INTRODUCTION
Tissue repair is defined as the restoration of tissue after injury, both in terms
of its conformation and its function1.
Healing is an evolutionary process preserved to this day and includes processes
such as inflammation, cell proliferation, and remodeling of the extracellular
matrix2,3. Incorrect or abnormal tissue repair of the skin causes
pathological situations such as keloids and hypertrophic scars. Keloids and
hypertrophic scars are forms of excessive scarring, which can be caused by skin
injury, burns, trauma, irritation, surgery, and piercing, among other types of
skin injuries4.
Exacerbated deposition of extracellular matrix components can occur during the
healing phases and, when the remodeling of the lesion shows progression of the
matrix, fibrosis occurs. Fibrogenesis can be characterized as dynamic, with a
varying degree of plasticity, which also depends on the tissue affected5. The remodeling of fibrotic tissue
directly depends on chronic inflammation and damage to tissue cells6. In these pathological situations there is
also continuous inflammation, the presence of myofibroblasts, and excessive
deposition of collagen, fibroblasts, inflammatory cells, and newly formed blood
vessels7,8. To date, the exact cause of these pathological situations
is not known, but several treatments are used to induce regression of these
excessive scars9. Despite advances in its
treatment, many patients still experience adverse effects from abnormal
scars9.
Galectins are proteins that belong to the lectin family and to date, 15 different
types have been identified. These proteins bind to β-galactoside and have a
carbohydrate-binding recognition domain (CRD) with the ability to recognize
carbohydrates of approximately 130 amino acids.10.11. A unique form of
galectin, galectin-3 (gal-3), called chimera, arises due to a disordered and
intrinsic sequence present in its N-terminal domain, which allows the
oligomerization and organization of gal-3 into pentamers. Gal-3 has
multifunctional capacity in numerous cellular and pathological conditions11.
Several studies have already demonstrated the ability of gal-3 to promote
re-epithelialization, angiogenesis, adhesion, and cell migration, both in murine
experimental models and in vitro models, including participation in the
regulation of the immune system12,13,14,15,16,17,18. The ability to act in cell-matrix
interaction makes gal-3 essential for promoting these processes19. Therefore, gal-3 plays roles in several
processes, such as scar formation, mediating monocyte recruitment, macrophage
differentiation plasticity, intercellular interaction, and matrix production,
and, thus, indirectly, in the regulation of fibrosis20,21,22,23.
Several factors may be involved in the development of excessive scarring.
Recently, some articles have suggested the involvement of gal-3 in various
pathological situations, including fibrosis, such as cardiac fibrosis and
pulmonary fibrosis24,25. Furthermore, recent work suggests that
gal-3, together with galectin-1, assists in the proliferation and survival of
fibroblasts, which are directly responsible for the excessive deposition of scar
matrix26. Therefore, more studies are
needed to correlate the expression and action of gal-3 in normal and abnormal
tissue repair.
OBJECTIVE
The present study aims to investigate and characterize the expression of gal-3 in
human samples of hypertrophic scars and keloids, comparing them with normal
scars.
METHOD
Patients and Samples
The study was approved by the Research Ethics Committee of the Hospital
Universitário Pedro Ernesto, according to protocol number 1,900,610. All
patients were informed about the study; participants over 18 years of age
who voluntarily consented to participate signed the Free and Informed
Consent Form (TCLE), while individuals between 13 and 17 years old signed
the Assent Form together with a guardian. Patients who chose not to undergo
the surgical procedure to remove scars, children under 13 years of age, or
individuals who refused to sign the Informed Consent Form were not included
in the study.
Normal scars, keloids, and hypertrophic scars were collected as samples from
patients treated in the Plastic Surgery Sector of the Hospital Universitário
Pedro Ernesto, in Rio de Janeiro, RJ, from 2015 to 2019, who wished to
undergo the procedure to remove these scars, which showed no signs of
regression and did not respond to treatment. The classification of normal
scars, hypertrophic scars, and keloids was carried out using strict clinical
criteria (assessment carried out by a trained doctor).
