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4
1 (Very Late Antigen (VLA)-4, CD49d/CD29) and 51 (VLA-5, CD49e/CD29) Integrins Mediate 2 (CD11/CD18) Integrin-Independent Neutrophil Recruitment to Endotoxin-Induced Lung Inflammation1
*
Departments of Pediatrics, Microbiology/Immunology, and Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; and
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2 integrin cell adhesion molecules (CAM) mediate
polymorphonuclear leukocyte (PMNL) emigration in most inflamed tissues,
but, in the lung, other yet to be identified CAMs appear to be
involved. In Lewis rats, the intratracheal injection of
Escherichia coli-LPS induced acute (6-h) PMNL
accumulation in the lung parenchyma (280 x 106 by
myeloperoxidase assay; PBS control = 35 x
106) and bronchoalveolar lavage fluid (BALF = 27
x 106; PBS = 0.1 x 106).
Parenchymal accumulation was not inhibited by a blocking Ab to
2 integrins and only minimally inhibited (20.5%;
p < 0.05) in BALF. We examined the role of
41 and 51
integrins and of selectins in this PMNL recruitment. Treatment with
mAbs to 41 or
51, even in combination, had no effect on
PMNL accumulation induced by intratracheal LPS. However,
anti-4 combined with anti-2 mAbs
inhibited PMNL recruitment to the parenchyma by 56%
(p < 0.001) and to BALF by 58%
(p < 0.01). The addition of
anti-5 mAb to 2 plus 4
blockade inhibited PMNL accumulation further (by 79%;
p < 0.05). In contrast, blockade of L-, P-, and
E-selectins in combination or together with 2,
4, and 5 integrins had no effect.
LPS-induced BALF protein accumulation was not inhibited by treatment
with anti-2 plus 4 mAbs, but was
prevented when 51 was also blocked. Thus,
while selectins appear to play no role,
41 and 51
function as major alternate CAMs to the 2 integrins in
mediating PMNL migration to lung and to pulmonary vascular and
epithelial permeability. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2
(CD18) family (LFA-1, CD11a/CD18 and Mac-1, and CD11b/CD18) with the Ig
superfamily (ICAM-1 and ICAM-2) present on the endothelium. This is
followed by transendothelial migration of the PMNL out of the vessel
and migration of the cell to the site of inflammation via additional
integrin interactions with the extracellular matrix (1, 3, 4). This multistep paradigm is based primarily on studies
conducted on peripheral tissues involved by inflammation.
Several studies have examined leukocyte recruitment mechanisms in acute
lung inflammation. The adhesion molecules implicated in PMNL
recruitment have been varied depending on the stimulus (LPS, C5a,
bacteria, immune complexes, etc.) used. For example, pulmonary IgG
immune complex injury induces PMNL infiltration that is in part
2 integrin dependent (5), whereas
the response to intrapulmonary C5a deposition is largely
2 integrin independent (6). In
vitro studies of PMNL migration across pulmonary endothelium have also
indicated that the adhesion molecule mechanisms are in part chemotactic
factor dependent, IL-8 in particular inducing
2 integrin-independent PMNL transmigration
(7, 8). It has also been shown that the mechanisms
involved vary with the chronicity of reactions. For example, PMNL
recruitment to lung inflammation induced by a single infection with
Pseudomonas aeruginosa is primarily
2 integrin dependent but becomes
2 integrin independent with repeated infection
(9). Furthermore, PMNL infiltration induced by
Streptococcus pneumoniae, Staphylococcus aureus, or HCl
aspiration was shown to be 2 integrin
independent even on initial exposure (10, 11, 12). These
findings are in marked contrast to PMNL infiltration in other tissues,
which is highly 2 integrin-dependent
(12, 13, 14). Despite the accumulated evidence that PMNL
recruitment to lung inflammation involves 2
integrin-independent mechanisms, the alternate mechanisms remain
unidentified.
