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Regular Articles |
From the Department of Dermatology,*
Kanazawa University
School of Medicine, Kanazawa, Ishikawa, Japan; and the Department of
Immunology,
Duke University Medical Center,
Durham, North Carolina
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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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The generation of adhesion
molecule-deficient mice has provided considerable insight into the
molecular interactions that occur during inflammation in
vivo. L-selectin-deficient (L-selectin-/-)
mice have decreased trauma-induced rolling of leukocytes in the
exteriorized mesentery and decreased rolling in cremaster muscle
venules after tumor necrosis factor-
treatment.6-8
L-selectin-/- mice also demonstrate decreased
leukocyte recruitment into an inflamed peritoneum at early and late
time points, decreased delayed-type hypersensitivity responses, delayed
rejection of allogeneic skin transplants, and resistance to
lipopolysaccharide-induced septic shock.6,9-12
ICAM-1-/- mice have significantly reduced
numbers of infiltrating neutrophils during the early stages of
peritonitis, reduced susceptibility to lipopolysaccharide-induced
septic shock, and impaired delayed-type hypersensitivity reactions,
although allogeneic skin graft rejection is normal.9,13,14
Recent studies in L-selectin/ICAM-1-/- mice
demonstrate a direct role for ICAM-1 in leukocyte rolling as the
frequency of rolling leukocytes in
L-selectin-/- mice treated with tumor necrosis
factor- is decreased significantly by the additional loss of ICAM-1
expression.15
Furthermore, the loss of both L-selectin and
ICAM-1 expression reduces leukocyte recruitment into sites of
inflammation beyond what is observed with loss of either receptor alone
in various experimental models of inflammation.16
Therefore, L-selectin and ICAM-1 mediate optimal leukocyte accumulation
during inflammation through overlapping as well as synergistic
functions.
Healing of cutaneous wounds is a complex process that progresses
through three general stages: 1) an inflammatory stage which consists
of platelet aggregation and recruitment of inflammatory cells to the
wound site; 2) a proliferative phase which involves the migration and
proliferation of keratinocytes, fibroblasts, and endothelial cells,
leading to re-epithelialization and granulation tissue formation; and
3) a long remodeling phase.17-19
Migration of
inflammatory cells to the wound site is important in wound repair.
Initially, neutrophils begin accumulating at the wound sites within
minutes of injury.18
Infiltrating neutrophils form a first
line of defense against local infections by clearing foreign particles
and bacteria. Recent studies have shown that neutrophils are also a
source of pro-inflammatory cytokines that probably serve as some of the
earliest signals to activate fibroblasts and
keratinocytes.19
Neutrophils are then extruded with the
eschar or phagocytosed by macrophages. Macrophages enhance the
debridement by phagocytosis of microorganisms and fragments of
extracellular matrix.20
In addition, macrophages are
important producers for a battery of growth factors such as
platelet-derived growth factor (PDGF), transforming growth factor-ß,
basic fibroblast growth factor (bFGF), heparin binding epidermal growth
factor, and transforming growth factor-.17,18
These
factors stimulate the synthesis of extracellular matrix by local
fibroblasts, generate new blood vessels, promote the granulation tissue
formation, and enhance re-epithelialization that takes places by the
migration of the keratinocytes from the edges of the wound toward the
center.17,18
The later stages of wound repair have been suggested to be strongly dependent on the initial inflammatory phase of the healing process. Depletion of macrophages by corticosteroids and anti-macrophage serum delays wound healing.21 Although depletion of neutrophils by anti-neutrophil antibody does not result in delayed wound repair,22 recent studies have shown that pro-inflammatory cytokines, which are predominantly expressed in neutrophils during the early phase of wound repair, are significantly reduced in healing-impaired corticosteroid-treated mice.19 In addition, there is increasing evidence that several adhesion molecules play a critical role in wound repair. Poor wound healing is observed in leukocyte adhesion deficiency type 1 patients who lack expression or function of ß2 integrins and thereby have impaired neutrophil migration into the sites of inflammation.23,24 Recent studies in P-selectin/E-selectin-/- mice demonstrate a direct role of P-selectin and E-selectin in wound healing in vivo.25 However, it is not known whether L-selectin or ICAM-1 contribute to the wound healing process by mediating the recruitment of leukocytes.