For surgery, the skin was previously prepared with local antiseptics such as
2% Chlorhexidine gluconate, degreaser, and alcohol. Patients underwent
surgical intervention under local anesthesia with 1% lidocaine and 1:200,000
adrenaline. Excision of hypertrophic and unsightly scars was performed in a
spindle covering the entire lesion, while in cases of keloid scars,
intralesional resection was performed due to the risk of recurrence.
The fragments were fixed in 10% formaldehyde for at least 24 hours. After
fixation in formalin, the fragments were processed in paraffin and
transferred to histological slides for histopathological and
immunohistochemical analysis. For general tissue analysis, the samples were
stained with hematoxylin and eosin (HE) and, to observe the collagen fiber
system, the samples were stained using the Picrosirius Red (PS) technique.
The HE and PS sections were visualized under a Leica DM 500 microscope,
under a bright field, or with a polarizer, respectively. After capturing
images of histological sections, analyses were performed using the Future
WinJoe capture program version 1.6 (Future Optics Sci. & Tech. Co,
Xiasha, Hangzhou, China).
Immunohistochemistry
To identify myofibroblasts, cells important in tissue repair and fibrosis, as
well as tissue vascularization, the immunohistochemistry technique was
performed using an antibody against alpha-smooth muscle actin (α-SMA;
Abcam-UK).
In this methodology, endogenous peroxidase was blocked in a 3% hydrogen
peroxide solution (Proquímios-BR) in methanol for 30 minutes. This was
followed by 5-minute washes in running water and 1x phosphate-buffered
saline (PBS), after which samples were blocked using the SpringBio blocking
kit. After 1 hour, the excess blocking solution was removed and sections
were incubated with mouse anti-α-SMA primary monoclonal antibody at a
concentration of 1/100 in 1% bovine serum albumin (BSA) in PBS at 4°C at
night; at this stage, the negative control slides were incubated only with
PBS/BSA 1%.
In the second step, the primary antibody was washed with 1x PBS, then
incubated with anti-mouse IgG secondary antibody - HighDef Complement Kit
(Cell Marque-USA) for 30 minutes. The labeling was developed with the
chromogen diaminobenzidine (DAB; Cell Marque-USA) for 5-8 minutes. The
sections were washed again with 1x PBS and counterstained with Harris
hematoxylin (Proquímios-BR). The slides were washed in running water, then
in distilled water, and then dehydrated, clarified, and mounted with
Entellan (Merck-Ger). The slices were viewed under a bright-field microscope
(Leica DM500).
To identify the presence of gal-3 in scar samples, immunohistochemistry was
performed using the anti-gal-3 primary monoclonal antibody (Clone M3/38;
American Type Culture Collection-USA). Samples were deparaffinized and
rehydrated and antigen retrieval was performed with Trilogy® solution (1:100
diluted in distilled water; Sigma-USA). The slides were then passed in a
distilled water bath followed by a 3% hydrogen peroxide solution to block
endogenous peroxidase. The slides were washed again in a distilled water
bath and 3 baths of PBS+Tween (10%), followed by blocking the specific site
with 16% milk and 20% BSA in distilled water for 1 hour.
Sections were then incubated with anti-gal-3 antibody at a concentration of
1:100 in PBS/BSA 1% for 1 hour; At this stage, the slides for the negative
control were incubated only with PBS/BSA 1%. Slides were washed three times
with PBS + Tween followed by incubation with an unconjugated anti-mouse IgG
secondary antibody (Vector-USA). Three washes were performed with PBS +
Tween and then, to amplify the secondary antibody signal, streptavidin
peroxidase (Sigma-USA) was added for 20 minutes. Sections were washed again
with PBS+Tween and DAB chromogen was added for 20 seconds. Contrast was
performed with Harris hematoxylin (Sigma-USA). Finally, dehydration and
clarification were performed, and the slides were mounted with Entellan and
viewed under a microscope (Leica DM 500).
