Abstract 144: Bone-Marrow Chimeras Demonstrate that the Epigenetic Signature in the Bone Marrow Myeloid Cells Influences the Peripheral Wound M1-Dominant Macrophage Phenotype

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Katherine A Gallagher ◽  
Amrita Joshi ◽  
Emily Hogikyan ◽  
Dawn Coleman ◽  
William Carson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Wound Healing ◽  
Normal Diet ◽  
Blood Analysis ◽  
Macrophage Phenotype ◽  
Chimeric Mice ◽  
Impaired Wound Healing ◽  
Normal Wound Healing ◽  
Dominant Phenotype ◽  
Inflammatory Phase

Introduction: Diabetic wounds are characterized by a chronic inflammatory state that is maintained by overexpression of pro-inflammatory cytokines generated by macrophages. In normal wound healing, macrophages mobilized from the circulation initially exhibit an M1 phenotype and secrete pro-inflammatory mediators (i.e., IL-12) followed by a prolonged M2 anti-inflammatory phase. In type 2 diabetes (T2D), this M1 to M2 switch appears to be markedly attenuated. We have previously demonstrated that post-translational histone methylation changes in BM cells are maintained in peripheral macrophages and promote an M1 dominant phenotype in T2D wounds that result in impaired wound healing. We hypothesize that chimeric mice reconstituted with bone marrow from our T2D murine model will demonstrate delayed wound healing and expression of this epigenetic signature in peripheral wound macrophages. Methods: BM chimeras were created using GFP+ mice on a C57BL/6 background. GFP+ mice were fed a high-fat diet (HFD, 60% fat) for 14 weeks and BM from these mice and normal diet (ND, 12% fat) mice was transferred into irradiated recipients. Change in wound area compared to initial wound size using Image J software (NIH) at day 3 post-wounding. Levels of the demethylase enzyme, Jmjd3, in macrophages (CD11b + ) MACS isolated from wounds at day 3 were quantified by RT-PCR in ND→ND and HFD→ND GFP + chimeric mice. (N=8) Data are expressed as mean ± S.E. Results: Peripheral blood analysis was performed weekly and at 8 weeks confirmed 96.5% donor chimerism. Wound healing was significantly delayed in HFD→ND GFP + chimeric mice compared to controls and analysis of wound tissue macropahges in mice at day 3 post-wounding demonstrated increased Jmjd3 and IL-12 production. Discussion: Epigenetic changes in BM cells appear to be maintained in peripheral wound macrophages and contribute to increased M1 macrophages and impaired wound healing in T2D wounds.

Abstract 199: Type 2 Diabetes Impairs Wound Healing By DNMT1-dependent Reduction of Hematopoietic Stem Cell Differentiation towards Monocytes/Macrophages and Skewing of the M1/M2 Polarization

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jinglian Yan ◽  
Guodong Tie ◽  
Lyne Khair ◽  
Elena Filippova ◽  
Louis Messina
Keyword(s):  
Type 2 Diabetes ◽  
Wound Healing ◽  
Epigenetic Modification ◽  
Stem Cell Differentiation ◽  
M1 Macrophages ◽  
Hematopoietic Stem ◽  
Impaired Wound Healing ◽  
Inflammatory Phase ◽  
M2 Polarization

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.

scholarly journals The Role of Matrix Metalloproteinases in Diabetic Wound Healing in relation to Photobiomodulation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Sandra Matabi Ayuk ◽  
Heidi Abrahamse ◽  
Nicolette Nadene Houreld
Keyword(s):  
Wound Healing ◽  
Matrix Metalloproteinases ◽  
Vascular Complications ◽  
Diabetic Patients ◽  
Main Function ◽  
Diabetic Wound ◽  
Impaired Wound Healing ◽  
Inflammatory Phase ◽  
Diabetic Wound Healing

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.

