Department of Dermatology, University of Würzburg Medical School, Würzburg, Germany
Correspondence: Reinhard Gillitzer, M.D., Department of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. E-mail: gillitzer-r.derma{at}mail.uni-wuerzburg.de
 TOP ABSTRACT BIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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Key Words: tissue repair • angiogenesis • inflammation • neutrophil migration • keratinocytes
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TOPABSTRACTBIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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Wound healing, whether sterile or not, is accompanied, for instance, by an inflammatory reaction, which does not subside with epithelialization. It rather persists until tissue remodeling, albeit with a different cellular composition as opposed to the early acute phase [2 , 3 ] and influences catabolic and anabolic reactions of tissue repair. In skin wound healing—the standard model of wound healing—the leukocyte subsets, as the cellular components of inflammation, are not only immunological effector cells against invading environmental pathogens but are also involved in the anabolic phase of tissue degradation through production of proteases and reactive oxygen intermediates and, in particular, in the catabolic phase of tissue formation through production of growth factors [4 ]. Therefore, understanding the network of wound healing requires a profound analysis of all soluble mediators and adhesion factors involved in the recruitment and trafficking of leukocytes during the inflammatory reaction.
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TOPABSTRACTBIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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(GRO-) (CXCL1) by vessel-associated cells (endothelial cells
and pericytes) [16
], which in contrast to NAP-2 has to
be newly synthesized, promotes further the process of neutrophil
diapedesis. Notably, in contrast to GRO-, we were unable to detect
interleukin (IL)-8 (CXCL8) mRNA expression in endothelial cells in
neutrophil-rich skin tissue (wound healing, psoriasis)
[5
, 17
], and in situ data from
lipopolysaccharide (LPS)-treated guinea pigs also demonstrated
selective endothelial expression of GRO- but not IL-8
[18
]. The recruitment of neutrophils is further
supported by ENA-78 (CXCL5), which is expressed at lower levels as
compared with GRO- in single mononuclear cells within the
provisional matrix of the wound (unpublished results). All three
chemokines (NAP-2, GRO-, and ENA-78) interact at physiological
concentrations with CXCR2 on neutrophils (see [12
,
19
] for review). It is well-known that chemotactic
responses saturate with increasing concentrations of attractants
specific for one receptor, which is a result of unresponsiveness
(desensitization) and down-regulation of the receptor
[19
]. Therefore, neutrophils would stop moving after
diapedesis and reside diffusely distributed in the blood clot. This
transient unresponsiveness to CXCR2-specific chemokines may be overcome
by the strong and selective expression of IL-8 under the wound surface,
the area of the highest concentration of neutrophil-specific chemokines
(Fig. 2
). Because IL-8 also stimulates the CXCR1 on neutrophils
[19
], they will be able to mount a second response and
migrate to the superficial wound bed. It is interesting that the
induction of the respiratory burst in neutrophils depends on
interaction of IL-8 with exclusively CXCR1 rather than with CXCR2
[20
]; thus, early and deleterious activation of
neutrophils prior to arriving at the wound surface can be avoided. The
band-like colocalization of neutrophils and, to a lesser extent,
macrophages with IL-8 on the denuded wound surface indicates that both
leukocyte subtypes produce IL-8 and attract further neutrophils. This
may be accelerated by GRO-, which is albeit at a lower concentration
coexpressed with IL-8 [5
].
 View larger version (35K): [in a new window] |
Figure 1. Model of neutrophil migration in incisional human-skin wounds. After
acute injury, platelets and neutrophils are released passively from
destroyed blood vessels. Platelets not only release growth factors but
also mediators such as CTAP-III, which is processed to NAP-2 by
proteases released from attached neutrophils. NAP-2 stimulates
migration and extravasation of neutrophils via CXCR2. In addition,
vessel-associated cells and endothelial cells produce GRO-, which
supports diapedesis of neutrophils. Further migration of
neutrophils is stimulated by dermal GRO- and ENA-78, expressed by
mononuclear cells in the provisional matrix. Continuous stimulation by
these chemokines via CXCR2 causes transient unresponsiveness of
neutrophils. This may be overcome by interaction of IL-8 with the
neutrophil CXCR1, which is not targeted by GRO- or ENA-78. IL-8,
which is expressed strongly in a band-like pattern by neutrophils
themselves and macrophages immediately below the denuded wound surface,
further mediates the recruitment of large numbers of neutrophils. The
strong expression of IL-8 below the wound surface is induced by
proinflammatory cytokines such as IL-1 and TNF-, bacterial products
(LPS), and hypoxia. In addition, peak levels of IL-8 below the wound
surface may stimulate migration and proliferation of keratinocytes,
which express the CXCR2 at the wound edge. Arrows indicate chemokine
gradients pointing from higher to lower concentrations.
