scholarly journals Blocking AGE-RAGE Signaling Improved Functional Disorders of Macrophages in Diabetic Wound

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Qi Wang ◽  
Guanya Zhu ◽  
Xiaozan Cao ◽  
Jiaoyun Dong ◽  
Fei Song ◽  
...  

Advanced glycosylation end products (AGEs) accumulate in diabetic wounds. Interactions between AGEs and their receptor (RAGE) leads to dermatologic problems in diabetes. Macrophage, which plays important roles in wound healing, highly expresses RAGE. Therefore, we investigated whether RAGE-expressing macrophages might be responsible for impaired wound healing on diabetes. We used anti-RAGE antibody applied topically on diabetic wounds. After confirming that wound healing was improved in anti-RAGE antibody group compared with normal mice, our results showed that macrophages appeared insufficient in the early stage and fading away slowly in the later proliferative phase compared with the control group, which was ameliorated in anti-RAGE antibody-applied wounds. Blocking AGE-RAGE signaling also increased neutrophils phagocytized by macrophages and promoted the phenotypic switch of macrophages from proinflammatory to prohealing activities. In vitro, phagocytosis of THP-1 (M0) and lipopolysaccharide- (LPS-) induced (M1) macrophages was impaired by treatment with AGEs, while IL-4- and IL-13-induced (M2) macrophages was not. Finally, AGEs increased the proinflammatory response of M1 macrophages, while inhibiting the polarization and anti-inflammatory functions of M2 macrophages. In conclusion, inhibition of AGE-RAGE signaling improved functional disorders of macrophages in the early inflammatory phase, which promoted the healing of wounds in diabetic mice.

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jinglian Yan ◽  
Guodong Tie ◽  
Lyne Khair ◽  
Elena Filippova ◽  
Louis Messina

Rationale: People with Type 2 Diabetes Mellitus (T2DM) have a 25x higher risk of limb loss than non-diabetics due in large part to impaired wound healing. The mechanisms that cause impaired wound healing remain incompletely characterized. Objective: We hypothesize that T2DM impairs wound healing by epigenetic modifications in hematopoietic stem cells (HSC) that reduce their differentiation towards monocytes/macrophages and disrupts the balance in M1/M2 polarization during the three phases of wound healing. Methods and Results: Wounds were created on the back of mice. Wound healing was significantly slower in diabetic db/db than in WT mice. During the early inflammatory phase, db/db wounds exhibited a significant decrease in total macrophages and M1 macrophages. Then, total macrophages and M2 macrophages were decreased, while M1 macrophages increased in tissue formation phase. In the late tissue remodeling phase, total macrophages and M1 macrophages were persistently increased. The impaired wound healing phenotype of db/db mice was recapitulated in WT recipients which were resconstituted with db/db HSCs, demonstrating that the impaired differentiation of HSCs towards macrophages as well as their M1/M2 polarization was due to a cell autonomous mechanism. Epigenetic studies indicated that DNMT1-dependent hypermethylation of Notch1, Pu.1 and KLF4 in T2D HSCs was responsible for the impaired differentiation towards monocytes/macrophages as well as the skewed M1/M2 polarization. Knockdown of DNMT1 in HSCs from db/db mice transplanted into lethally irradiated WT mice led to improved wound healing by an increase in macrophage infiltration as well as a normalization of the M1/M2 polarization. Conclusion: This study indicates that the dynamic changes of macrophage concentration and M1/M2 polarization in wound healing are regulated at the level of HSCs. Moreover, T2DM impairs wound healing by inducing DNMT1-dependent reduction of HSCs’ differentiation towards macrophages and their M1/M2 polarization. This novel finding indicates that inflammation is regulated at the level of HSCs, which creates new opportunities to develop epigenetic modification related therapies for T2DM and potentially other conditions that result from dysinflammation.


Nanomaterials ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1108
Author(s):  
Edorta Santos-Vizcaino ◽  
Aiala Salvador ◽  
Claudia Vairo ◽  
Manoli Igartua ◽  
Rosa Maria Hernandez ◽  
...  

