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Cutaneous and Ocular Toxicology

ISSN: 1556-9527 (Print) 1556-9535 (Online) Journal homepage: http://www.tandfonline.com/loi/icot20

The Reduction in Inflammation and Impairment


in Wound Healing by Using Strontium Chloride
Hexahydrate

Sibel Berksoy Hayta, Kasım Durmuş, Emine Elif Altuntaş, Esin Yıldız, Mehmet
Hisarcıklıo & Melih Akyol

To cite this article: Sibel Berksoy Hayta, Kasım Durmuş, Emine Elif Altuntaş, Esin Yıldız, Mehmet
Hisarcıklıo & Melih Akyol (2017): The Reduction in Inflammation and Impairment in Wound
Healing by Using Strontium Chloride Hexahydrate, Cutaneous and Ocular Toxicology, DOI:
10.1080/15569527.2017.1326497

To link to this article: http://dx.doi.org/10.1080/15569527.2017.1326497

Accepted author version posted online: 03


May 2017.

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Download by: [The UC San Diego Library] Date: 05 May 2017, At: 03:04
THE REDUCTION IN INFLAMMATION AND IMPAIRMENT IN WOUND

HEALING BY USING STRONTIUM CHLORIDE HEXAHYDRATE

Sibel Berksoy Hayta


Deparment of Dermatology, Faculty of Medicine Cumhuriyet University, 58140, Sivas,
Turkey
drberksoy@gmail.com

Kasım Durmuş
Department of Otolaryngology, Faculty of Medicine Cumhuriyet University, 58140, Sivas,
Turkey

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Kasimdurmus58@gmail.com

Emine Elif Altuntaş TE


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Department of Otolaryngology, Faculty of Medicine Cumhuriyet University, 58140, Sivas,
Turkey
ealtunta@yahoo.com
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Esin Yıldız
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Department of Pathology, Faculty of Medicine Cumhuriyet University, 58140, Sivas, Turkey


eyildiz@cumhuriyet.edu.tr
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Mehmet Hisarcıklıo
Department of Otolaryngology, Faculty of Medicine Cumhuriyet University, 58140, Sivas,
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Turkey
hisarcikli@gmail.com

Melih Akyol
Deparment of Dermatology, Faculty of Medicine Cumhuriyet University, 58140, Sivas,
Turkey
melakyol@gmail.com
Corresponding author:
Sibel Berksoy Hayta
drberksoy@gmail.com
0 505 875 20 44
Deparment of Dermatology, Faculty of Medicine Cumhuriyet University, 58140, Sivas,
Turkey.

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ABSTRACT

Background: Numerous growth factors, cytokine, mitogen, and chemotactic factors are

involved in wound healing. Even though inflammation is important for stimulation of

proliferative phase, excessive inflammation also causes impairment in wound healing.

Strontium salts suppress keratinocyte-induced TNF-alpha and interleukin 1 and 6 in in-vitro

cultures. This study was conducted to determine the effects of administration of topical

strontium chloride hexahydrate on wound healing through TNF-alpha and TGF-beta in

surgical wound healing model of in-vivo rat skin.

Material and methods: 24 rats were used in the study. After approximately 2-cm cutaneous-

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subcutaneous incision was horizontally carried out on the mid-neckline of the rats, the

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incision was again closed using 2.0 vicryl. The rats were assigned into three groups including

8 rats in each group. Placebo emollient ointment and also the ointments, which were
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containing 5% and 10% strontium chloride hexahydrate and were prepared at the same base

with placebo ointment, were administered to the groups by a blind executor twice a day for a
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week. At the end of seventh day, the rats were sacrificed and cutaneous and subcutaneous
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tissue of their wound site was resected for histopathological examination. Scoring of

histopathological wound healing and scoring of tissue TNF-alpha and TGF-beta level with
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immunohistochemical staining were performed.

Results: The groups, to which both 5% and 10% strontium chloride hexahydrate was
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administered, had lower immunohistochemical TNF-alpha levels and histopathological wound

scores compared to controls, which was statistically significant (p<0.05).

Conclusion: Strontium chloride hexahydrate can lead to impairment in wound healing by

suppressing inflammation through TNF-alpha.

Key words: Wound, wound healing, TNF-alpha, strontium, inflammation


INTRODUCTION

Cutaneous wound healing attracts interest of community health because skin wounds impair

quality of life in patients, which results in prolonged hospitalization period and considerable

health costs. A wide range of strategies have been developed for attaining a fast closure in

skin lesions (1).

Wound healing, which is a dynamic and complicated process, has a well-coordinated and

highly regulated series of events which include inflammation, tissue formation,

revascularization, and tissue remodeling (2). The inflammatory phase is an important process

for formation of a new tissue in wound healing. A monocyte-derived cytokine, tumor necrosis

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factor-alpha (TNF-alpha), may play a useful or detrimental part in wound healing (3).