|
 View larger version (125K): [in a new window] |
Figure 2. Strong expression of IL-8 mRNA 24 h after incisional wounding of
human skin. IL-8 mRNA is expressed in a rim of inflammatory cells
(neutrophils and macrophages) exclusively at the denuded wound surface,
whereas expression is quiescent in cells residing in the provisional
matrix below. In situ hybridization with
35S-UTP-labeled IL-8 anti-sense probe. (A,
Bright-field illumination; B, dark-field illumination)._art>
|
, and MCP-1 (CCL2)
are not available currently and remain speculative. The concept of multistep neutrophil migration is supported by data from Ludwig and colleagues [21 ], who demonstrated that CXC receptors, CXCR1 and CXCR2, are involved differentially in the chemotactic response of neutrophils to NAP-2. Low concentrations of NAP-2 led to down-regulation of the high-affinity CXCR2, whereas neutrophils are still responsive to IL-8 or high concentrations of NAP-2 via CXCR1. NAP-2 may be particularly important in occluded blood vessels, which are typically seen after an acute injury.
Albeit many resident skin cells and infiltrating leukocyte subsets are
capable of producing IL-8 and/or GRO- when stimulated appropriately
under in vitro conditions, expression in the setting of
cutaneous wound healing is timely and spatially strongly restricted
[5
]. As demonstrated in Figure 2
, IL-8 expression levels
peak at day 1 exclusively in those cells that line the uppermost part
of the wound, namely neutrophils and macrophages, and subside when
wound closure is completed. A similar situation as in skin wounds is
seen in psoriasis where neutrophils migrate to the upper epidermal
layer [22
]. In both conditions, IL-8 is produced by
upper-level neutrophils, whereas within the dermal compartment, only
GRO- and, in the case of wound healing, ENA-78 message is detectable
[5
, 17
, 22
]. Beside direct
induction of chemokines by bacterial products (e.g.,
lipopolysaccharides), the proinflammatory cytokines tumor necrosis
factor (TNF-) and IL-1 are expressed initially and predominantly
by neutrophils within a few hours after wounding and appear to act as
main inducers of chemokines [23
]. This is in accordance
with peak levels of IL-8 detected at day 1 [5
]. At later
stages of the repair process, expression of IL-1 and TNF- is also
seen in macrophages [23
]. The hypoxic situation
immediately below the wound surface may furthermore amplify IL-8
expression [24
]. This situation would resemble that
observed in tumors, where IL-8 is expressed particularly in
hypoxic/necrotic areas by neutrophils and tumor cells
[25
].
The simultaneous expression of several neutrophil-attractant chemokines in the acute phase of inflammation during wound healing may at first sight refer to the redundancy and robustness of the chemokine system as suggested by Mantovani [26 ]. The spatially and timely differential expression of multiple neutrophil-specific chemokines, however, argues strongly in favor of a sophisticated multistep event, which enables neutrophils to leave occluded vessels and to bridge a rather long distance rapidly to the denuded wound surface, which is severely prone to infections with extrinsic pathogens. It is interesting that because of the long half-life of IL-8 mRNA [27 ], it persists in neutrophils that are entrapped in the crust above the newly built epidermis [5 ].
Inasmuch as chemokines perpetuate inflammation, several mechanisms
operate to limit and down-regulate this activity. Such mechanisms
include down-regulation of chemokine expression by anti-inflammatory
cytokines such as IL-10 [28
], receptor unresponsiveness,
and down-regulation by high concentrations of ligands
[19
]. Furthermore, proinflammatory cytokines such as
TNF- not only induce IL-8 but may also conversely suppress CXCR2
expression on neutrophils [29
]. Whether
metalloproteinases down-regulate inflammation in wound healing via
cleavage of chemokines, which then act as antagonists as has recently
been shown for gelatinase A and MCP-3 (CCL7) in vitro
[30
], remains to be elucidated in vivo.
