Inflammation is a key phase in the cutaneous wound repair process. The activation of inflammatory cells is critical for preventing infection in contaminated wounds and results in the release of an array of mediators, some of which stimulate the activity of keratinocytes, endothelial cells, and fibroblasts to aid in the repair process. However, there is an abundance of data suggesting that the strength of the inflammatory response early in the healing process correlates directly with the amount of scar tissue that will eventually form. This review will summarize the literature related to inflammation and cutaneous scar formation, highlight recent discoveries, and discuss potential treatment modalities that target inflammation to minimize scarring.
The repair of wounds in mature skin has been studied extensively. This process is highly complex and interactive, and it is made up of a series of well-defined stages that include inflammation, proliferation, and remodeling/scar formation[
Although inflammation occurs relatively early after injury, it can impact later stages of repair such as scar formation. In the early stages of repair, the primary functions of inflammation are to clean the wound site, clear debris, and prevent infection[
A large number of studies suggest that the level of inflammation in injured skin correlates directly with scar formation. A direct association between the extent of injury (and hence the levels of inflammation) and the amount of scarring that will ultimately result from the wound healing process has been established. For example, larger/deeper wounds or injuries that cause more severe damage are associated with higher levels of inflammation and heal with more scar tissue[
Summary of the relationship between scarring and inflammation. Most studies published to date indicate that the robustness of the inflammatory response resulting from skin injury correlates with the amount of scar tissue that will be produced, with low levels of inflammation in scarless wounds and high levels of inflammation in cases of abnormal or excessive scarring
Keloids are abnormal, raised scars that develop after injury. These scars display some similarities with tumors, as they tend to invade the adjacent skin and extend beyond the initial site of injury. There are no widely accepted experimental animal models of keloid disease, so studies on keloid pathogenesis are generally limited to experiments on tissue from human patients. A number of studies have examined inflammation in keloid tissue and the vast majority have indicated that keloids are associated with an increase in pro-inflammatory mediators and inflammatory cells.
Several studies have suggested an increase in pro-inflammatory mediator expression in keloids. A study by Zhang
In addition to pro-inflammatory mediators, several inflammatory cell types are prominent in keloids, particularly mast cells and macrophages. A study by Dong
A more comprehensive analysis of inflammatory and immune cells was performed by Bagabir
While most published studies indicate an increase in mast cells and macrophages in keloid scars, one study comparing human keloids and equine exuberant granulation tissue (a fibrotic condition suggested to have some similarities to human keloids) reported minimal mast cells and macrophages in both fibrotic conditions[
HTS, which are raised red scars, also fall into the category of abnormal scars. Unlike keloids, HTS are confined to the borders of the original wound. A wide range of studies in both small and large animal models as well as human clinical samples have examined inflammation in hypertrophic scarring.
Several rodent models of HTS have been described. One such model uses the application of a mechanical loading device to apply tension to wounds, inducing a HTS-like phenotype reminiscent of human HTS[
Large animal models, such as pigs, are considered by many to be an ideal wound healing model based on similarities in skin anatomy between pig and human. A study by Harunari
In human HTS, there are conflicting results regarding whether inflammation is enhanced or reduced in HTS. Early studies by Kischer
There are only a few reports examining macrophages in human HTS. In one study comparing normal scars and HTS from breast surgeries, no differences were found in macrophages between scar types[
The data on pro-inflammatory cytokine expression in human HTS also appears to be somewhat mixed. One study compared inflammatory gene expression in a small prospective study comparing patients that developed normal scars or HTS[
Taken together, the data suggest that more detailed analysis of inflammatory cells and inflammatory mediators is needed to definitively show whether inflammation is associated with hypertrophic scarring in humans.