Negatively charged microspheres (NCMs) represent a new therapeutic approach for wound healing since recent clinical trials have shown NCM efficacy in the recovery of hard-to-heal wounds that tend to stay in the inflammatory phase, unlocking the healing process. The aim of this study was to elucidate the NCM mechanism of action. NCMs were extracted from a commercial microsphere formulation (PolyHeal® Micro) and cytotoxicity, attachment, proliferation and viability assays were performed in keratinocytes and dermal fibroblasts, while macrophages were used for the phagocytosis and polarization assays. We demonstrated that cells tend to attach to the microsphere surface, and that NCMs are biocompatible and promote cell proliferation at specific concentrations (50 and 10 NCM/cell) by a minimum of 3 fold compared to the control group. Furthermore, NCM internalization by macrophages seemed to drive these cells to a noninflammatory condition, as demonstrated by the over-expression of CD206 and the under-expression of CD64, M2 and M1 markers, respectively. NCMs are an effective approach for reverting the chronic inflammatory state of stagnant wounds (such as diabetic wounds) and thus for improving wound healing.


2017 ◽  
Vol 58 (3-4) ◽  
pp. 109-120 ◽  
Author(s):  
Kerstin Klinkert ◽  
Derek Whelan ◽  
Anthony J.P. Clover ◽  
Anne-Laure Leblond ◽  
Arun H.S. Kumar ◽  
...  

Background: A prolonged inflammatory phase is seen in aberrant wound healing and in chronic wounds. Macrophages are central to wound healing. Distinct macrophage subtypes have differing roles both in initial inflammation and in later tissue repair. Broadly, these cells can be divided into M1 and M2 macrophages. M2 macrophage proliferation and differentiation is regulated by colony-stimulating factor 1 (CSF-1) signalling and can be blocked by GW2580, a competitive cFMS kinase inhibitor, thereby allowing for analysis of the effect of M2 blockade on progression of surgical wounds. Materials and Methods: Macrophage Fas-induced apoptosis (MaFIA) transgenic mice with a macrophage-specific promoter used to express green fluorescent protein (GFP) were used to allow for cell tracking. The animals were treated by oral gavage with GW2580. Surgical wounds were created and harvested after 2 weeks for analysis. Results: GW2580-treated mice had significantly more GFP+ cells in the surgical scar than vehicle-treated animals (GW2580, 68.0 ± 3.1%; vehicle, 42.8 ± 1.7%; p < 0.001), and GW2580 treatment depleted CD206+ M2 macrophages in the scar (GW2580, 1.4%; vehicle, 19.3%; p < 0.001). Treated animals showed significantly higher numbers of neutrophils (vehicle, 18.0%; GW2580, 51.3%; p < 0.01) and M1 macrophages (vehicle, 3.8%; GW2580, 12.8%; p < 0.01) in the scar compared to vehicle-treated animals. The total collagen content in the area of the scar was decreased in animals treated with GW2580 as compared to those treated with vehicle alone (GW2580, 67.1%; vehicle, 79.9%; p < 0.005). Conclusions: Depletion of M2 macrophages in surgical wounds via CSF-1 signalling blockade leads to persistent inflammation, with an increase in neutrophils and M1 macrophages and attenuated collagen deposition.


2018 ◽  
Vol 33 (2) ◽  
pp. 70-76 ◽  
Author(s):  
A. E. Gombozhapova ◽  
Yu. V. Rogovskaya ◽  
M. S. Rebenkova ◽  
J. G. Kzhyshkowska ◽  
V. V. Ryabov