Integrins are a large family of heterodimeric, transmembrane
glycoproteins. Members of this family of CAMs have been found in all
tissues and on all leukocytes. There are two types of integrin subunits
( and ), which associate to form over 20 different
heterodimers (15). PMNLs are known to express several
integrins in addition to the 2 integrins
(CD11/CD18). For example, PMNLs also express several
1 integrins, including
21 (very late Ag
(VLA)-2), 41 (VLA-4),
51 (VLA-5),
61 (VLA-6), and
91
(16, 17, 18, 19, 20, 21, 22, 23). Although expressed at low levels on PMNLs,
41 and
91 have been shown to
mediate human PMNL rolling or transendothelial migration in vitro, and
41 can contribute to
PMNL migration in rat models of inflammation (19, 22, 24).
The 21,
41,
51,
61, and
91 integrins may also
mediate extravascular migration of PMNL (17, 20, 22).
In the analysis of the mechanisms of PMNL migration to lung
inflammation, studies to date have examined the effect of blocking
specific CAMs with Ab or knocking out CAMs by gene deletion. This
strategy has eliminated the function of one or, in a few cases, two or
three adhesion molecules. However, studies have not examined the role
of multiple 1 integrins possibly functioning
in concert with 2 integrins and selectins. In
this study, we examined the role of these families of CAMs in PMNL
recruitment to the lung in response to intratracheal (i.t.) injection
of bacterial LPS in the rat, which, in this species, induces marked
2 integrin-independent PMNL infiltration into
the parenchyma with alveoli. Our results demonstrate a major role for
41 and
51 integrins, in
addition to 2 integrins, in this process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male Lewis rats, weighing 250–350 g, were purchased from Charles River Canada (St.-Contant, Quebec, Canada) and used in all experiments. The experimental protocols were approved by the Dalhousie University committee of laboratory animal care.
Reagents
LPS (Escherichia coli 0111:B4) was obtained from List Biological Laboratories (Campbell, CA). Cetyltrimethylammonium chloride (CTAC) and 3,5,5-tetramethylbenzidine-dihydrochloride were obtained from Sigma (St. Louis, MO).
mAb treatments
The mouse IgG1 mAb WT.3 (a gift from M. Miyasaka, Osaka
University, Osaka, Japan) recognizes and functionally blocks the rat
2-chain of the leukocyte CD11/CD18 integrins
(25). The mouse IgG1 mAb TA-2 was generated in our
laboratory and has been shown to react with and functionally block the
rat 4-chain of VLA-4 (26). The
hamster IgG mAb HM5 reacts with and
blocks the rat 5 of VLA-5 (27, 28) and HRL-3 (a gift from D. Anderson, Pharmacia Upjohn,
Kalamazoo, MI, and M. Miyasaka, Osaka University) reacts with and
blocks rat L-selectin (29). The mouse IgG2a mAb RMP-1
recognizes and blocks rat P-selectin, and the mouse IgG1 mAb RME-1
blocks rat E-selectin (30, 31). These were generated in
our laboratory. All mAbs to -subunits and to selectins were used as
F(ab')2 generated by pepsin digestion, as
previously described (32). The mouse mAb B9 (IgG1)
anti-pertussis toxin was used as a control mAb, as previously
described (14, 19). Rats received 1 mg of each mAb i.v. as
indicated. None of the mAb treatments used, even in combination, caused
a decrease in the blood PMNL count. Measurement by immunofluorescent
titration and flow cytometry analysis of the concentration of Ab in the
serum of recipient animals at sacrifice indicated that this dose is
sufficient to maintain serum levels of the Abs at more than five times
saturation throughout the 6-h experiment.
Lung inflammation, perfusion, and bronchoalveolar lavage
Anesthetized rats (by Ketamine and Innovar i.v.) were given an i.p injection of 0.2 mg/kg atropine sulfate to reduce reflex coughing following LPS instillation. Then, the trachea was isolated, and 50 µg of LPS in PBS (total volume, 0.2 ml) or PBS alone (control) was injected via a 27-gauge butterfly needle. Within 5 min of i.t. administration of the LPS, the indicated mAbs were injected i.v.