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Impaired wound healing is characterized by excessive inflammation associated with increased

local and systemic TNF-alpha levels (4). Moreover, recent studies reveal that wound healing
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enhances by inhibition of excessive TNF-alpha expression (5-8).

Platelets release transforming growth factor- beta (TGF-beta), which is an important regulator
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of wound healing, very early during this process. Especially, TGF-beta induces chemotaxis of
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inflammatory and immune cells to the wound site. Additionally, TGF-beta also enables

stimulation to form granulation tissue and deposit extracellular matrix. Furthermore, TGF-
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beta, which is significant to mediate the replacement of collagen type III with collagen type I

and thus to realize last stages of tissue remodeling during wound healing, also supports wound
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epithelization by providing stimulation of keratinocyte proliferation and modulation of

integrin expression to induce a more migratory phenotype (9).

Calcium (Ca2+) is an important cation able to function as a second messenger in different cells

(10). Intracellular calcium mediates proinflammatory cytokine expression such as TNF-alpha

and IL-1. Strontium (Sr2+) is a trace element. Calcium and strontium act as competitive
inhibitors. Strontium blocks the influx of calcium in several cell types. Therefore it may

reduce proinflammatory cytokines expression indirectly (11).

This study was conducted to determine the effects of administration of topical strontium

chloride hexahydrate on wound healing through TNF-alpha and TGF-beta in surgical wound

healing model of in-vivo rat skin.

MATERIAL AND METHODS

Animals

The approval of the Animal Ethics Committee of Cumhuriyet University based on the

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Standards for the Care and Use of Laboratory Animals was obtained for the study. Adult

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female Wistar rats (180–230 g) were bought from the Animal Center of the Faculty of

Medicine, Cumhuriyet University, Sivas, Turkey. They were housed in standard cages. They
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were free to access standard rat feed and water ad libitum under standard conditions (12 h

light/dark cycle; 25 ± 3°C, 45–65% humidity). The tests were carried out under the light
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conditions between 08:00 and 12:00 in the morning to prevent circadian effects.
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Experimental design

After the rats were anesthetized with 3 mg/kg Xylazine subcutaneous (SC) and 90 mg/kg
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Ketamine HCL SC, neck areas of the rats to be surgically incised was stained with

polyvinylpyrrolidone iodine (betadine) and then shaved. The area was disinfected by cleaning
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with polyvinylpyrrolidone iodine again after shaving. After approximately 2-cm cutaneous-

subcutaneous incision was horizontally carried out on mid-neckline of the rats, the incision

was again closed using 2.0 vicryl.

The rats were assigned into three groups including 8 rats in each group. Rats in Group 1,

assigned as the controls, were treated with placebo ointment (glycerine, capric/ caprylic acid,
liquid paraffin, distilled water, and emulgators) twice a day for a week. Group 2 and Group 3

were treated with the ointments containing 5% and 10% strontium chloride hexahydrate,

respectively, twice a day for a week (12, 13).

Until absorption of drugs from skin was completed, the rats were kept separate for

approximately 30 minutes and after the applications, they were taken in individual cages as

maximum 5 rats in each group. Their daily cares were provided for the specified time in the

laboratory of experimental animals until the study was completed. On the 7th day after

surgical incision, the rats were sacrificed by using an overdose of anesthetics. After

sacrificing them, their wound sites were removed and fixed with 10% buffered formaldehyde

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for histopathological examination.

Histopathological examination
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The tissues were embedded in paraffin blocks. After 5-µm sections were prepared from these

blocks, they were stained with hematoxylin and eosin (H&E) staining and scored in terms of
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inflammation. Wound healing parameters (epithelialization, collagen density, inflammation,


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necrosis, neovascularization, and granulation) were scored from 0 to 5 points in

histopathological sections (14).


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Immunohistochemistry

The immune staining of TNF-alpha ve TGF-beta were made on the paraffin sections with the
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immunoperoxidase method. Tissues whose sections in the thickness of 3 micron were taken

on the slide were kept waiting in the incubator of 65 degrees for the deparaffinization 30

minutes long. The tissues whose deparaffinization was over were taken for

immunohistochemical staining in the device of Roche Ventana Bencmark XT (Country of

Origin, Arizona). The concentrated TGF-beta and TNF-alpha antibodies branded Birobyt
were diluted and incubated for 42 minutes. After the staining which lasted nearly 4 hours, the

preparates were dried and closed with entellanR (mounting medium for microscopy).

The cytoplasmic staining in the endothelial cells and fibroblasts were evaluated. A

cytoplasmic brown granule was marked as a positive expression of TNF-alpha and TGF-beta.