As a critical role for L-selectin and ICAM-1 in various inflammatory models has been demonstrated,15,16 we examined the in vivo function of L-selectin and ICAM-1 in wound healing. For this purpose, we analyzed cutaneous wound repair in mice lacking either L-selectin or ICAM-1, or both. The results demonstrate that ICAM-1 and L-selectin contribute to wound healing by mediating accumulation of leukocytes through synergistic functions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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L-selectin-/- mice were produced as described.6 ICAM-1-/- mice13 were obtained from The Jackson Laboratory (Bar Harbor, ME). These ICAM-1-/- mice express residual amounts of ICAM-1 splice variants in the thymus and spleen but not in other organs including skin.26 Mice lacking both L-selectin and ICAM-1 were generated by crossing F1 offspring from crosses of homozygous L-selectin-/- mice with homozygous ICAM-1-/- mice as described.15 All mice were healthy, fertile, and did not display any evidence of infection or disease. All mice were backcrossed between five to 10 generations onto the C57BL/6 background. Mice were 7 to 12 weeks old for all experiments and age-matched wild-type littermates or C57BL/6 mice (Jackson Laboratory) were used as controls. All mice were housed in a specific pathogen-free barrier facility and screened regularly for pathogens. All studies and procedures were approved by the Committee on Animal Experimentation of Kanazawa University School of Medicine.
Wounding and Macroscopic Examination
Mice were anesthetized with diethyl ether and their backs were shaved and wiped with 70% alcohol. Four full-thickness excisional wounds per mouse were made using a disposable sterile 6-mm punch biopsy (Maruho, Osaka, Japan), as described elsewhere.25 After surgery, mice were caged individually. At 3 days and 7 days after wounding, mice were anesthetized, and areas of open wounds were measured by tracing the wound openings onto a transparency. Any signs suggestive for local infection were not detected in the wounded skin. For macroscopic analysis of wound closure, 14 mice were used in each group. After distorted wounds were excluded, one wound was randomly selected in each mouse for the analysis.
Histological Examination and Immunohistochemistry
After the mice were sacrificed, wounds were harvested with a 2-mm rim of unwounded skin tissue. The wounds were cut into halves laterally, fixed in 3.5% paraformaldehyde, and were then paraffin embedded. Six-µm sections were stained with hematoxylin and eosin (H&E). All sections were derived from the center of the wounds. Neutrophils were counted in the entire section outside the blood vessels at 1 hour and 4 hours after wounding. Numbers of macrophages per field (0.07 mm2) were determined by counting in paraffin sections stained with antibody directed against macrophages (clone F4/80, American Type Culture Collection, Rockville, MD) as described below. The epithelial gap, which represents distance between the leading edge of migrating keratinocytes, was measured in H&E-stained sections of wounds. We identified the area that consists of newly formed capillaries and the collection of fibroblasts and macrophages as granulation tissue. Wound sections were visualized in the color monitor (PVM-14M4J, OLYNPUS, Tokyo, Japan) using the CCD camera (CS-900, OLYNPUS, Tokyo, Japan). Then, the area of granulation tissue was gated and measured by the video micrometer (VM-60, OLYNPUS, Tokyo, Japan). The number of mice used for each examination was as follows: 10 in each group for count of neutrophils and macrophages and 14 in each group for measurement of the epithelial gap and the granulation tissue area. After distorted wounds were excluded, one wound was randomly selected in each mouse for every microscopic analysis.