Before sacrifice at 6 h, rats were pretreated with 80 mg/kg pentoxifylline in 0.45% NaCl i.p. 15–20 min before vascular perfusion. The perfusion was performed as previously described (33) with minor modifications. Briefly, a 25-gauge butterfly needle was inserted into the inferior vena cava below the diaphragm of anesthetized animals (Ketamine, 50 mg/kg, and Xylazine, 10 mg/kg, i.p.). The abdominal aorta was transected to allow perfusate to drain, and 25 ml Tyrode’s solution with Ca2+ and Mg2+ was infused. Then, the butterfly needle was inserted into the inferior vena cava above the diaphragm, and 25 ml additional Tyrode’s solution with Ca2+ and Mg2+ was infused. The perfusion was completed with the infusion of 10 ml PBS-0.1% EDTA into the pulmonary artery. Bronchoalveolar lavage was then performed by inserting a polyethylene catheter into the trachea, and the lungs were lavaged four times with a total of 28 ml cold PBS-0.1% EDTA. In all animals, 20–25 ml of BALF was recovered, and the cell concentration was determined by hemocytometer counting with crystal violet staining. BALF protein concentration was determined by UV absorbance at 280 µm using albumin as standard. The lungs were removed and immediately frozen at -70°C until myeloperoxidase (MPO) extraction was performed.
For histological examination, bronchial lavage was omitted and, after vascular perfusion, 10 ml buffered formalin (3.7%) was infused via the pulmonary artery to fix the lung. Wedge segments from each lobe were paraffin embedded, and 5-µm sections were taken and stained with hematoxylin and eosin.
PMNL quantitation in lung parenchyma
Lungs were extracted as previously described (33, 34). Briefly, samples of lung tissue from each lobe were pooled
(350–450 mg, 
10–15% of total lung weight) and freeze-dried. These
samples were then homogenized in 50 mM HEPES (pH 8.0) at 0.5% dry w/v
with a pestle homogenizer (Talboys Engineering, Emerson, NJ) in
glass tubes at setting 30–40 until fully homogenized. Samples were
then centrifuged at 10,000 x g for 30 min at 4°C,
and the supernatant was discarded. The pellet was then rehomogenized in
the same volume of 50 mM HEPES (pH 8.0) and centrifuged again at
10,000 x g for 30 min. The resulting pellet was
homogenized again in the same volume of 0.5% CTAC in distilled water
and clarified by repeat centrifugation. The resultant clear supernatant
was analyzed for MPO activity. The same protocol was used to extract
MPO from BALF cell pellets.
The collected supernatant from the HEPES/CTAC extracts of lung tissue was diluted 10-fold with 10 mM citrate buffer (pH 5.0), and 75 µl of this solution was pipetted into 4 wells of a 96-well plate. As negative control, "stop solution" (4 N H2SO4) was added to two of the wells. Then, 75 µl of the substrate solution (3 mM 3,5,5-tetramethylbenzidine-dihydrochloride, 120 mM resorcinol, and 2.2 mM hydrogen peroxide in distilled water (H2O2)) was added to all the wells, and the reaction was stopped after 2 min at 22°C by adding stop solution to the test wells.
Determination of lung parenchyma PMNL content
A standard curve of MPO activity vs PMNL number was developed by homogenizing a known number of Percoll-purified blood PMNLs using the same technique used in MPO extraction from lung and also from BALF cells, as previously reported (34). The extract from these PMNLs was titrated, and a standard curve relating MPO activity to PMNL number was plotted. Aliquots of this standard extract were stored at -70°C, and a sample with known MPO content was tested in each assay as an internal standard and for calculation of PMNL concentration as previously described (34).