The results were evaluated semiquantitatively according to the percentage of positive cells in

ten randomly selected fields under highpower microscope for each sample. Scoring of TNF-

alpha and TGF-beta immunostaining in histopathological sections ranged from 0 to 3 points.

It was scored from 0 (no immunostaining), 1 (minimal immunostaining in some cells), 2

(weak immunostaining intensity in all cells), and 3 (strong immunostaining in all cells).

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Histopathological and immunohistochemistry evaluation were carried out by one pathologist

blinded to the groups.

Statistics
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The data was analyzed using SPSS 14.0 packaged software. Statistical evaluation was carried
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out by using Kruskal Wallis test and lineer regression analysis. The p value of <0.05 was
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accepted as significant.

RESULTS
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On the 7th days after incision, there was no clinically significant difference between the

groups in terms of wound healing.


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Light microscopic study of H&E (hematoxylene-eosin) of the biopsy specimens showed that

the control group had higher healing scores. On the other hand, necrosis was only seen in the

control group. Epithelialization, granulation tissue formation, collagen arrangement and

neovascularization were all impaired in the group 2 and group 3. The only wound healing

parameter showing statistically significant difference between group 2 and group 3 was
epithelialization. Histopathological examination of the samples revealed that wound healing

deteriorated in the groups of 5% and 10% strontium chloride hexahydrate (Table 1).

Table 1. Assesment of histopathological parameters for wound healing.

Group 1 Group 2 Group 3


(Controls) (5% SrCl2. 6H2O) (10% SrCl2. 6H2O)
Std. Std. Std.
Variables N Mean Deviation Mean Deviation Mean Deviation p
Epithelialization 8 4.00 0.00 3.13 0.64 4.00 0.53 0.004a
Collagenization 8 4.00 0.00 3.13 0.35 3.25 0.46 0.001b

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Inflammation 8 2.75 0.71 1.63 0.52 1.63 0.52 0.004c
Neovascularization 8 4.75 0.71 3.38 0.74 3.13 0.35 0.001d
Necrosis
Granulation tissue
8
8
0.25
4.00
0.71
0.00
0.00
2.63
0.00
0.52 TE 0.00
3.13
0.00
0.35
0.368
<0.001e
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Endothelial TNF-
8 2.50 0.53 2.00 0.00 2.00 0.53
alpha 0.052
Fibroblast TNF-
8 2.13 0.35 1.63 0.52 1.38 0.52
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alpha 0.022f
Endothelial TGF-
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8 2.25 0.46 1.88 0.35 2.25 0.46


beta 0.163
Fibroblast TGF-
8 1.88 0.64 2.00 0.00 2.00 0.53
beta 0.810
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a: The difference was caused by groups 1-2 (p=0.010). The difference was caused by groups 2-3 (p=0.021).
b: The difference was caused by groups 1-2 (p=0.002). The difference was caused by groups 1-3 (p=0.010).
c: The difference was caused by groups 1-2 (p=0.005). The difference was caused by groups 1-3 (p=0.005).
d: The difference was caused by groups 1-2 (p=0.010). The difference was caused by groups 1-3 (p=0.002).
e: The difference was caused by groups 1-2 (p<0.001). The difference was caused by groups 1-3 (p=0.002).
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f: The difference was caused by groups 1-3 (p=0.021).


Wound healing scores for epithelialization, collagenization, inflammation, necrosis, neovascularization, and granulation: 0 to 5 points (0:
none, 1: scant, 2: mild, 3: moderate, 4: strong, 5: abundant)
TNF-alpha and TGF-beta immunostaining scores: 0 to 3 points ( 0: no staining, 1: minimal staining in some cells, 2: weak staining intensity
in all cells, and 3: strong staining in all cells)
Figure 1 shows a decrease in inflammation in the group 2 and group 3. The inflammation

scores in the control group (group 1) was found to be statistically significantly higher than the

group 2 and group 3 (p=0.004). As shown in figure 2, the expressions of fibroblast-TNF-alpha

in the group 2 and group 3 reduced compared with the control group (group 1). Compared

with the control group, expressions of fibroblast-TNF-alpha in group 3 weakened in a dose-

dependent manner (p =0,022).

Linear regression analysis was performed to determine the relationship between reduction in

inflammation and TNF alpha. According to the results of linear regression analysis, there is a

causal relationship between both of them (F=248,647; p<0.05).