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(MIP-1; CCL3) and MIP-1ß (CCL4), I309 (CCL1), and
monocyte chemoattractant protein-1 (MCP-1) and MCP-3], MCP-1 was
almost exclusively found to be expressed during the first week after
wounding (Fig. 3
; [5
] and unpublished results). The multiple
functions of MCP-1 during wound healing are summarized schematically in
Figure 4
. Almost 20% of total cells (resident and infiltrating mononuclear
cells) expressed MCP-1 mRNA 1 day after wounding. Notably, after day 2,
MCP-1 was also expressed by basal keratinocytes at the wound edge,
which are hyperproliferative and the cellular source for migrating
keratinocytes to cover the wound surface. Thus, keratinocytes
contribute significantly to the inflammatory network in wounds. A
comparable MCP-1 expression pattern has been observed in human burn
wounds [32
]. The expression profile of MCP-1 is quite
reminiscent to the situation in psoriasis where basal
hyperproliferative keratinocytes produce MCP-1 and attract macrophages
[33
]. In analogy to neutrophils, it appears most likely
that macrophages also face different chemokine gradients. Considerable
amounts of additional monocyte-attractant chemokines have, at least in
human skin wounds, not been described. In murine skin-wound healing
models, however, MIP-1 and RANTES have, in addition to MCP-1, been
shown to play a critical role in macrophage recruitment
[34
35
36
37
38
]. This strongly indicates that data obtained
from animal models, in particular in mice with a different skin
morphology, are not easily transferable to the human wound-healing
situation. Therefore, murine transgenic and knock-out models may only
be of limited value for understanding wound healing in humans.
 View larger version (142K): [in a new window] |
Figure 3. MCP-1 mRNA expression in human skin 2 days after skin wounding. MCP-1
mRNA expression is detected by in situ hybridization with
35S-UTP-labeled MCP-1 anti-sense probe after
removing the artificially blistered epidermis. MCP-1 is expressed by
mononuclear inflammatory cells and in vessel areas within the full
depth of the dermis. (A, Bright-field illumination; B, dark-field
illumination).
|
 View larger version (34K): [in a new window] |
Figure 4. Model of MCP-1 expression and function in human skin wound healing.
MCP-1 is highly produced by resident cells (keratinocytes at the wound
edge, endothelial cells) and inflammatory cells (macrophages) and may
thus participate at different stages of monocyte, mast cell, and
lymphocyte attraction during cutaneous wound healing. Attracted
macrophages and lymphocytes produce regulatory and growth-promoting
factors. Mast cells release IL-4, which may stimulate fibroblast
activities and down-regulate MCP-1 expression. In addition, MCP-1 may
also contribute to endothelial-cell locomotion during angiogenesis.
Arrows indicate MCP-1 gradients pointing from higher to lower
concentrations.
|
Our own data suggest that during wound healing, MCP-1 does not only attract monocytes but also, at later time points, mast cells [9 ] (Fig. 4) . The fivefold increase in mast-cell numbers during wound healing is a result of an increased recruitment rather than proliferation.
Because these mast cells produce high levels of IL-4, which in turn stimulates proliferation of fibroblasts [39 ], MCP-1 does stimulate wound healing via recruitment of different leukocyte subsets. High levels of IL-4 may, as mentioned above, also down-regulate the expression of chemokines, e.g., MCP-1 and IL-8 [40 ], thus limiting the inflammatory reaction.
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TOPABSTRACTBIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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-inducible protein-10 (IP-10) (CXCL10), monokine
induced by interferon- (Mig) (CXCL9), and macrophage-derived
chemokine (MDC) (CCL22) are found to be spatially associated
with lymphocyte accumulation ([5
] and unpublished
results). The expression of all other lymphocyte-specific chemokines
investigated [TARC (CCL17), PARC (CCL18), LARC (CCL20), I-TAC
(CXCL11)] was quiescent or low. Most likely, macrophages are
the major source of these chemokines. Because IP-10 and Mig are induced
selectively by interferons (IFNs) [41
], their strong
expression from day 4 onward reflects a major shift in the cytokine
profile from TNF-/IL-1 to IFN-. |
TOPABSTRACTBIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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also elicit responses in nonhematopoietic
cells, namely in keratinocytes and endothelial cells. In
vitro studies have demonstrated that IL-8 is capable of
stimulating human keratinocyte migration and proliferation
[42
43
44
45
]. In healing incisional human wounds, IL-8 is
highly expressed along the denuded wound surface exactly where
keratinocytes migrate from the wound edge to close the epidermal defect
as schematically shown in Figure 1
. Expression of GRO- is
colocalized with IL-8, but GRO- mRNA levels are significantly lower
[5
]. Comparable results regarding GRO- were shown by