Statistical analysis
All data reported are arithmetic means. Error bars represent one SEM. Differences between means of indicated groups were analyzed by ANOVA with Bonferoni corrections for multiple comparisons.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rats received an i.t. injection of LPS or PBS as a control and
were sacrificed 6 h later. In rats receiving i.t. LPS (control),
the lung parenchyma PMNL content increased 9-fold over PBS control to
2.8 ± 0.1 x 108 PMNL (Fig. 1
). The PMNL content in BALF in PBS
control animals was consistently <1 x 106,
but in rats receiving i.t. LPS, the PMNL content reached 2.7 ±
0.1 x 107 (Fig. 2). The i.t. injection of LPS also led to
a significant increase in BALF protein concentration compared with PBS
control animals (Fig. 3). Protein
concentration in the PBS control was 0.14 ± 0.03 mg/ml, and, in
rats receiving i.t. LPS, the protein concentration increased to
0.30 ± 0.03 mg/ml (p < 0.001).
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To assess whether migration out of the vessel and through the lung
parenchyma into the airspaces induced significant PMNL degranulation
and release of cellular MPO, which may influence assessment of
parenchymal PMNL content using the MPO assay, we assayed the MPO
activity of PMNL in the BALF of rats 6 h following i.t. LPS and
compared this to MPO in blood PMNL. As Fig. 4 shows, the BALF PMNL number predicted
by MPO extraction, using blood PMNL MPO content as a standard, was not
significantly different from the PMNL number in BALF determined by a
visual hemocytometer quantitation of PMNL in BALF.
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The role of 2,
41 (VLA-4), and
51 (VLA-5) integrins
and of L-, P-, and E-selectins in PMNL migration into the lung during
acute LPS-induced inflammation was studied using blocking mAbs. As Fig. 1
illustrates, mAbs to 2 integrins, or
4 plus 5 integrins
separately or to L-, P-, and E-selectins as a group, had no effect on
PMNL accumulation in the parenchyma after i.t. LPS administration. In
contrast, mAbs to 2 in combination with
41 integrin inhibited
by >50% the PMNL accumulation in the parenchyma (1.34 ±
0.1 x 108 PMNLs; p <
0.001) as compared with LPS controls. Treatment of rats with mAbs to
2 plus
41 and also
51 in combination
inhibited PMNL accumulation significantly more (8.8 ± 1.0 x
107; p < 0.05) when compared
with the 2 plus
41 mAb-treated group.
To determine whether selectins may be involved in the remaining PMNL
infiltration, rats were additionally treated with mAbs to L-, P-, and
E-selectin in combination. However, no additional inhibition of PMNL
accumulation was observed (7.2 ± 0.5 x
107) compared with rats with
2,
41, and
51 blockade.
Effect of CAM blockade on PMNL migration into the BALF
As shown in Fig. 2, under nearly all conditions of integrin and
selectin blockade, PMNL accumulation in BALF mirrored the changes in
PMNL accumulation in the parenchyma. However, unlike the parenchyma,
the pretreatment of rats with mAb to 2
integrins slightly but significantly inhibited the migration of PMNLs
into the BALF of rats receiving i.t. LPS as compared with control
treated rats (21 ± 1.5 x 106;
p < 0.05). This inhibition was further enhanced by the
addition of mAb to 4 to the mAb treatment
(11 ± 1.1 x 106 PMNL;
p < 0.05, as compared with
anti-2 treatment alone). When
anti-5 mAb was added to the
2 and 4 mAbs,
inhibition was further and significantly increased (5.6 ±
0.8 x 106; p < 0.05, as
compared with anti-2 and
anti-4 treatment). As with PMNL
accumulation in the parenchyma, no additional inhibition of PMNL
accumulation was observed when L-,P-, and E-selectins were blocked in
concert with 2, 4,
and 5 integrins (5.6 ± 0.01 x
106).
Effect of CAM blockade on protein concentration in the BALF
As an indicator of the increase in lung vascular and epithelial
permeability resulting from inflammatory injury, BALF protein
concentration was quantified. As illustrated in Fig. 3, protein
concentration in the BALF of LPS-injected control mAb-treated rats was
twice that of rats receiving i.t. PBS (LPS group = 0.3 ±
0.03 mg/ml; PBS = 0.14 ± 0.03 mg/ml; p <
0.001). Protein concentration in BALF from rats treated with
anti-2 mAbs alone or in combination with
anti-4 mAb was not significantly different
from LPS control (0.27 ± 0.01 mg/ml). Inhibition of protein leak
into the BALF was only observed when animals received mAb to
2, 4, and also
5 integrin, irrespective of selectin blockade
(0.15 ± 0.01 mg/ml; p < 0.001).