Role of Nitric Oxide in Wound Healing

2002 ◽  
Vol 4 (1) ◽  
pp. 5-15 ◽  
Author(s):  
Beverly B. Childress ◽  
Joyce K. Stechmiller
Keyword(s):  
Nitric Oxide ◽  
Wound Healing ◽  
Growth Factors ◽  
Animal Studies ◽  
Chronic Wounds ◽  
Current Knowledge ◽  
Wound Care ◽  
Impaired Wound Healing ◽  
Normal Wound Healing ◽  
Age Related

Chronic wounds mainly affect elderly individuals and persons with comorbid diseases due to a compromised immune status. An age-related decline in immune function deters proper healing of wounds in an orderly and timely manner. Thus, older adults with 1 or more concomitant illnesses are more likely to experience and suffer from a nonhealing wound, which may drastically decrease their quality of life and financial resources. Novel therapies in wound care management rely heavily on our current knowledge of wound healing physiology. It is well established that normal wound healing occurs sequentially and is strictly regulated by pro-inflammatory cytokines and growth factors. A multitude of commercial products such as growth factors are available; however, their effectiveness in healing chronic wounds has yet to be proven. Recently, investigators have implicated nitric oxide (NO) in the exertion of regulatory forces on various cellular activities of the inflammatory and proliferative phases of wound healing. Gene therapy in animal studies has shown promising results and is furthering our understanding of impaired wound healing. The purpose of this article is to review the literature on NO and its role in wound healing. A discussion of the physiology of normal healing and the pathophysiology of chronic wounds is provided.

scholarly journals Reduction of ARNT in myeloid cells causes immune suppression and delayed wound healing

2014 ◽  
Vol 307 (4) ◽  
pp. C349-C357 ◽  
Author(s):  
Christopher Scott ◽  
James Bonner ◽  
Danqing Min ◽  
Philip Boughton ◽  
Rebecca Stokes ◽  
...  
Keyword(s):  
Wound Healing ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Delayed Wound Healing ◽  
Impaired Wound Healing ◽  
Environmental Signals ◽  
Aryl Hydrocarbon ◽  
Normal Wound Healing ◽  
Full Benefit ◽  
The Difference

Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that binds to partners to mediate responses to environmental signals. To investigate its role in the innate immune system, floxed ARNT mice were bred with lysozyme M-Cre recombinase animals to generate lysozyme M-ARNT (LAR) mice with reduced ARNT expression. Myeloid cells of LAR mice had altered mRNA expression and delayed wound healing. Interestingly, when the animals were rendered diabetic, the difference in wound healing between the LAR mice and their littermate controls was no longer present, suggesting that decreased myeloid cell ARNT function may be an important factor in impaired wound healing in diabetes. Deferoxamine (DFO) improves wound healing by increasing hypoxia-inducible factors, which require ARNT for function. DFO was not effective in wounds of LAR mice, again suggesting that myeloid cells are important for normal wound healing and for the full benefit of DFO. These findings suggest that myeloid ARNT is important for immune function and wound healing. Increasing ARNT and, more specifically, myeloid ARNT may be a therapeutic strategy to improve wound healing.

Angiogenic Nanoscaffold Accelerates Diabetic Wound Healing and Improves Wound Tissue Strength in db/db Mice

2009 ◽  
Author(s):  
Swathi Balaji ◽  
Abdul Q. Sheikh ◽  
Lee Morris ◽  
Foong Y. Lim ◽  
Timothy M. Crombleholme ◽  
...  
Keyword(s):  
Wound Healing ◽  
Healing Process ◽  
Wound Healing Process ◽  
Diabetic Patients ◽  
Diabetic Wound ◽  
Normal Wound Healing ◽  
Inflammatory Phase ◽  
Diabetic Wound Healing ◽  
Ecm Degradation ◽  
Chronic Ulcers

Chronic ulcers are a leading cause of morbidity in diabetic patients. Diabetes is associated with major changes in the wound microenvironment and disruption of normal wound healing process, characterized by a prolonged inflammatory phase with elevated levels of wound proteases and increased degradation of extracellular matrix (ECM) components [1]. This impedes wound healing due to a lack of provisional matrix, impaired recruitment and survival of endothelial (EC) and endothelial precursor (EPC) cells, and insufficient neovascularization, resulting in delayed healing. Therefore, strategies focused on restoring the diabetic wound microenvironment by decreasing ECM degradation and promoting neovascularization are promising for development of new therapies to treat chronic diabetic ulcers.