Nanney et al. [46
]. Keratinocytes have been
found to express CXCR2, the receptor for IL-8 and GRO-
[42
, 46
, 47
]. When studying
wound healing in CXCR2-/- mice, Devalaraja and colleagues
[48
] observed a severely retarded reepithelization
process in vivo as well as an impaired closure of
"wound" defects in confluent cultures of CXCR2-/- keratinocytes
in vitro. These data suggest that interaction of
keratinocyte CXCR2 with its ligand(s), IL-8 and GRO- in the human
system and MIP-2 and KC (CXCL1) in the murine system, plays a role
during wound repair. Topical application of IL-8 or GRO- to wounds
elicited in mouse skin appears to have a favorable but not overwhelming
effect on reepithelization [45
, 49
]. |
TOPABSTRACTBIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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Endothelial cells comprise of a broad repertoire of chemokines, which
may be expressed after appropriate stimulation. These include CC
chemokines such as MCP-1 and RANTES as well as CXC family members like
IL-8, GRO-, IP-10, Mig, and others [16
]. Chemokines,
as e.g., IL-8, may furthermore be presented by endothelial surface
glycosaminoglycans to allow interaction with leukocytes to be recruited
from the intraluminal compartment [50
]. Expression of,
e.g., MCP-1 by endothelial cells contributes to the establishment of a
chemokine gradient, which facilitates subset-specific recruitment of
leukocytes to sites of inflammation [51
]. Under flow
conditions, MCP-1 triggers firm adhesion of rolling monocytes to
E-selectin-expressing vascular endothelium [52
]. During
wound healing, MCP-1 mRNA can be detected in blood vessel areas
especially [5
, 32
]. However, because of the
strong signal intensity and the preponderance of MCP-1-expressing
mononuclear cells, the portion of endothelially expressed MCP-1 cannot
be estimated reliably (Fig. 3)
. Similar observations regarding GRO-
message have been made by Engelhardt et al.
[5
], whereas in another study, GRO- protein could not
be detected [46
]. Endothelial expression of other
proinflammatory, cytokine-inducible chemokines such as IL-8 or RANTES
under the conditions of wound healing has so far not been described.
The process of angiogenesis is closely related to the formation of granulation tissue. It depends on the concerted action of multiple factors produced by a variety of cells. These include macrophages and keratinocytes, which produce angiogenic factors such as vascular endothelial growth factor (see [6 ] and [53 ] for review). In parallel, proteolytic enzymes are released, which degrade extracellular matrix proteins to allow endothelial cell migration and formation of new vessels at sites of injury. Conversely, angiogenesis has to cease when the wound defect is filled with granulation tissue. These sequential events reflect temporal changes in the balance between (pro)angiogenic and angiostatic factors.
Chemokines, especially those of the CXC family, have been attributed to
a role for the regulation of angiogenesis. The work of Strieter and
colleagues (see [13
] for review) demonstrated that CXC
chemokines, which contain a Glu-Leu-Arg (ELR) motif [54
]
adjacent to their first cysteine amino acid in the NH2
terminus, are potent promoters of angiogenesis. This group of
ELR-containing chemokines includes IL-8, GRO-, GRO-ß (CXCL2),
GRO (CXCL3), as well as CTAP-III, ß-thromboglobulin, and
NAP-2 and is described to induce endothelial cell proliferation
in vitro and angiogenesis in vivo (see
[13
] for review). Studying expression of the
ELR-positive chemokines IL-8 (Fig. 2)
and GRO- in a human
wound-healing model, we found strong expression of both during days
1–4 after wounding. The expression levels of IL-8 and GRO-
correlated with an increasing number of vessels. After day 4,
expression of IL-8 and GRO- declined markedly, and vascularization
ceased concomitantly [5
]. Investigating cutaneous wound
repair after burns in humans, Nanney and colleagues [46
]
found strong expression of GRO- at dermal and epidermal sites as
well. In another species, chicken, the CXC chemokine 9E3/CEF4, which is
highly homologous to human IL-8 and GRO-, is strongly up-regulated
within the granulation tissue of wounded areas, especially at sites of
neovascularization [55
]. Furthermore, this avian
chemokine induces chemotaxis of endothelial cells and is angiogenic in
the chorioallantoic membrane assay [56
]. Because all
ELR-positive chemokines bind to the CXCR2, the latter is supposed to be
responsible for mediation of the angiogenic activity
[13
]. However, the detection of CXCR2 chemokine
receptors on endothelial cells is a controversal issue. In contrast to
Nanney et al. [46
], Kulke and colleagues
[47
] could not demonstrate CXCR2 expression by
endothelial cells in nondiseased skin. Similarly, conflicting data
exist regarding the in vitro expression of CXCR2 on
endothelium: Some groups identified CXCR2 expression by cultured
endothelial cells, whereas others could not confirm such data
[19
, 57
58
59
60
]. Investigating wound healing
in CXCR2 knock-out mice, Devalaraja et al.