Effect of CAM blockade on lung histology
Examination of lung sections from animals receiving either i.t.
PBS or LPS indicated that LPS induced a marked increase in leukocyte
infiltration into the lung interstitium (Fig. 5). The predominant cells in the
infiltrate at 6 h were PMNLs. In the lungs of animals treated with
mAbs to 2 and 4 plus
5 integrins, a marked decrease of PMNL
infiltration was observed (Fig. 5c).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2
integrin-independent mechanisms involved in this process. Our data are
consistent with these previous reports. We found that PMNL recruitment
into the parenchyma during LPS-induced acute lung inflammation in the
rat was not inhibited by function blocking mAb to the
2 integrins, and PMNL accumulation in the BALF
was only slightly, albeit significantly, inhibited (by 20%). This is
despite the fact that the anti-2 mAb used
(WT.3) has been shown by us to inhibit PMNL recruitment to inflammation
in skin by >80% and arthritic joints by >60% (19).
Here we show that multiple integrins participate in PMNL migration into
lung parenchyma and into the bronchoalveolar space in the rat during
LPS-induced lung inflammation. The
41 integrin has
recently been recognized on activated PMNL and to contribute to PMNL
capture, rolling, and migration (19, 24, 35). Our findings
demonstrate that it contributes to
2-independent PMNL recruitment, because
4 blockade in conjunction with
2 blockade significantly inhibited PMNL
accumulation in both the parenchyma and BALF (Figs. 1 and 2).
Furthermore, the 51
integrin, which is also expressed on PMNL at relatively low levels
(19, 24, 36), also contributes to PMNL recruitment to the
lung when 2 and 4
integrins are nonfunctional, because
anti-5 mAb inhibited PMNL accumulation in
the parenchyma and BALF significantly more than observed with
2 plus 4 blockade
(Figs. 1 and 2). These mechanisms appear to be functionally redundant
alternative pathways for PMNL recruitment to the lung, because neither
2 blockade nor 4 plus
5 blockade reduced PMNL accumulation in the
parenchyma and only minimally in the airspace (Figs. 1 and 2). The lack
of effect of treatment with mAb to 2 or to
4 plus 5 integrins or
of a nonbinding control mAb (B9) on PMNL accumulation in parenchyma
supports the conclusion that the inhibitory effects were not due to
nonspecific effects.
To our knowledge, this is the first report that PMNLs use
41 for migration to
lung inflammation. This leukocyte can be added to the lymphocyte,
monocyte, and eosinophil, which use 4 in
conjunction with 2 integrins for migration to
lung inflammation (33, 37). Further studies will be
required to ascertain the major counterligands used by
41 on PMNL. VCAM-1 is
one candidate, because it is up-regulated in the pulmonary vasculature
during inflammation (38, 39), although up-regulated
expression on endothelium of ligands such as the connecting segment-1
(CS-1) isoform of fibronectin may also contribute
(40). However, recent studies indicate that other
counterligands yet to be defined may play a predominant role in vivo
(41).
Our findings are the first evidence for a role of
5 in PMNL recruitment in vivo. Previous
studies have demonstrated the role of
51 in PMNL adhesion
to fibronectin and PMNL migration across fibroblast barriers (36, 42). The current in vivo results suggest that
51 may also
contribute to PMNL emigration from blood to some extent, because
5 blockade inhibited PMNL accumulation in the
parenchyma in the presence of 2 and
4 blockade. These ligands in vivo may involve
cell-associated as well as extracellular matrix-bound fibronectin or
possibly also the Ig superfamily member L1, which in the mouse
is recognized by 51
(43).