Tissue sections of skin biopsies were acetone-fixed and then incubated with 10% normal rabbit serum in phosphate-buffered saline (PBS) (10 minutes, 37°C) to block nonspecific staining. Sections were then incubated with rat monoclonal antibodies specific for macrophages (F4/80) and mouse ICAM-1 (Coulter, Inc., Miami, FL). Rat immunoglobulin G (Southern Biotechnology Associates Inc., Birmingham, AL) was used as a control for nonspecific staining. Sections were then incubated sequentially (20 minutes, 37°C) with a biotinylated rabbit anti-rat immunoglobulin G secondary antibody (Vectastain ABC method, Vector Laboratories, Burlingame, CA), then horseradish peroxidase-conjugated avidin-biotin complexes (Vectastain ABC method, Vector Laboratories). Sections were washed 3 times with PBS between incubations. Sections were developed with 3,3'-diaminobenzidine tetrahydrochloride and hydrogen peroxide, and then counterstained with methyl green. We identified the area surrounded by both sides of unwounded skin, fascia, regenerated epidermis, and eschar as the wound bed. The measurement of macrophages was performed by averaging the number of cells positive for the F4/80 staining in nine high power fields (magnification, x400) in the wound bed per section. Among the nine fields, six fields were selected from both edges of the wound bed, and the remaining three fields were chosen from the middle of the wound bed.
Application of Growth Factors
An optimal concentration of growth factors was applied to each wound in 20 µl of aqueous buffer, and wounds were covered with an occlusive dressing (Tegaderm, 3M Canada, London, ON). Growth factors were applied to wounds immediately after wounding and 12 hours after wounding. Growth factors and their amounts used in this study were as follows: PDGF B-B isoform (AUSTRAL Biologicals, San Ramon, CA) 800 ng/20 µl; transforming growth factor-ß3 (Novartis Pharmaceutical, Basel, Switzerland) 800 ng/20 µl; and bFGF (Kaken Pharmaceutical, Tokyo, Japan) 1000 ng/20 µl. These optimal amounts of growth factors were determined elsewhere.27 Macroscopic area of the open wound was measured at 3 days and 7 days after wounding. For the analysis, 14 mice were used in each group, and one wound was randomly selected after distorted wounds were excluded in each mouse.
Statistical Analysis
Analysis of variance was used to analyze the data and Mann-Whitney U test was used to determine the level of significance of differences in sample means.
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Results |
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The areas of open wounds were measured at 3 days and 7 days after
wounding to assess macroscopic healing defects (Figure 1A)
. At 3 days after injury, open wound
area was significantly larger in ICAM-1-/- mice
(24% increase, P < 0.0005) and
L-selectin/ICAM-1-/- mice (32%,
P < 0.0001) than that in wild-type mice. At day 7, the
difference was larger than that at day 3 as
ICAM-1-/- mice and
L-selectin/ICAM-1-/- mice exhibited 47%
(P < 0.001) and 66% (P
< 0.0001) larger open wound areas, respectively. By contrast, wound
healing was not delayed in L-selectin-/- mice
relative to wild-type littermates at either day 3 or day 7. The
additional loss of L-selectin in
ICAM-1-/- mice tended to delay wound
healing relative to ICAM-1-/- mice. Therefore,
macroscopic wound healing was delayed in the absence of ICAM-1 whereas
L-selectin loss did not affect macroscopic wound healing.
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Migration of keratinocytes under the eschar was assessed by
microscopically measuring the epithelial gap that is the distance
between the migrating edges of keratinocytes (Figure 1B)
. Keratinocyte
migration was significantly inhibited in
ICAM-1-/- mice relative to wild-type mice at
day 3 after wounding (by 27%, P < 0.05) and day 7
after wounding (44%, P < 0.05). Similarly,
L-selectin/ICAM-1-/- mice exhibited significant
inhibition of keratinocyte migration at both day 3 (by 52%,
P < 0.0001) and day 7 after wounding (63%,
P < 0.01) when compared with wild-type mice. The loss
of both L-selectin and ICAM-1 resulted in a significant inhibition of
keratinocyte migration relative to ICAM-1 loss alone
(P < 0.05) at 3 days after wounding, but this
difference was no longer significant at 7 days after injury. The
L-selectin deficiency alone did not significantly impair migration of
keratinocytes at either day 3 or day 7. Thus, although keratinocyte
migration was normal in L-selectin-/- mice,
keratinocyte migration in L-selectin/ICAM-1-/-
mice was significantly inhibited beyond the inhibition associated with
ICAM-1 deficiency alone.