[48
] not only found decreased recruitment of neutrophils
and reduced keratinocyte migration and proliferation during
epithelialization but also a significant delay in neovascularization.
They postulated that this would be a result of the diminished
angiogenic response toward MIP-2, the functional homologue of IL-8 in
the murine system.
The chemokine SDF-1 (CXCL12) is the only CXC subfamily member that
is angiogenic despite lacking the ELR motif [60
]. It
specifically binds to CXCR4 receptors on endothelial cells, induces
endothelial cell chemotaxis and formation of blood vessels
[60
, 61
], and appears to be important for
vascularization of the gastrointestinal tract [62
].
Whereas the angiogenic capacity of SDF-1-CXCR4 interaction has not
been elucidated yet during wound healing, a model has been proposed in
which vascular endothelial growth factor (VEGF) and basic fibroblast
growth factor (bFGF) up-regulate endothelial CXCR4 expression on
endothelial cells, which subsequently show increased responsiveness to
SDF-1 [60
, 63
]. However, because
SDF-1 and CXCR4 are already found to be strongly expressed by
endothelial and other cells in normal skin [64
], the
impact of these on angiogenesis during wound healing remains illusive.
Beyond direct angiogenic effects of chemokines, indirect mechanisms of
action have been demonstrated. DiPietro et al.
[35
] found that in the murine system, depletion of wound
MIP-1 by a neutralizing anti-serum significantly reduced angiogenic
activity of wound homogenates. MIP-1 does not appear to be a direct
angiogenic factor but promotes recruitment of macrophages to wound
sites, which in turn act as a source of angiogenic cytokines. A rather
similar role may be conceivable for MCP-1 [65
], which is
highly expressed during the course of wound repair [5
,
32
, 34
, 37
]. This indirect
action of MCP-1 has been challenged recently: Weber et al.
[66
] demonstrated expression of the MCP-1 receptor CCR2
by endothelial cells and migration of the latter upon stimulation with
MCP-1. Proliferation of endothelial cells, however, was not altered.
Basically, Salcedo and colleagues [67
] came to similar
results.
CXC chemokines lacking the ELR motif such as the IFN--inducible
cytokines IP-10, Mig, or I-TAC act as efficient inhibitors of
angiogenesis [13
, 54
]: They not only fail
to induce endothelial cell chemotaxis in vitro or corneal
neovascularization in vivo but also act as angiostatic
factors in the presence of ELR-positive chemokines or bFGF. The mode of
angiostatic action, however, is not clear yet. Neither cultured
endothelial cells [59
, 60
] nor endothelium
studied in normal skin or during wound healing in situ
(unpublished results) have been found to express CXCR3, the receptor
for IP-10, Mig, and I-TAC. Therefore, it is possible that the
angiostatic effects of these chemokines are mediated by an as yet
unidentified endothelial receptor or occur in an indirect manner. In
transgenic mice overexpressing IP-10 in the epidermis under control of
a keratin promoter, wound healing was disturbed by a prolonged and
disorganized granulation phase with impaired blood-vessel formation
[68
]. In a human wound-healing model, we detected
maximum levels of IP-10 and Mig expression with the onset of
angiostasis, i.e., cessation of endothelial cell proliferation
[5
].
|
TOPABSTRACTBIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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and, occasionally,
the corresponding receptor CXCR2 have been observed recently in
keloids, benign collagenous tumors that occur during dermal wound
healing in genetically predisposed individuals [72
].
Such an expression pattern, which was probably induced by
proinflammatory cytokines, was not detected in hypertrophic scars or
normal skin by these authors. Recent data suggest that fibroblasts are not only producers of but also targets for chemokines. Gharaee-Kermani and colleagues [73 ] showed that exposure of rat fibroblasts to MCP-1 resulted in the expression of transforming growth factor-ß (TGF-ß) as well as in collagen synthesis. More recent data by Yamamoto and colleagues [74 ] indicated that MCP-1 enhances gene expression of matrix metalloproteinase-1 (MMP-1) as well as of metalloproteinase-1 (TIMP-1) tissue inhibitor in primary human dermal fibroblasts. Thus, MCP-1 may act, at least in vitro, at the same time as profibrotic as well as collagenolytic mediator. It is not clear yet whether these paradoxically appearing observations are of relevance in vivo.