Another important finding is that these integrins may play a role in
PMNL-mediated lung injury, as reflected in increased BALF protein
accumulation. These integrins likely contribute to this process in
concert, because blockade of 2 alone or
4 plus 5 had no
effect, but the protein leakage was prevented with simultaneous
blockade of 2, 4, and
5 integrins (Fig. 3). The
51 integrin may be as
important as 2 or
41 integrins in this
response, because no attenuation of the protein exudation was observed
unless 5 was blocked.
The analysis of BALF protein accumulation revealed that this lung
inflammatory injury may require a threshold of PMNL infiltration to
develop or that it is a PMNL-independent response, because we observed
either a maximum BALF protein concentration of 0.3 mg/ml or the normal
PBS control level of 0.15 mg/ml, despite various degrees of inhibition
of PMNL recruitment. For example, although 2
plus 4 blockade inhibited PMNL recruitment by
56–58%, this had no effect on BALF protein, whereas further
inhibition of PMNL accumulation (up to 80%) with blockade of also
51 eliminated the
protein leakage (
Figs. 1–3). Whether a critical threshold for PMNL
transendothelial migration, activation, mediator release, and
transepithelial migration are required to induce the vascular and
epithelial permeability increase deserves further investigation because
of the therapeutic implications.
Studies of the role of selectins in PMNL recruitment to lung
inflammation have indicated either a partial or no role in PMNL
recruitment to the lung, depending on the inflammatory stimulus
(45, 46, 47, 48). Because the mechanisms and mediators involved in
different pulmonary reactions are likely to be varied, the results have
not been directly comparable. Our finding that blockade of L-, P-, and
E-selectin had no effect on PMNL accumulation or on BALF protein
increase, even in rats treated with mAbs to 2,
4, and 5 integrins,
suggests that the selectins are not required for these responses to
LPS, at least in the lungs of rats. This is likely because the
predominant site of PMNL emigration in this model is at the alveolar
level where close contact between PMNL and pulmonary endothelium occurs
due to the small diameter of alveolar capillaries. This may minimize
the requirement for selectin-mediated tethering and rolling (1, 49, 50, 51).
In summary, our studies indicate a major role for the
2 family,
41, and
51 integrins, but no
detectable role for selectins in PMNL migration into the lung during
acute LPS-induced inflammation. Further studies examining the role of
these integrins in other models of lung inflammation are required to
define their contribution to PMNL trafficking to the lung, activation,
and the associated endothelial and epithelial injury during pulmonary
inflammation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Andrew C. Issekutz, Department of Pediatrics, Division of Immunology, Rheumatology, and Infectious Diseases, IWK Grace Health Center, 5850 University Avenue, Halifax, Nova Scotia, B3J 3G9, Canada.
3 Abbreviations used in this paper: PMNL, polymorphonuclear leukocyte; CAM, cell adhesion molecule; BALF, bronchoalveolar lavage fluid; VLA, very late Ag; i.t., intratracheal; CTAC, cetyltrimethylammonium chloride; MPO, myeloperoxidase.
Received for publication September 22, 2000. Accepted for publication January 17, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1, 2
integrins and ICAM-1 in lung injury after deposition of IgG and IgA
immune complexes. [Published erratum appears in 1993 J.
Immunol. 150:5209.] J. Immunol.
150:2407.
2-integrin CD18 in the local accumulation of neutrophils in pulmonary and cutaneous inflammation in the rabbit. Am. J. Respir. Cell Mol. Biol. 10:391.[Abstract]
1 integrin-dependent adherence of granulocytic HL60 to fibronectin. J. Leukocyte Biol. 57:592.[Abstract]
1 integrin, very late activation antigen-4 on human neutrophils can contribute to neutrophil migration through connective tissue fibroblast barriers. Immunology 90:448.[Medline]
1-dependent adhesion pathway on neutrophils: a mechanism invoked by dihydrocytochalasin B or endothelial transmigration. FASEB J. 9:1103.[Abstract]
21 (VLA-2) is a principal receptor used by neutrophils for locomotion in extravascular tissue. Blood 95:1804.91 mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule-1. J. Cell Biol. 145:413.91 integrin is expressed on human neutrophils and contributes to neutrophil migration through human lung and synovial fibroblast barriers. J. Leukocyte Biol. 66:809.[Abstract]
41-integrin under flow conditions. Blood 89:3837.4 (CD49d) and 2 (CD18) integrins in eosinophil and neutrophil migration to allergic lung inflammation in the Brown Norway rat. Am. J. Respir. Cell Mol. Biol. 20:448.4 and 1 integrins and bind to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Blood 91:2341.
