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*
Departments of Pediatrics and Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada; and
Department of Bioregulation, Biomedical Research Center, Osaka University Medical School, Osaka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and a
ß-chain that mediate cell to cell and cell to extracellular matrix
adhesion. In the blood vessels, the integrins on leukocytes bind to the
Ig superfamily cell adhesion molecules, including ICAM-1, ICAM-2, and
VCAM-1, which mediate firm adhesion and subsequent transendothelial
migration of leukocytes out of the circulation. Blood monocytes, which
are found in most inflammatory reactions, express three
ß2 (CD11/CD18) integrins, CD11a/CD18 (LFA-1), CD11b/CD18
(Mac-1), and CD11c/CD18 (p150/95), and several ß1
integrins, including 4ß1
(VLA-4).3 The CD11/CD18 and
VLA-4 integrins have been shown to be essential in mediating monocyte
endothelial cell adhesion in vitro (3, 4, 5, 6) and monocyte migration to
inflammatory sites in the skin, peritoneum, and inflamed joints in vivo
(6, 7, 8). Blood neutrophils express primarily the CD11/CD18 integrins,
and these mediate neutrophil endothelial adhesion and in vivo migration
to inflammatory sites (7, 9, 10, 11, 12, 13). Recent studies have also suggested
that both human and rat neutrophils express low levels of functional
VLA-4 on their surface, which at least in rats is capable of mediating
the migration of blood neutrophils to inflammation (14, 15). Our goal was to examine the roles of these integrins in leukocyte infiltration in the lung. A number of studies have examined the infiltration of neutrophils in the lung in several animal models. It has been shown that systemic administration of cobra venom factor in rats induced marked neutrophil infiltration in the lung, and the associated lung injury was significantly reduced by blocking CD11/CD18 (16). In contrast, the accumulation of neutrophils in the lung and the subsequent lung damage induced by IgG immune complexes were not inhibited by blocking CD11/CD18 (17). In rabbits, infiltration of the lung alveoli by neutrophils in response to intratracheal (i.t.) instillation of Escherichia coli endotoxin or phorbol ester was partially inhibited in animals pretreated with an anti-CD18 mAb (18), whereas neutrophil migration into the inflamed lung induced by i.t. instilled C5a, Streptococcus pneumoniae, or hydrochloric acid was not inhibited by blocking CD18 (18, 19). More recently, Doerschuk et al. (20) have shown that neutrophil migration to acute lung inflammation induced by Pseudomonas aeruginosa was mediated primarily by CD18, while accumulation in the lung induced by repeated infection with this bacteria was largely CD18 independent. These findings suggest that neutrophil infiltration in the lung in response to i.t. stimuli involves both CD18-dependent and CD18-independent adhesion pathways.
An i.t. injection of Gram-negative bacterial LPS in rats induces a massive cellular infiltrate in the lung consisting predominantly of neutrophils and monocytes (21). Monocytes probably play an important role in acute inflammatory lung injury given their capacity to elaborate inflammatory cytokines, growth factors, oxygen free radicals, and proteolytic enzymes (22, 23, 24). However, the possible adhesion pathways used by monocytes to migrate into lung inflammation has not been examined. In the present study we used a recently developed quantitative technique to study blood monocyte migration into the lung parenchyma and the bronchoalveolar space after i.t. LPS and compared the migration of monocytes to that of neutrophils. Our results demonstrate that the majority of blood monocytes appear to use a CD11/CD18- and VLA-4-independent adhesion pathway to migrate into the LPS-inflamed lung.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Inbred male Lewis rats, weighing 200–225 g, were purchased from Harlan Sprague-Dawley (Indianapolis, IN) and used in all experiments.
Reagents
LPS (E. coli 0111) was obtained from List Biologics (Campbell, CA). Hespan, consisting of 6% hetastarch in 0.9% sodium chloride, was obtained from DuPont Canada (Scarborough, Canada). Percoll was obtained from Pharmacia (Uppsala, Sweden). Zymosan-activated serum (ZAS), a source of the chemotactic factor C5adesArg, was generated by activating complement in normal rat serum with zymosan A (Sigma, St. Louis, MO) as described previously (25).