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Figure 1. Density of inflammatory cells. Group 1 showed more dense inflammation than the group 2 and group 3
(H&E, objective 4X).
(a) Control group (group 1),
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(b) 5% strontium chloride hexahydrate group (group 2),


(c) 10% strontium chloride hexahydrate (group 3).
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Figure 2. TNF-alpha expressions. Group 1 showed more prominent TNF-alpha expressions by fibroblasts
compared with the group 2 and group 3 (immunperoxidase, objective 40X).
(a) Control group (group 1),
(b) 5% strontium chloride hexahydrate group (group 2),
(c) 10% strontium chloride hexahydrate (group 3).
DISCUSSION

Some clinical situations including diabetes mellitus, chemotherapy, and malnutrition are

related to an increased incidence of impaired wound healing. Impaired wound healing can

result in morbidities and expenses. For this reason, it is significant and required to modulate

wound healing (1, 2).

TGF beta regulate cell migration and proliferation as well as synthesis of extracellular matrix

proteins, which are important for formation of granulation tissue and differentiation of

fibroblasts from myofibroblasts in granulation tissue; therefore, these growth factors are

thought to have a significant role in wound healing (15-17). In the present study, strontium

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chloride hexahydrate did not have any significant effect on TGF beta.

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Wound healing is characterized by a dynamic process regulated with a complex signaling

network of growth factors, cytokines, and chemokines that induce changes in growth,
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differentiation, and metabolism of target cells (15, 18). Some acute or chronic wounds can

cause an increased inflammation which may delay the healing process and cause scarring (18,
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19). However, complete suppression of the inflammation may result in impairment in wound
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healing since the inflammation is necessary to stimulate the proliferation phase in wound

healing (19, 20). Therefore, it is essential to control inflammation for a better wound healing.
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It is supposed that therapeutic strategies used for a fast wound healing have the capacity to

modulate the release of pro-inflammatory cytokines and so decrease these negative


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influences (18).

During wound healing, TNF-alpha acts primarily as a promoter of re-epithelialization and

inflammation mediator. Also, while TNF-alpha enables stimulation of dermal fibroblast

proliferation, it prevents endothelial proliferation and leads to apoptosis of endothelial cells.

Low levels of TNF-alpha can indirectly stimulate inflammation and increase macrophage-
produced growth factors and thus enhance wound healing (21). Persistent inflammation and

tissue destruction are caused by overproduction of TNF-alpha, which is a pleiotropic

cytokine. It is known that excessive inflammation is one of significant reasons of impaired

wound healing, and chronic elevation of TNF-alpha causes impaired wound healing by

increasing fibroblast apoptosis and reducing expression of tissue inhibitor of

metalloproteinases, growth factors and collagen production (4, 16, 18, 20-23).

Some treatment methods can be used to relieve the excessive inflammation in wound healing.

One of these methods is inhibition of TNF-alpha (5-7, 24, 25).

Cytokine expressions, including lymphocytes and immune cells, are based on calcium influx

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through the cell membranes. While intracellular calcium increases providing calcium-

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calmodulin complex, calcineurin results in proinflammatory cytokine expression such as

TNF-alpha and IL-1 (11). As alkali metal salts, strontium salts are very significant for
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cosmetic and pharmaceutical compounds (26). Strontium, which competitively blocking the

influx of calcium, may reduce indirect expression of proinflammatory cytokines, such as TNF
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alpha. While calcium is a secondary messenger for cells, strontium can act as an imperfect
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surrogate for calcium (11, 27).

The results of our study shows that strontium suppress inflammation in acute wound.
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Suppressing acute inflammation impairs wound healing. However, strontium could be useful

in chronic wounds, where TNF-alpha would be higher rather than acute wound. Strontium
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may reduce TNF-alpha in chronic wounds without affecting TGF-beta level, which may cause

a positive effect. One of the limitations of the present study was that the model used in the

study was an acute wound healing model.

In accordance with the results of the present study, strontium chloride hexahydrate can

decrease TNF-alpha levels in a dose-dependent manner. Another limitation of this study was
that the effects of strontium chloride hexahydrate at lower concentrations were not examined

on acute wound healing. Lower concentrations of strontium chloride hexahydrate could

decrease inflammation without impairing wound healing.

We also know that Strontium-doped calcium polyphosphate has the potential to promote

angiogenesis and strontium-substituted octacalcium phosphate coating promoted cell

differentiation during tissue repair (28, 29). These studies suggest that strontium may have

potential beneficial effects in wound healing.

In this study, it was revealed that an ointment of topical 5% and 10% strontium chloride

hexahydrate suppressed inflammation and TNF-alpha expression in the skin in a rat wound

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healing model. Strontium chloride hexahydrate has a negative effect on wound healing

parameters including epithelialization,


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collagenization, granulation tissue,

neovascularization. However, to determine the possible beneficial effects of strontium in


and
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different concentrations with more objective histopathologic evaluations, acute or chronic

wound healing models should be studied.


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