B is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment. J. Inflamm. 45:283.[Medline]
integrin-expressing T lymphocytes are associated with immunity to pulmonary Mycobacterium tuberculosis infection. J. Immunol. 164:4853.4 integrin subunit with a modulatory role in VLA-4-mediated cell adhesion to fibronectin. Biochem. J. 327:727.
4 integrin-dependent leukocyte recruitment does not require VCAM-1 in a chronic model of inflammation. J. Immunol. 164:3337.2 (CD11/CD18) integrins and the 1 (CD29) integrins VLA-5 and VLA-6. Cell. Immunol. 163:178.[Medline]
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 E. M. Conway, M. Van de Wouwer, S. Pollefeyt, K. Jurk, H. Van Aken, A. De Vriese, J. I. Weitz, H. Weiler, P. W. Hellings, P. Schaeffer, et al. The Lectin-like Domain of Thrombomodulin Confers Protection from Neutrophil-mediated Tissue Damage by Suppressing Adhesion Molecule Expression via Nuclear Factor {kappa}B and Mitogen-activated Protein Kinase Pathways J. Exp. Med., September 2, 2002; 196(5): 565 - 577. [Abstract] [Full Text] [PDF]
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 M. Pelletier, V. Lavastre, and D. Girard Activation of Human Epithelial Lung A549 Cells by the Pollutant Sodium Sulfite: Enhancement of Neutrophil Adhesion Toxicol. Sci., September 1, 2002; 69(1): 210 - 216. [Abstract] [Full Text] [PDF]
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G. Andonegui, S. M. Goyert, and P. Kubes Lipopolysaccharide-Induced Leukocyte-Endothelial Cell Interactions: A Role for CD14 Versus Toll-Like Receptor 4 Within Microvessels J. Immunol., August 15, 2002; 169(4): 2111 - 2119. [Abstract] [Full Text] [PDF]
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 S. Tasaka, S. E. Richer, J. P. Mizgerd, and C. M. Doerschuk Very Late Antigen-4 in CD18-Independent Neutrophil Emigration during Acute Bacterial Pneumonia in Mice Am. J. Respir. Crit. Care Med., July 1, 2002; 166(1): 53 - 60. [Abstract] [Full Text] [PDF]
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R.-F. Guo, N. C. Riedemann, I. J. Laudes, V. J. Sarma, R. G. Kunkel, K. A. Dilley, J. D. Paulauskis, and P. A. Ward Altered Neutrophil Trafficking During Sepsis J. Immunol., July 1, 2002; 169(1): 307 - 314. [Abstract] [Full Text] [PDF]
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J. C. Leemans, M. J. B. M. Vervoordeldonk, S. Florquin, K. P. van Kessel, and T. van der Poll Differential Role of Interleukin-6 in Lung Inflammation Induced by Lipoteichoic Acid and Peptidoglycan from Staphylococcus aureus Am. J. Respir. Crit. Care Med., May 15, 2002; 165(10): 1445 - 1450. [Abstract] [Full Text] [PDF]
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X.-p. Gao, N. Xu, M. Sekosan, D. Mehta, S. Y. Ma, A. Rahman, and A. B. Malik Differential Role of CD18 Integrins in Mediating Lung Neutrophil Sequestration and Increased Microvascular Permeability Induced by Escherichia coli in Mice J. Immunol., September 1, 2001; 167(5): 2895 - 2901. [Abstract] [Full Text] [PDF]
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 T. S. Olson, K. Singbartl, and K. Ley L-selectin is required for fMLP- but not C5a-induced margination of neutrophils in pulmonary circulation Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2002; 282(4): R1245 - R1252. [Abstract] [Full Text] [PDF]
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