Blood monocyte and neutrophil isolation and radiolabeling
Donor rats were immunized by s.c. injection of 1 mg of killed Mycobacterium butyricum (Difco, Detroit, MI) in 0.1 ml of mineral oil into two sites at the base of the tail. This immunization protocol induces a blood leukocytosis resulting in a two- to fourfold increase in the yield of monocytes at 10 to 14 days after the immunization. The in vivo migration of monocytes isolated from these immunized animals was comparable to that of monocytes from nonimmunized donors as previously reported (26).
Blood monocytes and neutrophils were purified from the immunized rats using a Hespan exchange transfusion and Percoll gradient centrifugation method (26). Under ketamine (90 mg/kg) and xylazine (5 mg/kg) anesthesia, a 25-gauge needle was inserted into the femoral vein, and the total blood volume of the donor rat was gradually exchanged using 50 ml of Hespan. After recovery of 40–45 ml of perfusate, the RBCs were allowed to sediment, and the leukocyte-rich plasma was harvested. The leukocytes were recovered by centrifugation, resuspended in calcium-magnesium free Tyrode’s solution plus 5% platelet-poor plasma (Tyr-5% PPP), and layered onto 63% Percoll on top of a 74% Percoll gradient. After centrifugation at 400 x g for 30 min, the mononuclear cells on top of the 63% Percoll and the neutrophils at the 63/74% interface were harvested, washed, and resuspended in Tyr-5% PPP. The neutrophil layer consisted of >95% granulocytes with minimal RBC contamination. The mononuclear layer was composed of 50–70% small lymphocytes, 30–40% monocytes, and <0.5% neutrophils. The mononuclear cells were washed and resuspended in 5 ml of Tyr-5% PPP, and the osmolarity of this cell suspension was slightly increased by the addition of 25 µl of 9% sodium chloride to improve the separation of monocytes from lymphocytes. This cell suspension was layered onto a 40/55/58% Percoll gradient and centrifuged for another 30 min. Monocytes were harvested from the 40/55% and the 55/58% interfaces. The purity of monocytes was >85% and usually >90% as determined by cell size (>185 µm3) and neutral red vital dye staining as previously reported (26).
The purified monocytes were washed in Tyr-5% PPP, resuspended in Tyr-10% PPP at 5 x 107 cells/ml, and then labeled with Na251CrO4 (Amersham, Oakville, Canada) at 1 µCi/million cells at 37°C for 30 min. Neutrophils were washed in Tyr, resuspended in saline-HEPES solution (0.8% NaCl in 20 mM HEPES), and labeled with 111InCl3 (Frosst, Quebec, Canada) at 37°C for 10 min. After the labeling, cells were washed three times in Tyr-5% PPP and resuspended in Tyr-10% PPP for injection. Cells (4–7 x 106) carrying 1–2 x 105 cpm were injected i.v. into each rat. The viability of labeled cells was >95% as judged by trypan blue dye exclusion.
mAbs and Ab treatment
The mAb WT.3 (IgG1) binds to the common ß-chain of the
CD11/CD18 integrins (27). TA-2 mAb (IgG1), which reacts with the
4 chain of VLA-4, and an isotype control mAb B9 (IgG1)
that recognizes pertussis toxin were generated in our laboratory (28, 29). WT.3 and TA-2 mAbs have been shown to block leukocyte adhesion and
in vivo cell migration (15, 28, 30). F(ab')2 were generated
from TA-2 by pepsin digestion.
The effects of these mAbs on monocyte and neutrophil migration to the lung were studied by giving each rat 2 mg of mAbs WT.3, TA-2 F(ab')2, a combination of WT.3 and TA-2 F(ab')2, or the B9 control mAb i.v. immediately before the i.v. injection of radiolabeled cells. A second injection of TA-2 F(ab')2 was given 8 h later. Measurement of the concentration of mAbs in the blood of the rats demonstrated that the dose of mAbs used produced plasma levels at least 5–10 times that required to saturate the receptors on the leukocytes in the blood. Treatment with higher doses of WT.3 and TA-2 F(ab')2 were no more effective. None of the mAb treatments caused neutropenia, monocytopenia, lymphopenia, or clearance of radiolabeled cells from the circulation.