scholarly journals Insights into Host–Pathogen Interactions in Biofilm-Infected Wounds Reveal Possibilities for New Treatment Strategies

Antibiotics ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 396
Author(s):  
Hannah Trøstrup ◽  
Anne Sofie Boe Laulund ◽  
Claus Moser
Keyword(s):  
Wound Healing ◽  
Host Response ◽  
Chronic Wounds ◽  
Therapeutic Potential ◽  
Recent Observation ◽  
Treatment Strategies ◽  
Normal Wound Healing ◽  
Inflammatory Phase ◽  
The Impact

Normal wound healing occurs in three phases—the inflammatory, the proliferative, and the remodeling phase. Chronic wounds are, for unknown reasons, arrested in the inflammatory phase. Bacterial biofilms may cause chronicity by arresting healing in the inflammatory state by mechanisms not fully understood. Pseudomonas aeruginosa, a common wound pathogen with remarkable abilities in avoiding host defense and developing microbial resistance by biofilm formation, is detrimental to wound healing in clinical studies. The host response towards P. aeruginosa biofilm-infection in chronic wounds and impact on wound healing is discussed and compared to our own results in a chronic murine wound model. The impact of P. aeruginosa biofilms can be described by determining alterations in the inflammatory response, growth factor profile, and count of leukocytes in blood. P. aeruginosa biofilms are capable of reducing the host response to the infection, despite a continuously sustained inflammatory reaction and resulting local tissue damage. A recent observation of in vivo synergism between immunomodulatory and antimicrobial S100A8/A9 and ciprofloxacin suggests its possible future therapeutic potential.

Wound Healing In Glaucoma

2013 ◽  
Author(s):  
Kimberly A. Mankiewicz ◽  
Leonard K. Seibold
Keyword(s):  
Wound Healing ◽  
Blood Cells ◽  
Healing Process ◽  
White Blood Cells ◽  
Glaucoma Surgery ◽  
Scar Formation ◽  
Wound Site ◽  
Normal Wound Healing ◽  
Inflammatory Phase ◽  
Repair Phase

The goal of wound healing in most surgeries is to bring the injured tissue back to its original state to prevent the wound from reopening. However, in glaucoma surgery, the goal is to have incomplete wound healing. Scar formation prevents the filtering mechanism and bleb from functioning properly, leading to poor pressure control and failure of the surgery. However, if there is too little wound healing, surgical failure may be marked by overfiltration and hypotony. Several modulators are currently used in conjunction with glaucoma surgery, and new targets are under investigation to improve our ability to control the healing process. Normal wound healing occurs in 3 phases: the inflammatory phase, the proliferative/repair phase, and the remodeling phase. In the inflammatory phase, blood cells and plasma proteins are released around the wound site. These proteins attract other wound healing factors, such as cytokines and growth factors. White blood cells are also recruited to the site, clearing out undesired cellular debris through phagocytosis. Additionally, platelet aggregation and fibrin clot formation occur. In the proliferative/repair phase, fibroblasts, crucial cells for tissue repair and scarring, begin reforming the extracellular matrix (ECM) and other components of connective tissue. Angiogenesis also occurs, and the wound begins to close. In the final phase, blood vessels are resorbed and fibroblasts disperse. Fibroblasts produce matrix metalloproteinases that, along with collagen and elastin, allowing for wound remodeling and scar formation. The modulators used in glaucoma surgery, as well as new agents in development, disrupt various aspects of this cycle. Use of topical corticosteroids in conjunction with filtering surgery is a routine part of postoperative management and has been for many decades. Corticosteroids blunt the wound healing response by altering the inflammatory phase through reducing the amount of inflammatory cells and cytokines that migrate to the wound site. Corticosteroids also prevent the complexing and conversion of inflammatory mediators, as well as reduce vascular permeability to limit mobility of wound healing factors to the wound site.