In this context, it is interesting to mention that chemokines such as
IL-8, RANTES, MIP-1, MIP-1ß, and/or MCP-1 induce expression of
metalloproteinases in various leukocyte subtypes
[75
76
77
]. Thus, chemokines not only regulate locomotion
of resident and passenger cells but may also influence tissue
remodeling.
Moreover, IP-10, an ELR-negative CXC chemokine with angiostatic properties (see above), inhibits epidermal growth factor-induced motility of fibroblasts [78 ]. This in vitro observation fits very well with our data demonstrating that IP-10 and Mig are expressed highly in the late phase of normal wound healing after day 4 [5 ], thus limiting recruitment of fibroblasts and consecutive, excessive scarring. High concentrations of another ELR-negative CXC chemokine, platelet factor-4 (PF4, CXCL4)—present at high concentrations within and in close vicinity to the platelet plug as a result of platelet degranulation immediately after wounding—might result in the arrest and accumulation of migrating/infiltrating fibroblasts. In addition, PF4 inhibits the mitogenic activity of bFGF on fibroblasts [79 ], which, however, appears to be less desirable during early phases of wound healing. Taken together, these ELR-negative CXC chemokines exhibit growth-inhibitory functions in the later phase of wound healing and could possibly provide a therapeutic approach against excessive wound healing, as seen in hypertrophic scarring or keloid formation (Table 1).
|
View this table: [in a new window] |
Table 1. Chemokines and their Target Cells in Cutaneous Wound
Healinga
|
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TOPABSTRACTBIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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, Mig, IP-10,
PF4) has to be taken into account. Therefore, the orchestrated
processes of wound healing with respect to treatment certainly require
a highly complex and sophisticated approach and should target
chemokines as important traffic lights for migration of resident and
inflammatory cells as well as essential regulators of repair
mechanisms.
Received December 1, 2000; revised January 8, 2001; accepted January 16, 2001.
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TOPABSTRACTBIOLOGY OF WOUND HEALINGINFLAMMATION IN WOUND HEALINGNEUTROPHIL RECRUITMENTMACROPHAGE AND MAST-CELL...LYMPHOCYTE RECRUITMENTCHEMOKINES AND...ENDOTHELIAL CELLS AND...FIBROBLASTS AND CHEMOKINESCHEMOKINES IN WOUND...REFERENCES |
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, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing Am. J. Pathol. 153,1849-1860 and IL-8 mRNA in psoriasis: a model for neutrophil migration and accumulation in vivo J. Investig. Dermatol. 107,778-782[Medline] gene and its rapid expression in the tissues of lipopolysaccharide-injected guinea pigs Int. Arch. Allergy Immunol. 119,101-111[Medline] J. Immunol. 160,4518-4525 as a critical macrophage chemoattractant in murine wound repair J. Clin. Invest. 101,1693-1698[Medline] Am. J. Pathol. 154,1125-1135 loop J. Immunol. 164,6174-6179Related Articles
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 E. C. Keeley, B. Mehrad, and R. M. Strieter Chemokines as Mediators of Neovascularization Arterioscler. Thromb. Vasc. Biol., November 1, 2008; 28(11): 1928 - 1936. [Abstract] [Full Text] [PDF]
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D. A. Armstrong, J. A. Major, A. Chudyk, and T. A. Hamilton Neutrophil chemoattractant genes KC and MIP-2 are expressed in different cell populations at sites of surgical injury J. Leukoc. Biol., April 1, 2004; 75(4): 641 - 648. [Abstract] [Full Text] [PDF]
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E. Nemoto, H. Tada, and H. Shimauchi Disruption of CD40/CD40 ligand interaction with cleavage of CD40 on human gingival fibroblasts by human leukocyte elastase resulting in down-regulation of chemokine production J. Leukoc. Biol., September 1, 2002; 72(3): 538 - 545. [Abstract] [Full Text] [PDF]
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J. C. Varela, M. H. Goldstein, H. V. Baker, and G. S. Schultz Microarray Analysis of Gene Expression Patterns during Healing of Rat Corneas after Excimer Laser Photorefractive Keratectomy Invest. Ophthalmol. Vis. Sci., June 1, 2002; 43(6): 1772 - 1782. [Abstract] [Full Text] [PDF]
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