Lung and dermal inflammation
Rats were anesthetized with ketamine and xylazine as described above. Endotracheal intubation was performed through the mouth with a 60-cm polyethylene tube (PE-240), and a catheter was inserted into the trachea through the endotracheal tube so the tip of the catheter reached the carina. The rats then received 100 µg of LPS in 0.2 ml of saline through the i.t. catheter at the time of inspiration. Control animals were given 0.2 ml of saline intratracheally. Dermal inflammatory reactions in recipient rats were induced by intradermal injection of LPS and ZAS. Briefly, the skin on the back of the animals was shaved and injected with LPS (10 ng), ZAS (50%), and 0.05 ml of diluent as a control intradermally in triplicate sites.
Lung perfusion and bronchoalveolar lavage (BAL)
Rats were anesthetized, and a 21-gauge butterfly needle was inserted into the right ventricle of the heart. The abdominal aorta was incised to allow the perfusate to drain, and the lung vasculature was perfused with 50 ml of saline. BAL was performed immediately after the vascular perfusion to harvest cells from the bronchoalveolar space. Briefly, a polyethylene catheter attached to a three-way stopcock was inserted into the trachea through an incision, and the lavage was performed with 30 ml of saline. After recovering 26–28 ml of lavage fluid, the cell concentration was determined using a Coulter counter (Coulter Electronics, Luton, U.K.). The cells in the lavage fluid were harvested by centrifugation, and the radioactivity was measured using a 1480 Wizard gamma counter (Wallac, Turku, Finland).
In vivo cell migration assay
The in vivo cell migration assay was performed as previously described (8). Briefly, rats were injected i.v. with radiolabeled cells, followed by i.t. injection of LPS or saline as a control. In the same experiments, animals also received an i.v. injection of blocking or isotype control mAbs after the injection of radiolabeled cells. Intradermal injection of LPS, ZAS, and diluent controls on the back of the rats was performed after the i.t. injection. The rats were anesthetized 18 h later, and blood samples were collected by cardiac puncture. The lung vasculature was then flushed with saline, and the lungs were lavaged to collect cells that had accumulated in the bronchoalveolar space as described above. The lung tissue was harvested immediately after the perfusion and lavage, dissected into right and left lobes, and weighed, and the radioactivity in each lung was determined by gamma counting. In addition, in some experiments leukocyte migration was measured 18–36 h after i.t. LPS injection.
The dorsal skin, including the area of the dermal inflammatory reactions, was removed, washed, and frozen at -80°C. The injected skin sites were punched out with a 12-mm leather punch, and the radioactivity at these sites was determined. In addition, samples of spleen, liver, and lymph nodes were collected from each animal for gamma counting. The radioactivity in these samples was normalized as counts per minute per million counts per minute injected on the radiolabeled cells.
Pathology
Tissue samples were obtained from the lung at sacrifice, fixed in 10% buffered formaldehyde, and embedded in paraffin. The tissue samples were cut at 3 µm, stained with hematoxylin-eosin, and examined microscopically for evidence of cellular infiltrates and tissue damage.
Statistics
Data are expressed as the mean ± SEM, and statistical significance was determined using Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Radiolabeled monocytes and neutrophils were used to quantify
leukocyte migration from the blood into the lung in response to i.t.
LPS. Blood monocytes were labeled with
Na251CrO4, and blood neutrophils
were labeled with 111InCl3, then cells were
injected i.v. into recipient rats given an i.t. injection of 100 µg
of LPS or saline as a control. The accumulation of radiolabeled cells
in the lung parenchymal tissue was assessed 18 h later, since in
pilot experiments this was the time of maximum leukocyte accumulation
in the LPS-injected lung. The left lung in rats was almost twice the
size of the right lung as demonstrated by its wet weight. As shown in
Fig. 1
A, the saline-injected
control animals had about 3,500 and 6,500 cpm of
51Cr-labeled monocytes in the right and left lungs,
respectively, which is equivalent to about 6.5 x 103
cpm/g (right) and 6.9 x 103 cpm/g (left) in each
lung. The i.t. injection of LPS increased the accumulation of
51Cr-labeled monocytes in the lungs by 10- to 12-fold to
about 55,000 cpm (6.7 x 104 cpm/g) and 74,000 cpm
(5.3 x 104 cpm/g) in the right and left lungs,
respectively (p < 0.001).