Purpose. Myocardial regeneration is one of the most ambitious goals in prevention of adverse cardiac remodeling. Macrophages play a key role in transition from inflammatory to regenerative phase during wound healing following myocardial infarction (MI). We have accumulated data on macrophage properties ex vivo and in cell culture. However, there is no clear information about phenotypic heterogeneity of cardiac macrophages in patients with MI. The purpose of the project was to assess cardiac macrophage infiltration during wound healing following myocardial infarction in clinical settings taking into consideration experimental knowledge.Material and Methods. The study included 41 patients with fatal MI type 1. In addition to routine analysis, macrophages infiltration was assessed by immunohistochemistry. We used CD68 as a marker for the cells of the macrophage lineage, while CD163, CD206, and stabilin-1 were considered as M2 macrophage biomarkers. Nine patients who died from noncardiovascular causes comprised the control group.Results. The intensity of cardiac macrophage infiltration was higher during the regenerative phase than during the inflammatory phase. Results of immunohistochemical analysis demonstrated the presence of phenotypic heterogeneity of cardiac macrophages in patients with MI. We noticed that numbers of CD68+, CD163+, CD206+, and stabilin-1+ macrophages depended on MI phase.Conclusion. Our study supports prospects for implementation of macrophage phenotyping in clinic practice. Improved understanding of phenotypic heterogeneity might become the basis of a method to predict adverse cardiac remodeling and the first step in developing myocardial regeneration target therapy.


2015 ◽  
Vol 51 (2) ◽  
pp. 415-427 ◽  
Author(s):  
Juliana Neves Rodrigues Ract ◽  
Fabiana Andreia Schäfer De Martini Soares ◽  
Hosana Gomes Rodrigues ◽  
José Ricardo Bortolon ◽  
Gilson Masahiro Murata ◽  
...  

<p>Two oil blends (sunflower/canola oils 85/15 (BL1) and canola/linseed oils 70/30 (BL2)), were prepared and enzymatically interesterified to be applied to surgically-induced wounds in rats. Following surgery, the animals were submitted to the Treatment with Physiological Saline (TPS) (control group), Blends (TBL), and Structured Lipids (TSL). The control group (TPS) received physiological saline solution for 15 days. In TBL, BL1 was administered during the inflammation phase (days 0-3) and BL2 in the tissue formation and remodeling phase (days 4-15). In TSL, Structured Lipid 1 (SL1) and Structured Lipid 2 (SL2) were used instead of BL1 and BL2, respectively. The aim of this study was to compare wound closure evolution among rats treated with the blends or structured lipids versus control rats treated with physiological saline. The wound healing process was evaluated by measuring the wound areas along the treatments and the concentrations of cytokines. An increase in the areas of wounds treated with the blends and structured lipids in the inflammatory phase was observed, followed by a steeper closure curve compared to wounds treated with physiological saline. The changes observed during the inflammatory phase suggest a potential therapeutic application in cutaneous wound healing which should be further investigated.</p>


2018 ◽  
Vol 4 (2) ◽  
pp. 109
Author(s):  
Mufimah Mufimah ◽  
Uti Rusdian Hidayat ◽  
Ichsan Budiharto

Abstract: Efectiveness Gel Extract Of White On The Process Of Healing Inflamation Phase Heating. The inflammatory phase is a favorable body response as a protection mechanism. In the process of wound healing becomes a very important phase. Management of inflammation that is often used Non-Steroid Anti-Inflammatory class of salicylates on the skin that have side effects. The content of allicin in garlic can be used for problems that begin with the inflammatory phase. The use of gel from garlic extract is also easier to use and easier to clean. The study aim to determine the effectiveness of garlic extract gel to process wound inflammatory phase healing. This research is an experimental research with pre and post test with control group method with 24 samples. Conducted injury to the back area of rat length of wound 1 cm, depth to dermis. Conducted wound care, given gel extract of garlic concentration of 20%, 40%, 80% of the control using 0.9% NaCl compress. Using Kruskal Wallis test and Anova oneway showed concentration of 20%, 40%, and 80% of sig <0,05 ie 0.00. It was concluded that 20%, 40%, 80% garlic extract gel was effective against inflammatory wound healing process. The use of garlic extract gel is more effective in the wound inflammatory wound healing process.Abstrak: Efektivitas Gel Ekstrak Bawang Putih  terhadap Proses Penyembuhan Luka Fase Inflamasi.  Fase inflamasi merupakan respon tubuh yang menguntungkan sebagai mekanisme perlindungan. Pada proses penyembuhan luka menjadi fase yang sangat penting. Penatalaksanaan inflamasi yang sering digunakan Anti-Inflamasi Non Steroid golongan salisilat pada kulit yang memiliki efek samping. Kandungan zat allicin pada bawang putih dapat dimanfaatkan untuk masalah yang diawali dengan fase inflamasi. Pemanfaatan gel dari ekstrak bawang putih pun dalam penggunaannya lebih mudah diabsorsi dan mudah dibersihkan. Penelitian ini bertujuan untuk mengetahui efektifitas gel ekstrak bawang putih terhadap proses penyembuhan luka fase inflamasi. Penelitian ini merupakan penelitian eksperiment dengan metode pre and post test with control grup dengan jumlah sampel sebanyak 24 ekor tikus. Dilakukan perlukaan pada daerah punggung tikus panjang luka 1 cm, kedalaman sampai dermis. Dilakukan perawatan luka, diberi gel ekstrak bawang putih konsentrasi berbeda yaitu 20%, 40%, 80%  kontrol menggunakan kompres NaCl 0,9%. Hasil uji Kruskal Wallis dan Anova oneway menunjukkan konsentrasi 20%, 40%, dan 80%  nilai sig <0,05 yaitu 0,00. Disimpulkan bahwa 20%, 40%, 80% gel ekstrak bawang putih efektif terhadap proses penyembuhan luka inflamasi. Penggunaan gel ekstrak bawang putih lebih efektif dalam proses penyembuhan luka inflamasi luka.   Disimpulkan bahwa 20%, 40%, 80% gel ekstrak bawang putih efektif terhadap proses penyembuhan luka inflamasi. Penggunaan gel ekstrak bawang putih lebih efektif dalam proses penyembuhan luka inflamasi luka.