Granulation Tissue Formation
The area of granulation tissue was microscopically measured
because granulation tissue formation is one of the most important
components in wound repair (Figure 1C)
. At 3 days after wounding,
granulation tissue formation was significantly reduced in
ICAM-1-/- (41%, P < 0.0005)
and L-selectin/ICAM-1-/- mice (52%,
P < 0.0001) relative to wild-type controls. At 7 days
after injury, granulation tissue formation was also inhibited in
ICAM-1-/- mice (23%, P <
0.005) and in L-selectin/ICAM-1-/- mice (30%,
P < 0.005) when compared with wild-type controls.
Granulation tissue formation was significantly reduced in
L-selectin/ICAM-1-/- mice relative to
ICAM-1-/- mice at day 3
(P < 0.05), but not at day 7. L-selectin
deficiency alone did not affect granulation tissue formation at either
day 3 or day 7. Thus, although ICAM-1 loss alone impaired granulation
tissue formation, the combined L-selectin/ICAM-1 loss resulted in a
greater reduction in granulation tissue formation than the loss of
ICAM-1 alone.
Infiltration of Neutrophils and Macrophages
Numbers of neutrophils that migrated outside the blood vessels
were assessed in the wound tissues (Figures 2 and 3)
.
At 1 hour and 4 hours after wounding, neutrophil numbers were
significantly reduced in ICAM-1-/- mice (53%
and 45%, P < 0.001 and P < 0.0005,
respectively) and L-selectin/ICAM-1-/- mice
(72% and 56%, P < 0.0005). At 1 hour after wounding,
the additional loss of L-selectin in ICAM-1-/-
mice resulted in significantly reduced numbers of neutrophils relative
to ICAM-1-/- mice (P <
0.01), but the difference was no longer significant at 4 hours after
injury. Neutrophil numbers in
L-selectin-/- mice were 20% lower than
those in wild-type mice at 4 hours after injury; however, the
difference did not reach statistical significance
(P = 0.07). Macrophage infiltration was assessed
by immunohistochemistry using the F4/80 mAb (Figures 4 and 5)
.
Macrophage numbers were significantly reduced in
ICAM-1-/- mice (~25%) and
L-selectin/ICAM-1-/- mice (~35%) when
compared with wild-type mice at both 3 days and 7 days after injury
(P < 0.0005). However, there was no difference
in macrophage infiltration between ICAM-1-/-
mice and L-selectin/ICAM-1-/- mice. Thus, the
loss of ICAM-1 resulted in reduced infiltration of both neutrophils and
macrophages, and additional loss of L-selectin in
ICAM-1-/- mice inhibited early neutrophil
infiltration more than ICAM-1-/- mice.
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ICAM-1 has been found on the surface of keratinocytes and
endothelial cells of inflamed skin and several pro-inflammatory
cytokines up-regulate ICAM-1 expression on various types of
cells.5,28
Therefore, ICAM-1 expression was
assessed in the wounded skin immunohistochemically. In normal skins,
ICAM-1 was detected exclusively on endothelial cells (Figure 6A)
. ICAM-1 expression was up-regulated
on endothelial cells in granulation tissues at both 3 days
and 7 days after wounding (Figure 6, B and C)
. At day 3, keratinocytes
in the migrating edges did not express ICAM-1 (Figure 6B)
. By day 7,
ICAM-1 expression was detected in keratinocytes, particularly basal
keratinocytes, above granulation tissue, although its staining
intensity was much weaker than that of endothelial cells (Figure 6C)
.
By contrast, fibroblasts in granulation tissues did not express ICAM-1
at either 3 days or 7 days after wounding (Figure 6, B and C)
. ICAM-1
expression was not detected in the intact or wounded skin from
ICAM-1-/- mice (data not shown). In addition,
the loss of L-selectin expression did not affect ICAM-1 expression in
the intact or wounded skin (data not shown). Thus, ICAM-1 was
predominantly expressed on wound endothelial cells.
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As neutrophils and macrophages in the initial inflammatory phase
are a source of cytokines and growth factors that promote wound repair,
the effect of growth factors on the delayed wound healing observed in
ICAM-1-/- mice and
L-selectin/ICAM-1-/- mice was examined (Figure 7)
. Wound healing was assessed by
macroscopic area of the open wound at 3 days and 7 days after wounding.
