activation, and migration of
circulating leukocytes by inducing the expression of adhesion molecules
and chemoattractants.30
In summary, our results suggest that during the development of HP there
is an up-regulation of lung L-selectin, which may contribute to the
persistence of lymphocytic inflammation observed in patients with HP
(Fig 5
).
|
Acknowledgements
|
|---|
The authors thank Miss Guadalupe Hiriart
for her excellent technical support.
|
Footnotes
|
|---|
Abbreviations: EAS = exposed but asymptomatic;
ELISA = enzyme-linked immunosorbent assay; HC = healthy control
subject; HP = hypersensitivity pneumonitis; IL = interleukin;
MIP = macrophage inflammatory protein; PBS = phosphate-buffered
saline solution; TNF = tumor necrosis factor
This work was partially support by Conacyt grant No. 127177M.
Received for publication March 15, 2001.
Accepted for publication August 17, 2001.
|
References
|
|---|
-
Frenette, PS, Wagner, DD (1996) Adhesion molecules: part I. N Engl J Med 334,1526-1529[Free Full Text]
-
Frenette, PS, Wagner, DD (1996) Adhesion molecules: part II. Blood vessels and blood cells. N Engl J Med 335,43-45[Free Full Text]
-
Vestweber, D, Blanks, JE (1999) Mechanisms that regulate the function of the selectins and their ligands. Physiol Rev 79,181-213[Abstract/Free Full Text]
-
Kansas, GS (1996) Selectins and their ligands: current concepts and controversies. Blood 88,3259-3287[Free Full Text]
-
Selman M. Hypersensitivity pneumonitis In: Schwarz M, King TE, eds. Interstitial lung disease. Hamilton, ON, Canada: Decker, 1998; 393–422
-
Semenzato, G (1991) Immunology of interstitial lung diseases: cellular events taking place in the lung of sarcoidosis, hypersensitivity pneumonitis and HIV infection. Eur Respir J 4,94-102[Abstract]
-
Denis, M (1995) Proinflammatory cytokines in hypersensitivity pneumonitis. Am J Respir Crit Care Med 151,164-169[Abstract]
-
Sugiyama, Y, Kasahara, T, Mukaida, N, et al (1995) Chemokines in bronchoalveolar lavage fluid in summer-type hypersensitivity pneumonitis. Eur Respir J 8,1084-1090[Abstract]
-
Pforte, A, Schiessler, A, Gais, P, et al (1993) Expression of the adhesion molecule ICAM-1 on alveolar macrophages and in serum in extrinsic allergic alveolitis. Respiration 60,221-226[ISI][Medline]
-
Shijubo, N, Imai, K, Shigehara, K, et al (1995) Soluble intercellular adhesion molecule-1 (ICAM-1) in sera and bronchoalveolar lavage (BAL) fluids of extrinsic allergic alveolitis. Clin Exp Immunol 102,91-97[ISI][Medline]
-
Salmi, M, Jalkanen, S (1997) How do lymphocytes know where to go: current concepts and enigmas of lymphocyte homing. Adv Immunol 64,139-218[ISI][Medline]
-
Butcher, EC, Picker, LJ (1996) Lymphocyte homing and homeostasis. Science 272,60-66[Abstract]
-
Burns, AR, Bowden, RA, Abe, Y, et al (1999) P-selectin mediates neutrophil adhesion to endothelial cell borders. J Leukoc Biol 65,299-306[Abstract]
-
Diacovo, TG, Roth, SJ, Morita, CT, et al (1996) Interactions of human alpha/beta and gamma/delta T lymphocyte subsets in shear flow with E-selectin and P-selectin. J Exp Med 183,1193-1203[Abstract/Free Full Text]
-
Wilson, E, Aydintug, MK, Jutila, MA (1999) A circulating bovine
T cell subset, which is found in large numbers in the spleen, accumulates inefficiently in an artificial site of inflammation: correlation with lack of expression of E-selectin ligands and L-selectin. J Immunol 162,4914-4919[Abstract/Free Full Text]
-
Horie, Y, Chervenak, RP, Wolf, R, et al (1997) Lymphocytes mediate TNF-alpha-induced endothelial cell adhesion molecule expression: studies on SCID and RAG-1 mutant mice. J Immunol 159,5053-5062[Abstract]
-
Perez-Padilla, R, Salas, J, Chapela, R, et al (1993) Mortality in Mexican patients with chronic pigeon breeder’s lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis 148,49-53[ISI][Medline]
-
Pardo, A, Barrios, R, Gaxiola, M, et al (2000) M. Increase of lung neutrophils in hypersensitivity pneumonitis is associated with lung fibrosis. Am J Respir Crit Care Med 161,1698-1704[Abstract/Free Full Text]
-
Pardo, A, Barrios, R, Maldonado, V, et al (1998) Gelatinases A and B are upregulated in lung rats by subacute hyperoxia: pathogenetic implications. Am J Pathol 153,833-844[Abstract/Free Full Text]
-
Semenzato, G, Agostini, C, Zambello, R, et al (1986) Lung T cells in hypersensitivity pneumonitis: phenotypic and functional analysis. J Immunol 137,1164-1172[Abstract]
-
Barrios, R, Selman, M, Franco, R, et al (1987) Subpopulations of T cells in lung biopsies from patients with pigeon breeder’s disease. Lung 165,181-187[ISI][Medline]
-
Trentin, L, Migone, N, Zambello, R, et al (1990) Mechanisms accounting for lymphocytic alveolitis in hypersensitivity pneumonitis. J Immunol 145,2147-2154[Abstract]
-
Trentin, L, Zambello, R, Facco, M, et al (1997) Selection of T lymphocytes bearing limited TCR-Vß regions in the lung of hypersensitivity pneumonitis and sarcoidosis. Am J Respir Crit Care Med 155,587-596[Abstract]
-
Schall, TJ, Bacon, K, Camp, RD, et al (1993) Human macrophage inflammatory protein 1 alpha (MIP-1) and MIP-1ß chemokines attract distinct populations of lymphocytes. J Exp Med 177,1821-1825[Abstract/Free Full Text]
-
Pan, LH, Yamauchi, K, Sawai, T, et al (2000) Inhibition of binding of E- and P-selectin to sialyl-lewis X molecule suppresses the inflammatory response in hypersensitivity pneumonitis in mice. Am J Respir Crit Care Med 161,1689-1697[Abstract/Free Full Text]
-
Kaseda, M, Kadota, J, Mukae, H, et al (2000) Possible role of L-selectin in T lymphocyte alveolitis in patients with active pulmonary sarcoidosis. Clin Exp Immunol 121,146-150[CrossRef][ISI][Medline]
-
Fournier, E, Tonnel, AB, Gosset, PH, et al (1985) Early neutrophil alveolitis after antigen inhalation in hypersensitivity pneumonitis. Chest 88,563-566[Abstract/Free Full Text]
-
Kuebler, WM, Borges, J, Sckell, A, et al (2000) Role of L-selectin in leukocyte sequestration in lung capillaries in a rabbit model of endotoxemia. Am J Respir Crit Care Med 161,36-43[Abstract/Free Full Text]
-
Hafezi-Moghadam, A, Ley, K (1999) Relevance of L-selectin shedding for leukocyte rolling in vivo. J Exp Med 189,939-947[Abstract/Free Full Text]
-
Bahra, P, Rainger, GE, Wautier, JL, et al (1998) Each step during transendothelial migration of flowing neutrophils is regulated by the stimulatory concentration of tumour necrosis factor-alpha. Cell Adhes Commun 6,491-501[ISI][Medline]
TOP
Abstract
Introduction