2019 ◽  
Vol 131 (6) ◽  
pp. 1301-1315 ◽  
Author(s):  
Thomas J. Gerber ◽  
Valérie C. O. Fehr ◽  
Suellen D. S. Oliveira ◽  
Guochang Hu ◽  
Randal Dull ◽  
...  

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sevoflurane with its antiinflammatory properties has shown to decrease mortality in animal models of sepsis. However, the underlying mechanism of its beneficial effect in this inflammatory scenario remains poorly understood. Macrophages play an important role in the early stage of sepsis as they are tasked with eliminating invading microbes and also attracting other immune cells by the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Thus, the authors hypothesized that sevoflurane mitigates the proinflammatory response of macrophages, while maintaining their bactericidal properties. Methods Murine bone marrow–derived macrophages were stimulated in vitro with lipopolysaccharide in the presence and absence of 2% sevoflurane. Expression of cytokines and inducible NO synthase as well as uptake of fluorescently labeled Escherichia coli (E. coli) were measured. The in vivo endotoxemia model consisted of an intraperitoneal lipopolysaccharide injection after anesthesia with either ketamine and xylazine or 4% sevoflurane. Male mice (n = 6 per group) were observed for a total of 20 h. During the last 30 min fluorescently labeled E. coli were intraperitoneally injected. Peritoneal cells were extracted by peritoneal lavage and inducible NO synthase expression as well as E. coli uptake by peritoneal macrophages was determined using flow cytometry. Results In vitro, sevoflurane enhanced lipopolysaccharide-induced inducible NO synthase expression after 8 h by 466% and increased macrophage uptake of fluorescently labeled E. coli by 70% compared with vehicle-treated controls. Inhibiting inducible NO synthase expression pharmacologically abolished this increase in bacteria uptake. In vivo, inducible NO synthase expression was increased by 669% and phagocytosis of E. coli by 49% compared with the control group. Conclusions Sevoflurane enhances phagocytosis of bacteria by lipopolysaccharide-challenged macrophages in vitro and in vivo via an inducible NO synthase–dependent mechanism. Thus, sevoflurane potentiates bactericidal and antiinflammatory host-defense mechanisms in endotoxemia.