Topical treatment of either bFGF or PDGF that were applied at the time
of injury and 12 hours after injury normalized the delayed wound
healing in ICAM-1-/- mice by 3 days after
injury. Wound repair was also recovered by application of bFGF in
L-selectin/ICAM-1-/- mice to the levels
observed in wild-type littermates by 3 days after wounding. By
contrast, PDGF application did not normalize the delayed wound repair
in L-selectin/ICAM-1-/- mice at both 3 days and
7 days after wounding. Impaired wound healing in
ICAM-1-/- mice and
L-selectin/ICAM-1-/- mice was not affected by
application of transforming growth factor-ß3 at either 3 days or 7
days after injury. Thus, topical application of some growth factors
could normalize the delayed wound healing observed in
ICAM-1-/- mice and
L-selectin/ICAM-1-/- mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. By contrast,
the L-selectin deficiency alone did not affect any of these parameters
in the wound healing process. However, the loss of both L-selectin and
ICAM-1 led to inhibited keratinocyte migration and retarded granulation
tissue formation beyond those caused by loss of ICAM-1 alone at an
early time point after wounding. Therefore, the role of ICAM-1 in
cutaneous wound repair is predominant relative to L-selectin. However,
L-selectin may also contribute to wound repair through overlapping and
synergistic functions with ICAM-1. This is consistent with the finding
that L-selectin and ICAM-1 function synergistically to mediate optimal
rolling as well as to recruit leukocytes into sites of
inflammation.15,16
The impaired wound repair was
accompanied by significantly reduced infiltration of neutrophils and
macrophages in ICAM-1-/- mice and
L-selectin/ICAM-1-/- mice (Figures 2, 3, 4, and 5)
. As the significant difference between
ICAM-1-/- mice and
L-selectin/ICAM-1-/- mice was observed only for
infiltration of neutrophils at 1 hour after wounding, the reduced early
neutrophil infiltration might result in the delayed keratinocyte
migration and retarded granulation tissue formation in
L-selectin/ICAM-1-/- mice relative to
ICAM-1-/- mice. Therefore, the results of this
study demonstrate a distinct role of ICAM-1 and L-selectin in a process
of wound healing and that the delayed wound healing in the absence of
these molecules is likely because of decreased leukocyte accumulation
into the wound site.
Wound healing is normal in both P-selectin-/-
mice and E-selectin-/- mice, although
neutrophil infiltration is reduced in
P-selectin-/- mice at 1 hour and 4 hours after
injury.25
Similarly, this study showed that wound repair
was not impaired in L-selectin-/- mice,
although neutrophil recruitment at 4 hours after injury was slightly
inhibited in these mice (Figures 1, 2, and 3)
. Therefore, the loss of a
single selectin member is not sufficient to cause impaired wound
healing. Although L-, P-, and E-selectin have distinct roles, the
selectins support optimal leukocyte rolling through overlapping
functions.2
In the absence of L-selectin or E-selectin,
P-selectin primarily mediates rolling whereas L-selectin primarily
mediates rolling in P-selectin-/-
mice.8,29-31
The loss of both P-selectin and E-selectin
leads to delayed wound repair and inhibited keratinocyte migration at 3
days, but not at 7 days after wounding.25
Significantly
decreased numbers of infiltrating neutrophils and macrophages in
P-selectin/E-selectin-/- mice may contribute to
the delayed wound repair. Therefore, reduced leukocyte rolling by
combined loss of the selectins may cause the defect in the wound
healing process.
The loss of ICAM-1 expression resulted in dramatic inhibition of wound
healing at both 3 days and 7 days after wounding (Figure 1)
. Because
wound repair is delayed in
P-selectin/E-selectin-/- mice at 3 days, but
not 7 days after injury,25
the loss of ICAM-1 resulted in
greater effect on wound repair than the combined loss of P-selectin and
E-selectin. This suggests that ICAM-1-mediated firm adhesion and
transmigration of leukocytes contribute to wound repair more than
selectin-mediated rolling. In normal skin, ICAM-1 was expressed
exclusively on endothelial cells (Figure 6)
. However, ICAM-1 expression
on various types of cells, including keratinocytes and fibroblasts, is
induced by stimulation with several pro-inflammatory cytokines in
vitro.5,28
Furthermore, the ICAM-1 expression on
fibroblasts may mediate migration of neutrophils and macrophages
through fibroblast layers.32,33
Therefore, the loss of
ICAM-1 expression on fibroblasts and keratinocytes might contribute to
the delayed wound healing observed in ICAM-1-/-
mice. ICAM-1 expression on endothelial cells was up-regulated in
granulation tissues of the wounded skin (Figure 6)
. However,
fibroblasts in granulation tissues did not express ICAM-1 and basal
keratinocytes of the epidermis above granulation tissues were weakly
positive for ICAM-1. This suggests that the delayed wound healing in
the absence of ICAM-1 is attributed mainly to impaired interaction
between leukocytes and endothelial cells by loss of ICAM-1 expression
on endothelial cells. Taken together, these findings demonstrate a
critical role of ICAM-1 in wound healing.