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B). Effect of i.t. LPS on monocyte and neutrophil accumulation in the bronchoalveolar space
The accumulation of blood monocytes and neutrophils in the BAL was also determined in animals given i.t. LPS or saline. The total number of cells recovered from the BAL of saline-injected control animals was about 7 x 106 cells/rat, and there were about 40 cpm of 51Cr-labeled monocytes and 100 cpm of 111In-labeled neutrophils, suggesting that almost all the cells in the BAL of control animals are resident cells. An i.t. injection of LPS increased the total number of cells in the BAL by about 9-fold to 6.8 x 107 cells/rat. However, the accumulation of 51Cr-labeled monocytes in the BAL increased >170-fold to about 7,000 cpm (p < 0.001). The accumulation of 111In-labeled neutrophils in the BAL of LPS-injected rats increased >500-fold to about 59,000 cpm compared with that in the saline-injected controls (p < 0.001).
Blood monocytes and neutrophils also demonstrated different patterns of accumulation in the LPS-inflamed lung parenchyma and the bronchoalveolar space. More than 94% of the 51Cr-labeled monocytes recovered from the lung 18 h after i.t. LPS were in the parenchymal tissue, and only about 6% were in the BAL, suggesting that only a small proportion of the large number of monocytes entering the lung could be recovered in the BAL. In contrast, 20% of the 111In-labeled neutrophils accumulated in the BAL and 80% accumulated in the lung parenchyma.
Effects of anti-CD18 and anti-VLA-4 on monocyte and neutrophil migration to the lung
The roles of CD18 and VLA-4 in the migration of blood monocytes
and neutrophils into the LPS-inflamed lung were studied using specific
blocking mAbs against CD18 and VLA-4. As shown in Fig. 2A, treatment of animals with
anti-CD18 mAb reduced blood monocyte accumulation in the
LPS-injected lung by about 30% compared with that in control
Ab-treated animals (p < 0.05). In contrast,
the accumulation of blood monocytes in the LPS-inflamed lung was
not inhibited by treatment of animals with anti-VLA-4.
Treatment with a combination of anti-CD18 and anti-VLA-4 mAb
inhibited monocyte accumulation in the LPS-inflamed lung about 30%
compared with that in control Ab-treated animals
(p < 0.05) and did not result in further
inhibition compared with that produced by anti-CD18 treatment
alone.
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B). Effects of anti-CD18 and anti-VLA-4 mAbs on monocyte and neutrophil recovery in BAL
The effects of anti-CD18 and anti-VLA-4 mAb on the
recovery of monocytes and neutrophils in the BAL of LPS-injected rats
were also determined. As shown in Fig. 3A, accumulation of blood
monocytes in the BAL of LPS-injected rats was inhibited 30% by
blocking CD18 compared with that in control Ab-treated animals, but
this inhibition was not significant (p >
0.05). Blocking VLA-4 failed to inhibit the accumulation of blood
monocytes in the BAL of LPS-injected rats. In contrast, treatment with
a combination of anti-CD18 and anti-VLA-4 mAbs blocked the
accumulation of blood monocytes in the BAL by about 80%
(p < 0.001).
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B). Effects of CD18 and VLA-4 blockade on lung histology
Histologic examination of the lung tissue after i.t. saline was
unremarkable (data not shown). However, after the i.t. injection of LPS
there was an intense cellular infiltrate in the lung (Fig. 4). This infiltrate consisted
predominantly of neutrophils and monocytes. In animals that received
i.t. LPS and were treated with both anti-CD18 and anti-VLA-4,
the infiltration of the lung and the bronchoalveolar space by
neutrophils and monocytes was still present. These findings suggest
that a large proportion of blood monocytes and neutrophils infiltrate
the LPS-inflamed lung using a CD18- and VLA-4-independent adhesion
pathway.