scholarly journals Immunology of Acute and Chronic Wound Healing

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 700
Author(s):  
Kamila Raziyeva ◽  
Yevgeniy Kim ◽  
Zharylkasyn Zharkinbekov ◽  
Kuat Kassymbek ◽  
Shiro Jimi ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Chronic Wound ◽  
Healing Process ◽  
Inflammatory Factors ◽  
Wound Healing Process ◽  
Macrophage Phenotype ◽  
Microbial Biofilms ◽  
Inflammatory Phase ◽  
Persistent Inflammation

Skin wounds greatly affect the global healthcare system, creating a substantial burden on the economy and society. Moreover, the situation is exacerbated by low healing rates, which in fact are overestimated in reports. Cutaneous wounds are generally classified into acute and chronic. The immune response plays an important role during acute wound healing. The activation of immune cells and factors initiate the inflammatory process, facilitate wound cleansing and promote subsequent tissue healing. However, dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wounds. The microenvironment of a chronic wound is characterized by high quantities of pro-inflammatory macrophages, overexpression of inflammatory mediators such as TNF-α and IL-1β, increased activity of matrix metalloproteinases and abundance of reactive oxygen species. Moreover, chronic wounds are frequently complicated by bacterial biofilms, which perpetuate the inflammatory phase. Continuous inflammation and microbial biofilms make it very difficult for the chronic wounds to heal. In this review, we discuss the role of innate and adaptive immunity in the pathogenesis of acute and chronic wounds. Furthermore, we review the latest immunomodulatory therapeutic strategies, including modifying macrophage phenotype, regulating miRNA expression and targeting pro- and anti-inflammatory factors to improve wound healing.

POST-OPERATTVE CHANGES IN PROIEINASE INHIBITORS IN NORMAL AND IMPAIRED WOUND HEALING

1987 ◽  
Author(s):  
M Reitz ◽  
H Sauer ◽  
G Witzke ◽  
M Neher
Keyword(s):  
Wound Healing ◽  
Marked Reduction ◽  
Mean Value ◽  
Striking Difference ◽  
Impaired Wound Healing ◽  
Normal Wound Healing ◽  
At Iii ◽  
Group A ◽  
Group B ◽  
Tissue Trauma

Tissue trauma after surgery activates blood coagulation. This results in a change and in the consumption of important inhibitors.We investigated the oonoentraticn of antithrorfoin III (AT III), ∝ 1-antitrypsin (∝l-AT), ∝ 2- macrogloublin (∝ 2-M) and Cl-inactivator (Cl-INH) in the blood plasma by means ofradial iirmunodiffusicn in 16 patients before surgery, after surgery and cn the 1st, 3rd and 7th days after surgery. In 11 patients normal wound healing wasobserved (group A), while in 5 patients amplicationsoccurred (group B). AT III: Fall in concentration upto the 3rd day after surgery, then a rise in concentration. In the patients with impaired wound healing there was a particularly marked reduction in AT III cn the 3rd day.∝ 1-AT: Fall in concentration after surgery, followed by a rise in concentration. In impaired wound healing a lower mean value was determined on the 3rd day after surgery than in normal wound healing. ∝ 2-M: Fall in concentration up to the 3rd day after surgery, followed by a slight increase in concentration. No striking difference between the normal group and the group with complications. Cl-INH: Fall in concentration after surgery, followed by arise in concentration; in the patients with impaired wound healing there was adelayed rise in concentration.

scholarly journals pH-switchable nanozyme cascade catalysis: a strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in diabetic ulcer

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Xuancheng Du ◽  
Bingqing Jia ◽  
Weijie Wang ◽  
Chengmei Zhang ◽  
Xiangdong Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Wound Healing ◽  
Glucose Oxidase ◽  
Cascade Reaction ◽  
Temporal Modulation ◽  
Diabetic Ulcer ◽  
Normal Tissues ◽  
Normal Wound Healing ◽  
Inflammatory Phase ◽  
Cascade Catalysis

AbstractThe management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe3O4-GOx). The Fe3O4-GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe3O4-GOx-instructed spatial–temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases. Graphical Abstract

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