It is well established that developing fetal skin is capable of healing wounds in a scarless, regenerative manner at certain gestational stages. Fetal skin heals scarlessly at early stages of development (until about the third trimester), but as the skin matures at later stages of development it heals through a fibrotic repair process that produces a permanent scar[
Several studies have been performed to identify specific differences in the inflammatory response between scarless and fibrotic wounds. Levels of pro-inflammatory mediators, such as lipids (PGE2)[
In addition to reduced pro-inflammatory mediators, fewer inflammatory cells or reduced inflammatory cell activation have been described in scarless fetal wounds. Fetal platelets do not aggregate to the same extent and release lower levels of cytokines compared to adult platelets[
Studies examining human fetal skin also support the idea that less developed skin has a suppressed inflammatory response. An early study by Rowlatt described a lack of an acute inflammatory reaction and granulation tissue formation at the site of limb amputations caused by amniotic constriction bands in a 20 week human fetus[
Besides fetal skin, scarless healing has also been described in mucosal tissues, such as the oral mucosa[
Scarless healing has also been documented in a unique mouse species, the African spiny mouse (
In addition to correlative data, which generally link higher inflammatory mediator levels and/or elevated inflammatory cell numbers in a wound to more abundant scar formation, there are also functional data supporting a role for inflammation in promoting scar formation. These include studies showing that inflammatory cells or inflammatory mediators stimulate scar tissue/collagen production as well as studies showing that depletion or knockdown of inflammatory components reduces scar formation.
Two general approaches have been used to study the function of mast cells in wound healing and scar formation: treatment with mast cell stabilizing drugs and examination of mast cell-deficient mouse strains.
Drugs that act as mast cell stabilizers, which prevent mast cell degranulation, have been used in animal models of wound healing to study the importance of mast cells in scar formation. By preventing mast cell degranulation, these drugs inhibit the release of pre-stored mediators present within the granules. Disodium cromoglycate (also known as cromolyn) has been shown to reduce collagen content in a rat model when injected directly into wounds[
The role of mast cells in scar formation has also been examined in mast cell-deficient mouse strains (either naturally occurring mutants or genetically modified mice), and the results seem to differ depending on the mouse strain and wound model used. KitW/W-v mice are mutant mice that lack mast cells due to functional mutations in the tyrosine kinase receptor c-kit, which binds an important growth factor for mast cells (stem cell factor). Younan
Several mutant mouse strains have been used to examine the importance of neutrophils and macrophages in wound-induced scar formation. One of the first studies of this kind explored wound healing in mice lacking the transcription factor PU.1[
More specific studies examining the role of macrophages in collagen deposition and scar formation have been performed using several approaches. Studies from two groups have used slightly different genetically modified mouse strains in combination with diphtheria toxin to deplete macrophages. Mirza
Aside from specific inflammatory cell types, a wide range of inflammatory mediators, including both pro- and anti-inflammatory mediators, have been shown to play a functional role in cutaneous scar formation.
Both fetal and adult wound healing studies in animal models have implicated specific pro-inflammatory mediators in the stimulation of scar formation. Fetal wound healing models have been useful for identifying inflammatory mediators with fibrogenic potential since a specific mediator can be injected into fetal wounds to determine whether it can convert the scarless healing process into a fibrotic repair process. With this approach, the formation of a scar in a wound that would otherwise heal scarlessly can be used as a readout of pro-fibrotic activity. A number of pro-inflammatory mediators have been shown to promote scar formation in fetal wounds using this system, including cytokines such as IL-6 and IL-33[
In contrast to pro-inflammatory mediators, anti-inflammatory mediators have been shown to limit scar formation in fetal and adult wound healing models. The most well-documented example of this is the anti-inflammatory cytokine IL-10. Studies have shown that IL-10 levels are higher in scarless fetal wounds compared to scar-forming wounds[
Given the evidence supporting the idea that inflammation promotes scar formation, it seems logical that targeting inflammation might be a viable therapeutic strategy for restricting scar tissue production and enhancing the cosmetic and functional clinical outcomes resulting from skin injury. There are data supporting various anti-inflammatory approaches that could be effective for minimizing the appearance of scars and several other proposed scar therapies may reduce scarring in part by altering inflammation. These will be discussed below.
Steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are traditional anti-inflammatory drugs that may be beneficial for preventing or treating scars. Corticosteroids are anti-inflammatory drugs commonly used in clinical settings to treat raised scars such as HTS and keloids. Steroid therapy can be used in an attempt to induce scar regression, but may be more effective when used to prevent recurrence after scar revision surgery[
NSAIDs are another class of anti-inflammatory drugs that block the production of inflammatory lipid mediators, such as PGE2, by inhibiting the function of one or more cyclooxygenase enzymes. These drugs are commonly used to treat pain, fever, and inflammation. Some of these drugs have been suggested to reduce collagen deposition and scar formation in animal models of wound healing. In an incisional murine wound model, topical application of celecoxib resulted in decreased PGE2 production, inhibition of neutrophil recruitment, and significantly reduced scar size[
Drugs that target innate immune receptors have the potential to be used to limit scar formation based on their anti-inflammatory mechanism of action. TLR4 inhibitors are one example. TLR4 is a pattern recognition receptor that binds to many different pathogen-associated molecular patterns as well as damage-associated molecular patterns (also known as alarmins) that stimulate inflammation in response to microbes or tissue damage, respectively[
Another potential target is the chemokine receptor CXCR4, which binds to stromal-derived factor-1 (SDF-1), also known as CXCL12. Upregulation of SDF-1/CXCR4 signaling has been reported in human burn patients and in HTS tissue[
Pirfenidone is an anti-fibrotic drug with anti-inflammatory properties used to treat idiopathic pulmonary fibrosis. Although the ability of pirfenidone to treat or prevent skin scarring has not been thoroughly investigated, several studies suggest that it may be a promising option. Multiple studies have shown that pirfenidone can inhibit the pro-fibrotic behavior of cultured dermal fibroblasts. For example, pirfenidone can reduce TGF-β-induced fibroblast proliferation, migration, collagen expression, and myofibroblast formation[
Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol known to have antioxidant, anti-inflammatory, and anti-tumor effects. The ability of EGCG to be photoprotective and inhibit cutaneous inflammation in response to ultraviolet light-induced skin damage is well documented[
Fibromodulin is a member of the small leucine-rich proteoglycan family that has been shown to have an inverse relationship with scar formation. Fibromodulin levels are initially high in fetal skin at stages associated with scarless healing, then levels decrease during development as the skin starts to heal with a scar[
Studies have shown that maintaining hydration and allowing healing to occur in a moist environment can be beneficial for healing and reducing scar formation. The underlying mechanisms appear to be related to reduced inflammation. Saline-filled polyurethane or vinyl chambers used to maintain a moist healing environment caused wounds to heal with less inflammation and less scarring compared to dry, air-exposed wounds[
Fibroblast behavior is known to be influenced by mechanical signals, and wounds that heal under tension typically heal with more scar tissue. Data from animal models have illustrated this concept, as devices which increase mechanical loading on a wound increase scar formation[
Several approaches have been tested to target mechanosignaling as a way to prevent or reduce scarring. A stress-shielding device, which reduces the tension on a healing wound, has been shown to improve scarring in large animal pre-clinical models as well as human clinical trials[
There is a large body of evidence suggesting that the magnitude of the inflammatory response influences the amount of scar tissue that will result from the healing process
Summary of cellular interactions leading to cutaneous scar formation. When the skin is damaged, an inflammatory response is induced. Initially, resident inflammatory cells (e.g., mast cells and macrophages) in the dermis are activated. These activated cells secrete molecules that stimulate fibroblast activity and promote collagen production and scar tissue deposition. The resident cell-derived mediators, particularly cytokines (and chemokines) as well as lipids, stimulate the recruitment of circulating inflammatory cells (e.g., neutrophils, monocytes, and mast cell precursors) into the tissue. These cells become activated, and in some cases mature (monocytes become macrophages and mast cell precursors become mature mast cells), leading to even higher local levels of mediators that stimulate fibroblast activity and perpetuate scar tissue production. Several types of mediators produced by inflammatory cells have been linked to scar formation, including growth factors (TGF-β1), cytokines/chemokines [interleukin (IL)-6, IL-17, IL-33, MCP-1, SDF-1, OPN], proteases (mast cell chymase/tryptase, neutrophil elastase), lipids (PGE2), and reactive oxygen species or ROS (H2O2)
Despite the large number of studies on inflammation and scar formation, more research is needed to fully understand this relationship. Conflicting data from some studies demonstrates the complexity of the relationship between inflammation and scar formation and highlights the lack of standardized approaches for studying this relationship experimentally. In particular, variability in experimental models can make it difficult to draw broad conclusions; these models include the use of human tissue, large animal models (e.g., pigs, which have similar skin anatomy to human), and small animal models (e.g., mice, which have loose skin, but can be used for advanced functional studies). More precise characterization of inflammation that includes an expanded view of different inflammatory cell types as well as the specific subtypes of each cell and how changes in these cells over time affect scar formation are needed, especially in human specimens. In addition, further investigation is needed to determine how beneficial various anti-inflammatory approaches could be for minimizing scar formation in human skin.
The author contributed solely to the article.
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The author has received research support from NIH (AR071115).
The author declared that there are no conflicts of interest.
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© The Author(s) 2020.