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The migration of monocytes and neutrophils from the blood into
dermal inflammatory sites was also determined in the same animals given
i.t. LPS or saline. As shown in Fig. 5,
blood monocytes and neutrophils actively accumulated at dermal
inflammatory sites in response to LPS and ZAS, a source of the
chemotactic factor, C5adesArg. Animals given i.t. LPS
showed a decreased accumulation of monocytes and neutrophils in
response to intradermally injected LPS compared with animals receiving
i.t. saline (p < 0.05).
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A shows that migration
of blood monocytes to dermal inflammatory sites induced by LPS and ZAS
in animals receiving i.t. LPS was significantly (60–70%) inhibited by
treatment with anti-CD18, but not by blocking VLA-4. Moreover,
monocyte accumulation at both the LPS- and ZAS-injected dermal sites
was completely abolished (>98%) by anti-CD18 plus anti-VLA-4,
even though in these same animals, monocyte accumulation in the
LPS-injected lung was decreased by only 30%.
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B) even though neutrophil migration to the
LPS-inflamed lung was not inhibited by this treatment in the same
animals (Fig. 2B). Treatment of animals with anti-VLA-4
mAb did not block neutrophil migration to LPS- and ZAS-injected dermal
sites. However, blocking both CD18 and VLA-4 tended to be more
effective than blocking CD18 alone and completely abolished neutrophil
migration to the skin sites. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Monocyte accumulation in the lung after i.t. LPS injection was surprisingly large. Thirteen percent of the labeled monocytes injected i.v. were found in the lung after LPS injection. Neutrophil accumulation was also dramatically increased, with 24% of the injected neutrophils in the lung. These results suggest that there is substantial monocyte migration from the blood into the lung, which is not readily appreciated by histology, possibly because of the rapid differentiation of monocytes into macrophages.
There was a >170-fold increase in labeled monocytes and a >500-fold increase in labeled neutrophils in the BAL after LPS injection. The large increase in monocytes recovered in the BAL demonstrates the substantial contribution that monocytes make to these inflammatory exudates. The BAL fluid contained 6% of the labeled monocytes and 20% of the labeled neutrophils accumulating in the lungs. This suggests that the transit time of monocytes from the lung parenchyma into the bronchoalveolar space may be longer for monocytes than for neutrophils, although it cannot be excluded that the monocytes entered the lung sometime after the neutrophils. However, it does demonstrate that BAL may provide a selective sample of the cells infiltrating the lung, since BAL measures only cells that migrated into the bronchoalveolar space. Transmigration of the lung epithelium may also affect the composition of the BAL.
A key finding from our studies is the contribution of the CD18 and
VLA-4 integrins to leukocyte accumulation in the LPS-treated lung.
Previous studies showed that blood neutrophil migration in lung
inflammation was partially dependent upon CD18 integrins but could also
be CD18 independent (17, 18, 19, 20). Blockade of CD18 inhibited the
accumulation of neutrophils in response to i.t. E.
coli, phorbol esters, and, significantly, but not completely
to LPS, IL-1, and IgG immune complexes (17, 18, 19). Neutrophil
accumulation in response to C5a, S. pneumoniae, and
hydrochloric acid was not reduced by CD18 blockade in rabbits (17, 19).
The mechanisms of the CD18-independent migration to these stimuli
is unknown. Our studies of neutrophil migration into the LPS-challenged
lung show no reduction in neutrophil migration after anti-CD18,
even though in the same animals CD18 blockade inhibited >90% of the
neutrophil migration to the skin in response to LPS and ZAS (Fig. 6).
The lack of an effect of CD18 blockade in our studies compared with
studies in rabbits may be explained by the higher dose of LPS (100 vs
10 µg), the difference in timing (18 vs 4 h), or species
differences between rats and rabbits (18). Higher doses of an
inflammatory stimulus or repeated administration of bacteria have been
shown to increase the CD18-independent component of neutrophil
migration, suggesting that the dose of LPS may be the major reason for
the small CD18-dependent component in our experiments (20).