2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Sandra Matabi Ayuk ◽  
Heidi Abrahamse ◽  
Nicolette Nadene Houreld

The integration of several cellular responses initiates the process of wound healing. Matrix Metalloproteinases (MMPs) play an integral role in wound healing. Their main function is degradation, by removal of damaged extracellular matrix (ECM) during the inflammatory phase, breakdown of the capillary basement membrane for angiogenesis and cell migration during the proliferation phase, and contraction and remodelling of tissue in the remodelling phase. For effective healing to occur, all wounds require a certain amount of these enzymes, which on the contrary could be very damaging at high concentrations causing excessive degradation and impaired wound healing. The imbalance in MMPs may increase the chronicity of a wound, a familiar problem seen in diabetic patients. The association of diabetes with impaired wound healing and other vascular complications is a serious public health issue. These may eventually lead to chronic foot ulcers and amputation. Low intensity laser irradiation (LILI) or photobiomodulation (PBM) is known to stimulate several wound healing processes; however, its role in matrix proteins and diabetic wound healing has not been fully investigated. This review focuses on the role of MMPs in diabetic wound healing and their interaction in PBM.


2021 ◽  
Vol 12 (4) ◽  
pp. 423-432
Author(s):  
Jessica Balikji ◽  
Maarten M. Hoogbergen ◽  
Johan Garssen ◽  
Joris C. Verster

The gut–brain–skin axis is important in wound healing. The aim of this study was to investigate the association between experiencing irritable bowel syndrome (IBS) symptoms, perceived immune fitness, and impaired wound healing. N = 1942 Dutch students (mean (SD) age 21.3 (2.1), 83.6% women) completed an online survey. They were allocated to one of four groups: (1) control group (N = 1544), (2) wound infection (WI) group (N = 65), (3) slow healing wounds (SHW) group (N = 236), or (4) a combination group (COMBI), which experienced both WI and SHW (N = 87). Participants rated their perceived immune fitness on a scale ranging from very poor (0) to excellent (10), and the severity of IBS symptoms (constipation, diarrhea, and pain) was assessed with the Birmingham IBS Symptom Questionnaire. Compared to the control group, perceived immune fitness was significantly poorer for the SHW group (p < 0.001) and COMBI group (p < 0.001), but not for the WI group. Compared to the control group, constipation was reported significantly more frequently by the SHW group (p < 0.001) and the WI group (p = 0.012), diarrhea was reported significantly more frequent by the SHW group (p = 0.038) and the COMBI group (p = 0.004), and pain was reported significantly more frequent by the SHW group (p = 0.020) and COMBI group (p = 0.001). Correlations between IBS complaints and perceived immune fitness were statistically significant (p < 0.001), and also a highly significant and negative association was found between the percentage of participants that reported impaired wound healing and perceived immune fitness (r = −0.97, p < 0.001). In conclusion, among participants with self-reported impaired wound healing, IBS complaints were significantly more severe, and accompanied by a significantly reduced perceived immune fitness.


2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Gaochao Zhang ◽  
Liyan Yang ◽  
Yu Han ◽  
Haiyue Niu ◽  
Li Yan ◽  
...  

Background. This study is aimed at assessing the subsets of bone marrow macrophages in patients with myelodysplastic syndrome (MDS) and exploring the role of macrophages in the pathogenesis of MDS. Methods. Thirty-eight newly diagnosed MDS patients were enrolled in the Department of Hematology of General Hospital of Tianjin Medical University from June 2015 to June 2016. Bone marrow monocytes and macrophage subsets (M1/M2) were detected in patients with MDS and normal controls by flow cytometry. M1 macrophages were cultured in vitro, and the expression of IL-1β and TNF-α mRNA was measured using real-time polymerase chain reaction. Results. Compared with the normal control group, the proportion of bone marrow monocytes was higher ( 2.11 ± 0.93 % vs. 3.66 ± 3.38 % ), and the mean fluorescence intensity of surface molecule CD14 was lower in the higher-risk (HR) MDS group ( 639.05 ± 359.78 vs. 458.26 ± 306.72 , p < 0.05 ). The ratio of M2 macrophages to monocytes was higher in patients with HR-MDS ( 1.82 ± 2.47 % vs. 3.93 ± 3.81 % , p < 0.05 ). The ratio of M1 to M2 macrophages was lower in the HR-MDS group ( 3.50 ± 3.22 vs. 1.80 ± 0.88 , p < 0.05 ). The expression of IL-1β and TNF-α mRNA in M1 macrophages was significantly lower in the MDS group ( p < 0.05 ). Conclusions. Patients with MDS had abnormal macrophage polarization, which may be involved in the alteration of bone marrow microenvironments.


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