Galectin-3 quantitative analysis and image capture
Three random fields from each slide were imaged for the epidermis, dermis,
and subcutaneous tissue. After capturing images of the histological
sections, analyses were performed using the Future WinJoe capture
program.
Future WinJoe software was used to process the captured digital images and
the volume density of gal-3 positive cells (%Vv [gal-3]) was evaluated using
a stereological system consisting of 36 points, as previously described by
Petito et al.27. Vv = PP/PT (%) (PP
represents the evaluated points that reach the structure and PT represents
the total number of points present in the grid). The results were expressed
as mean ± standard deviation.
Statistical analysis
Significant differences between groups were determined by the non-parametric
Mann-Whitney test, in which p<0.05 was considered significant. Analyzes
were performed using GraphPad Prism software version 6.0 (GraphPad Software,
San Diego, CA, USA).
RESULTS
Scars
The patients were subdivided into three groups (normal scars, hypertrophic
scars, and keloids) to allow statistical analysis, as shown in Table 1. All subjects in the normal
scar group were women (n=9) and aged between 20 and 57 (average 37.3 years).
The majority of normal scars were located in the breast (18%) and pelvic
region (18%), followed by the lower abdomen (9%), navel (9%), and
hypochondrium (9%). In the keloid group (n=16) the majority of patients were
women (62.5%) and aged between 13 and 66 (average 28.3 years). And most of
the keloids were collected in the ears (50.0%), followed by the abdomen
(12.4%), anterior trunk (12.4%), cervical region (6.2%), scalp (6. 2%),
superciliary region (6.2%) and mandible (6.2%). Finally, the group with
hypertrophic scars (n=4) was composed of 3 women and 1 man, aged between 21
and 61 (average 34.25 years). And these scars were collected from each
umbilical, pre-auricular, face, and shoulder area. The average duration of
typical scars was 65 months, while keloids averaged 83 months and
hypertrophic scars averaged 30 months.
Table 1. - Clinical sociodemographic data of the population involved in the
study.
|
Normal scar (N = 09) |
Keloid (N = 16) |
Hypertrophic Scar (N = 04) |
| Years |
37.33±12.76 |
28.37±15.31 |
34.25±18.46 |
| Sex |
09 (100%) F |
10 (62.5%) F |
03 (75%) F |
| 00 (0%) M |
06 (37.5%) M |
01 (25%) M |
| Skin color * |
| White |
07 |
01 |
01 |
| Brown |
02 |
11 |
01 |
| Black |
00 |
02 |
01 |
| S.D. |
00 |
02 |
01 |
Table 1. - Clinical sociodemographic data of the population involved in the
study.
Stained samples
HE-stained samples from all scars revealed a small number of cells in the
reticular dermis, demonstrating greater deposition of the extracellular
matrix. Furthermore, keloids and hypertrophic scars had straighter epidermis
and fewer dermal papillae compared to normal scars (Figure 1A, B, and
C).
Figure 1. - Photomicrographs of normal and excessive scar sections.
Representative images of the slides analyzed (CN - normal scar,
CH - hypertrophic scar, and Q - keloid), captured from sections
stained with hematoxylin and eosin (A, B, and C), Picrosirius
Red (D, E, and F), and marked against a-SMA (G, H and I). A)
Asterisks highlighting the concentration of fibers in the
reticular dermis compared to the papillary dermis. Normal scars
also had more dermal papillae. B) Asterisks indicating slightly
accentuated and distributed papillae, with large deposition of
extracellular matrix in the reticular dermis. C) Asterisks
demonstrating a more straight papillary dermis with few cells in
the dermis due to the large deposition of matrix and fibers. D)
Asterisks showing more united and fragmented fibers. E)
Asterisks highlighting exacerbated deposition of thick and
random fibers. F) Asterisks indicating fibers arranged
exaggeratedly, with little fragmentation. G) Arrows showing
regions with vessels in the reticular dermis. H) Arrows showing
regions of high vascularization and even infiltrates that may
suggest inflammation. I) Arrows showing regions with many
capillaries intensely vascularized and with asterisks showing
regions with positive staining for myofibroblasts. Bar: 100
μm.