Our laboratory previously reported that neutrophils in the rat express low levels of VLA-4, and this integrin can mediate in vivo neutrophil migration (15). Here we show that VLA-4 blockade alone does not affect neutrophil migration to the LPS-inflamed lung, and in combination with anti-CD18 inhibits neutrophil accumulation by only about 30% in the lung parenchyma. Interestingly, anti-CD18 or anti-VLA-4 alone did not reduce neutrophil migration into the bronchoalveolar space, as indicated by the recovery of cells in the BAL, but dual blockade of CD18 and VLA-4 decreased the recovery of neutrophils in the BAL by 80%. This suggests that migration of neutrophils from the lung parenchyma across the pulmonary epithelium into the bronchoalveolar space is mediated by both CD18 and VLA-4 integrins. Pulmonary epithelium in the LPS-inflamed lung expresses high levels of ICAM-1, an important ligand for the CD18 integrins (31, 32). In addition, VLA-4, which can bind to both VCAM-1 and fibronectin, may contribute to neutrophil transepithelial migration by binding to fibronectin in the interstitium. Thus, these studies show that neutrophil migration to LPS-induced lung inflammation in the rat is CD18 independent and that the CD18-independent component is only partially mediated by VLA-4, but that migration into the bronchoalveolar space by neutrophils depends to a large extent upon both CD18 and VLA-4.
Unlike neutrophils, which have been previously shown to use a CD18-independent pathway for migration to the lung and to inflamed joints, the recruitment of monocytes to cutaneous inflammation and to arthritic joints was shown to be completely dependent on CD18 and VLA-4 (6, 8). Monocyte accumulation in LPS-induced lung inflammation was inhibited 30% by anti-CD18 treatment and was not affected by anti-VLA-4, and the effect of the combination was similar to that of anti-CD18 alone. Thus, in contrast to other tissues previously studied, monocytes use a CD18- and VLA-4-independent pathway for most of the migration to LPS-induced lung inflammation. In addition, VLA-4 appears to play no role in monocyte migration into the lung parenchyma, even though VLA-4 mediates monocyte recruitment to cutaneous inflammation, including LPS inflammation, and to inflamed joints (6, 8). The lack of a greater effect on monocyte accumulation in the lung parenchyma was not due to inadequate Ab treatment, since treatment with higher doses of these mAbs did not have a greater effect, the rats had circulating levels of the mAbs well above those required to saturate the receptors on the blood leukocytes, and the anti-CD18 plus anti-VLA-4 treatment abolished neutrophil and monocyte accumulation in the skin in response to LPS and ZAS.
Monocyte recovery in the BAL was reduced, although not significantly (p = 0.2), by anti-CD18 treatment, was unaffected by treatment with anti-VLA-4, and was inhibited by 80% when CD18 and VLA-4 were both blocked. This pattern is similar to that of neutrophils and suggests that CD18 and VLA-4 together mediate much of the migration of monocytes across the epithelium into the bronchoalveolar space. As discussed above, the mechanism of this migration may well depend upon the interaction of CD18 with ICAM-1 on epithelial cells and of VLA-4 with VCAM-1 or fibronectin.
The reason for the lack of inhibition of monocyte and neutrophil accumulation in the lung parenchyma by CD18 and VLA-4 blockade is unclear. Anti-CD18 plus anti-VLA-4 treatment increases the blood leukocyte concentration and thereby might increase the leukocyte content in the vasculature of the lung. However, the lungs were exhaustively perfused to remove intravascular leukocytes before dissection to minimize this effect. Furthermore, compared with the huge increase in labeled leukocytes in the lung parenchyma, the increase in the blood leukocyte count could account for only a very small component (<10%) of the labeled cells in the lungs. In addition, the lung histology clearly demonstrated that in rats treated with both anti-CD18 and anti-VLA-4 large numbers of leukocytes were in the lung parenchyma.