Treatment of bFGF normalized the delayed wound repair in both
ICAM-1-/- mice and
L-selectin/ICAM-1-/- mice (Figure 7)
. bFGF acts
mainly as a potent angiogenic factor during wound healing because wound
angiogenesis is almost completely blocked when this growth factor is
experimentally depleted with monospecific antibodies raised against
bFGF.34
Furthermore, bFGF promotes angiogenesis during the
early stage of wound healing.35
Therefore, angiogenesis
enhanced by exogenous bFGF application may overcome the reduced
infiltration of neutrophils and macrophages by the loss of ICAM alone
or both ICAM-1 and L-selectin, leading to the normalization of wound
repair. bFGF is released at the wound site by macrophages and damaged
endothelial cells.17,18
The decreased release of bFGF by
reduced numbers of wound macrophages might account for the impaired
wound repair in both ICAM-1-/- mice and
L-selectin/ICAM-1-/- mice. PDGF accelerates
deposition of provisional wound matrix and collagen synthesis by
fibroblasts.36
Early in repair, PDGF augments the acute
inflammatory response, specifically recruiting and activating wound
macrophages.37
PDGF is also a chemoattractant for wound
fibroblasts.37
These various functions of PDGF may
cooperatively normalize the delayed wound healing in
ICAM-1-/- mice. By contrast, PDGF activities
were not sufficient for normalization of impaired wound repair in
L-selectin/ICAM-1-/- mice. This reinforces an
important role of L-selectin in wound healing.
Understanding regulation of cutaneous wound repair at the molecular level is important because there are many disorders based on abnormal wound repair, including stasis ulcer, diabetic ulcer, keloids, and hypertrophic scars.17 Understanding the contributions of L-selectin and ICAM-1 to the wound repair process could provide new clues to regulating wound healing.
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Acknowledgements |
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Footnotes |
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Supported by a grant from NOVARTIS Foundation (Japan) for the promotion of science (to S. S.) and National Institutes of Health grants AI26872, CA54464, and HL50985 (to T. F. T.).
Accepted for publication April 13, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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but not interleukin-1 induces polymorphonuclear leukocyte migration through fibroblast layers by a fibroblast-dependent mechanism. Immunology 1991, 74:107-113[Medline]
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Y. Hamaguchi, Y. Nishizawa, M. Yasui, M. Hasegawa, Y. Kaburagi, K. Komura, T. Nagaoka, E. Saito, Y. Shimada, K. Takehara, et al. Intercellular Adhesion Molecule-1 and L-Selectin Regulate Bleomycin-Induced Lung Fibrosis Am. J. Pathol., November 1, 2002; 161(5): 1607 - 1618. [Abstract] [Full Text] [PDF]
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Y. Kaburagi, M. Hasegawa, T. Nagaoka, Y. Shimada, Y. Hamaguchi, K. Komura, E. Saito, K. Yanaba, K. Takehara, T. Kadono, et al. The Cutaneous Reverse Arthus Reaction Requires Intercellular Adhesion Molecule 1 and L-Selectin Expression J. Immunol., March 15, 2002; 168(6): 2970 - 2978. [Abstract] [Full Text] [PDF]
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G. F. Pierce Inflammation in Nonhealing Diabetic Wounds : The Space-Time Continuum Does Matter Am. J. Pathol., August 1, 2001; 159(2): 399 - 403. [Full Text]
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