Figure 1. - Photomicrographs of normal and excessive scar sections.
Representative images of the slides analyzed (CN - normal scar,
CH - hypertrophic scar, and Q - keloid), captured from sections
stained with hematoxylin and eosin (A, B, and C), Picrosirius
Red (D, E, and F), and marked against a-SMA (G, H and I). A)
Asterisks highlighting the concentration of fibers in the
reticular dermis compared to the papillary dermis. Normal scars
also had more dermal papillae. B) Asterisks indicating slightly
accentuated and distributed papillae, with large deposition of
extracellular matrix in the reticular dermis. C) Asterisks
demonstrating a more straight papillary dermis with few cells in
the dermis due to the large deposition of matrix and fibers. D)
Asterisks showing more united and fragmented fibers. E)
Asterisks highlighting exacerbated deposition of thick and
random fibers. F) Asterisks indicating fibers arranged
exaggeratedly, with little fragmentation. G) Arrows showing
regions with vessels in the reticular dermis. H) Arrows showing
regions of high vascularization and even infiltrates that may
suggest inflammation. I) Arrows showing regions with many
capillaries intensely vascularized and with asterisks showing
regions with positive staining for myofibroblasts. Bar: 100
μm.
Under the polarization microscope, it was possible to observe that all
samples had thick, reddish fibers, demonstrating a large deposition of
collagen in the reticular dermis. The collagen fibers in a normal scar tend
to be fragmented and intertwined. Keloids and hypertrophic scars have longer
and thicker fibers, deposited parallel to the surface, providing more
exacerbated, irregular, and stratified fibrous deposition (Figure 1D, E, and F).
α-SMA expression in excessive scar samples
Tissue samples from normal scars, keloids, and hypertrophic scars showed
considerable positive staining for α-SMA in blood vessel walls; however,
normal scars showed less vascularity throughout the cut, compared to keloids
and hypertrophic scars, especially in the reticular dermis region (Figure 1G, H and I).
Galectin-3 expression in excessive scar samples
In general, gal-3 expression was observed in the epidermis and throughout the
papillary dermis and areas of the reticular dermis. Its staining was more
intense in cells of blood vessels and attached glands, but gal-3 was not
present in regions with deposition of collagen fibers. In normal scars,
positive staining for gal-3 was observed throughout the tissue, mainly in
the papillary dermis, while in the reticular dermis, it was not possible to
detect relevant staining in the regions of fiber deposition, only positivity
around the blood vessels and sweat glands (Figure 2A, B and C).
Figure 2. - Photomicrographs of galectin-3 expression. In the first
column (A, B, and C) the images demonstrate samples of normal
scars (NC) labeled for gal-3 and are representative of normal
scars from 9 patients. In the second column (D, E, and F) the
images show keloid samples (Q) labeled for gal-3, from 16
patients. In the third column (G, H, and I) the images
demonstrate samples of hypertrophic scars (CH) labeled for gal-3
and are representative of hypertrophic scars from 4 patients.
Squares indicate enlarged, gal-3-positive regions.
Anti-galectin-3 immunoperoxidase with hematoxylin counterstain.
Bar: 100 μm.
Figure 2. - Photomicrographs of galectin-3 expression. In the first
column (A, B, and C) the images demonstrate samples of normal
scars (NC) labeled for gal-3 and are representative of normal
scars from 9 patients. In the second column (D, E, and F) the
images show keloid samples (Q) labeled for gal-3, from 16
patients. In the third column (G, H, and I) the images
demonstrate samples of hypertrophic scars (CH) labeled for gal-3
and are representative of hypertrophic scars from 4 patients.
Squares indicate enlarged, gal-3-positive regions.
Anti-galectin-3 immunoperoxidase with hematoxylin counterstain.
Bar: 100 μm.