Thus, there appears to be a CD18- and VLA-4-independent pathway for migration of both monocytes and neutrophils into the lung. The mechanism behind this migration may lie in the highly specialized vasculature of the lung. Leukocytes entering the lung migrate through the capillaries rather than the postcapillary venules as in the systemic circulation (33). In the capillaries, the requirement for strong adhesion mediated by the integrins may be less than that for migration out of the postcapillary venules in the systemic circulation. This may allow leukocytes to migrate out of the blood in the presence of integrin blockade. E-selectin, P-selectin, and platelet endothelial cell adhesion molecule-1 (PECAM-1) have been shown to contribute to migration in inflammatory tissues, including the lung (34, 35, 36, 37, 38, 39). Selectin-mediated adhesion or adhesion directly mediated by PECAM-1 in the tight junctions between adjacent endothelial cells may be sufficient to allow leukocyte transendothelial migration. Further studies using strategies to block multiple selectins and/or PECAM-1 may help identify the CD18- and VLA-4-independent pathway for monocyte and neutrophil migration.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas B. Issekutz, Department of Pediatrics, IWK Grace Health Center, 5850 University Ave., Halifax, Nova Scotia, Canada B3J 3G9. E-mail address:
3 Abbreviations used in this paper: VLA-4, very late activation antigen-4; i.t., intratracheal; ZAS, zymosan-activated serum; Tyr, Tyrode’s solution; PPP, platelet-poor plasma; BAL, bronchoalveolar lavage.
Received for publication July 9, 1997. Accepted for publication July 27, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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J. A. Burns, T. B. Issekutz, H. Yagita, and A. C. Issekutz The {{alpha}}4{{beta}}1 (Very Late Antigen (VLA)-4, CD49d/CD29) and {{alpha}}5{{beta}}1 (VLA-5, CD49e/CD29) Integrins Mediate {{beta}}2 (CD11/CD18) Integrin-Independent Neutrophil Recruitment to Endotoxin-Induced Lung Inflammation J. Immunol., April 1, 2001; 166(7): 4644 - 4649. [Abstract] [Full Text] [PDF]
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V. C. Ridger, B. E. Wagner, W. A. H. Wallace, and P. G. Hellewell Differential Effects of CD18, CD29, and CD49 Integrin Subunit Inhibition on Neutrophil Migration in Pulmonary Inflammation J. Immunol., March 1, 2001; 166(5): 3484 - 3490. [Abstract] [Full Text] [PDF]
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U. Maus, S. Herold, H. Muth, R. Maus, L. Ermert, M. Ermert, N. Weissmann, S. Rosseau, W. Seeger, F. Grimminger, et al. Monocytes recruited into the alveolar air space of mice show a monocytic phenotype but upregulate CD14 Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L58 - L68. [Abstract] [Full Text] [PDF]
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I. Eue, B. Pietz, J. Storck, M. Klempt, and C. Sorg Transendothelial migration of 27E10+ human monocytes Int. Immunol., November 1, 2000; 12(11): 1593 - 1604. [Abstract] [Full Text] [PDF]
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 A. J. Mackarel, K. J. Russell, C. S. Brady, M. X. FitzGerald, and C. M. O'Connor Interleukin-8 and Leukotriene-B4, but Not Formylmethionyl Leucylphenylalanine, Stimulate CD18-Independent Migration of Neutrophils across Human Pulmonary Endothelial Cells In Vitro Am. J. Respir. Cell Mol. Biol., August 1, 2000; 23(2): 154 - 161. [Abstract] [Full Text]
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E. E. Schneeberger, Q. Vu, B. W. LeBlanc, and C. M. Doerschuk The Accumulation of Dendritic Cells in the Lung Is Impaired in CD18-/- But Not in ICAM-1-/- Mutant Mice J. Immunol., March 1, 2000; 164(5): 2472 - 2478. [Abstract] [Full Text] [PDF]
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S. Rosseau, J. Selhorst, K. Wiechmann, K. Leissner, U. Maus, K. Mayer, F. Grimminger, W. Seeger, and J. Lohmeyer Monocyte Migration Through the Alveolar Epithelial Barrier: Adhesion Molecule Mechanisms and Impact of Chemokines J. Immunol., January 1, 2000; 164(1): 427 - 435. [Abstract] [Full Text] [PDF]
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