In keloids, positive staining was observed throughout the epithelium and in
the papillary dermis, mainly in the blood vessels of the papillary and
reticular dermis. Furthermore, the keloid group showed the highest staining
of gal-3-positive cells, however, no positive staining was observed in sites
with excessive extracellular matrix deposition (Figures 2D, E, and
F). In hypertrophic scars, positive
staining for gal-3 was also observed in the blood vessels of the papillary
and reticular dermis, but no positive staining was observed in the region of
extracellular matrix deposition. In general, the hypertrophic scar group
showed a similar pattern to the keloid group, but with a lower number of
gal-3-positive cells (Figure 2G, H, and I).
As the distribution pattern of gal-3 was similar between the groups studied,
cells positive for gal-3 were then quantified by stereology. By determining
and comparing the expression of gal-3 in cells distributed throughout the
dermis, it was possible to observe a significant difference in the volume
density of gal-3-positive cells in keloids compared to normal scars (p =
0.0075) (Figure 3). However, there was
no statistically significant difference between the volume density of
gal-3-positive cells between hypertrophic and normal scars, nor between
keloids and hypertrophic scars. Samples from the keloid group showed 28% of
cells positive for gal-3, while the group with normal scars showed 18% and
the group with hypertrophic scars 22% (Figure 3).
Figure 3. - Volume density plot of galectin-3 positive cells. The Y-axis
of the graph represents the percentage volume of gal-3,
evaluated by stereology, in immunohistochemical slides labeled
with anti-gal-3. The X-axis shows the shapes of the scars
evaluated in this study (CN – normal scar, CH – hypertrophic
scar, and Q – keloid). p = 0.0075.
Figure 3. - Volume density plot of galectin-3 positive cells. The Y-axis
of the graph represents the percentage volume of gal-3,
evaluated by stereology, in immunohistochemical slides labeled
with anti-gal-3. The X-axis shows the shapes of the scars
evaluated in this study (CN – normal scar, CH – hypertrophic
scar, and Q – keloid). p = 0.0075.
DISCUSSION
Galectin-3 has been described as having a role in inflammatory and angiogenic
processes16,28 and is therefore implicated in wound healing processes,
but its role has not yet been specifically defined. It is also not yet known how
keloids and hypertrophic scars arise; The present study aimed to characterize
the expression of gal-3 in normal scars and excessive scars in humans.
Healing is a type of repair mechanism that is activated when tissue damage
occurs. On some occasions, the healing process of skin wounds does not occur
normally, leading to the formation of excessive scars, such as keloids and
hypertrophic scars. This excessive scarring is characterized by persistent
inflammation, with unbalanced cell recruitment and remodeling, which leads to
excessive deposition of matrix components, resulting in fibrosis5. Tissue fibrosis is dependent on key
mediators and specific molecular pathways, therefore, fibrosis can occur in
completely different organs, just by the presence of these mediators and
molecular pathways6.
Galectins are proteins known to have a carbohydrate-binding recognition domain
(CRD). Type 3 galectin is the most different of the 17 known galectins and is
best known for having interaction domains with proteins and carbohydrates, in
addition to the ability to pentamerize, allowing different interactions with
molecules and tissues11. According to
Peiró et al.6, gal-3 is related to the
fibrogenesis pathway, including cutaneous fibrosis, corroborating the data found
in our study, in which we quantified more gal-3 in fibrotic tissue, such as
keloids. Furthermore, according to the literature, gal-3 is also related to
angiogenesis and macrophage recruitment16,21,23. Therefore, it is understood that this protein is
directly linked to the healing process. Also, other galectins have already been
studied regarding their role in tissue repair, such as galectin-1, which has
been suggested as having therapeutic potential, as its subcutaneous application
in wound sites accelerated healing29.
Arciniegas et al.26 demonstrated the
expression of gal-3 in the basal lamina and the dermal/epidermal interface, as
well as in some immune cells, microvessels, collagen bundles, and fibroblasts in
keloid tissues, which agrees with our data but does not compare the expression
of gal-3 with tissue samples from normal scars and hypertrophic scars.
The data presented by Amadeu et al.7 and
agreed by Tan et al.8 highlighted the
difference between the vascularization of normal scars and abnormal scars,
hypertrophic scars, and keloids, in which the tissue of excessive scars was more
vascularized. This difference in vascularization corroborated the data found in
our study for the expression of the smooth muscle markers α-SMA and gal-3 in
normal and excessive scars. Our work also found that blood vessels were more
present in excessive scars and that there was greater expression of gal-3 in the
blood vessels of excessive scars, in addition to greater expression of gal-3 in
keloids in general.
The findings of Mostacada et al.28
suggested that gal-3 is vital for the recruitment of macrophages, influencing
their eliminative action against apoptotic cells and microorganisms. A decrease
in gal-3 therefore leads to a less pronounced inflammatory response, due to less
recruitment of pro-inflammatory cells. Furthermore, Sciacchitano et al.11 demonstrated the ability of gal-3 to
mediate the activation of IL- 4-induced macrophages, known as alternatively
activated macrophages, to stimulate fibrosis and matrix production. These data
could explain the higher expression of gal-3 in keloids compared to normal
scars, but further studies are needed to fully understand the higher expression
of gal-3 in keloids compared to hypertrophic scars.
It has not yet been possible to induce excessive scarring in animal models,
therefore studies must be based on human samples. The present study was limited
due to the scarce number of samples, mainly from hypertrophic scars, which
probably impacted the statistical analysis when comparing gal-3 expression
between groups. Furthermore, due to this small number of samples, only tissue
analysis was performed and no investigation of gal-3 in the fibrogenesis pathway
could be performed. Furthermore, the cuts already had a complete healing
structure, therefore, the period of cellular modulation during healing could not
be evaluated. The absence of normal skin samples was our choice because this
study aims to compare two types of excessive scarring in human skin
(hypertrophic scars and keloids) with the normal wound healing process (normal
scars). Despite the limitations of this study, the results obtained are valuable
for a pilot study.
CONCLUSION
In this study, gal-3 protein expression was detected in normal and abnormal
scars, suggesting its involvement in typical and atypical cutaneous wound
healing processes, particularly angiogenesis and re-epithelialization. Despite
the heterogeneity of the normal and abnormal scar samples used in this study,
gal-3 was identified and its expression showed significant differences.
Furthermore, its expression was notably higher in the dermis of keloids compared
to typical scars, indicating a fundamental role of gal-3 in keloid formation.
Consequently, further investigations are needed to evaluate the deposition and
function of gal-3 throughout the healing cascade and in chronic conditions such
as diabetes and ischemic injuries. Such studies may reveal the potential of
gal-3 as a biomarker for keloid formation or as a target for therapeutic
interventions in wound treatment.
ACKNOWLEDGMENT
The authors would like to thank Elaine N. Silva, Igor Rodrigues, Bárbara Dantas,
Flavia Loureiro, and Gabriel Marujo for the technical support and collection of
patient samples, respectively.
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1. Universidade do Estado do Rio de Janeiro,
Patologia Geral, Laboratório de Imunopatologia, Rio de Janeiro, RJ,
Brazil.
2. Universidade Federal do Rio de Janeiro,
Instituto de Ciências Biomédicas, Rio de Janeiro, RJ, Brazil.
3. Universidade do Estado do Rio de Janeiro, Setor
de Cirurgia Plástica, Rio de Janeiro, RJ, Brazil.
4. Fiocruz, Laboratório de Imunofarmacologia, Rio
de Janeiro, RJ, Brazil.
Corresponding author: Thaís Porto
Amadeu Av. Professor Manoel 444, 4oº andar, Maracanã, Rio
de Janeiro, RJ, Brazil CEP: 20550-170 E-mail:
tpamadeu@gmail.com
Article received: March 05, 2024.
Article accepted: April 30, 2024.
Conflicts of interest: none.
