Wound Healing Research Group

Wound Healing Research Group

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Zhu Z.,Shantou University | Ding J.,Wound Healing Research Group | Ma Z.,Wound Healing Research Group | Iwashina T.,Wound Healing Research Group
Wound Repair and Regeneration | Year: 2017

Macrophages play a key role in the wound healing process and can be divided into classically activated macrophages (M1) and alternatively activated macrophages (M2). Fibroblasts maintain the physical integrity of connective tissue, participate in wound closure as well as produce and remodel extracellular matrix. Macrophages have a close relationship with fibroblasts by increasing the production of matrix metalloproteinase-1 (MMP-1) for faster wound closure and remodeling and myofibroblast differentiation from fibroblasts. In this study, resting state (M0), M1 and M2 macrophages differentiated from the human monocytic THP-1 cell line were used to co-culture with human dermal fibroblasts (HDF) for 48, 96 and 144 hours to investigate the effect of macrophages subsets on the fibrogenic activity of fibroblasts. The differentiation and polarization from THP-1 cells to M0, M1 and M2 macrophages were characterized by flow cytometry and cell cycle analysis. Cell sorting was performed to purify M0 and M2 macrophages. Cell proliferation, collagen synthesis, myofibroblast formation, gene expression of anti-fibrotic and pro-fibrotic factors, MMP-1 activity, and cytokine concentration were investigated. Results showed differentiation of M0 and polarization of M1 and M2 macrophages. M2 macrophages promoted the fibrogenic activities of co-cultured HDF by facilitating cell proliferation, increasing the collagen content, alpha-smooth muscle actin expressed cells, expression of the pro-fibrotic genes and concentration of M2 macrophage related factors, as well as decreasing the expression of the anti-fibrotic genes and MMP-1 activity. These findings reinforce the pro-fibrotic role of M2 macrophages, suggesting therapeutic strategies in fibrotic diseases should target M2 macrophages in the future. © 2017 by the Wound Healing Society.


Metcalfe P.D.,Wound Healing Research Group | Wang J.,Wound Healing Research Group | Jiao H.,Wound Healing Research Group | Huang Y.,Wound Healing Research Group | And 5 more authors.
BJU International | Year: 2010

OBJECTIVE To investigate the progression of urodynamic changes, as well as histological and biochemical outcomes over a prolonged period of partial bladder outlet obstruction (pBOO) in an animal model with physiologically relevant pBOO. MATERIALS AND METHODS Healthy, adult, female Fischer rats underwent surgical creation of a pBOO for either 2, 4, 8, or 13 weeks and were compared with sham-operated rats. Urodynamic measurements were used to compare bladder volumes and pressure. Tissue was grossly analysed with light microscopy and bladder weights and thicknesses were compared. Reverse transcription-polymerase chain reaction for collagen, transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), hypoxia inducible factor 1α (HIF-1α), and platelet-derived growth factor (PDGF-A) was performed on all samples, as well as immunohistochemistry (IHC) for α-smooth muscle actin (α-SMA). Finally, mass spectrometry was used to quantify the collagen content of the bladders as a measure of fibrosis. RESULTS After induction of pBOO, all rats remained healthy. Initial urodynamics showed an increase in capacity while maintaining normal pressures, but then deteriorated into small capacity, high-pressure bladders. Haematoxylin and eosin (H&E) staining showed an initial inflammatory response, and this was confirmed with significantly increased mRNA levels of TGF-β, CTGF, HIF-1α, and PDGF. The progression to smooth muscle hypertrophy was evident on H&E and confirmed with increased bladder mass and thickness. IHC for α-SMA showed a progressive increase associated with the elevated bladder pressures. Masson's trichrome and mass spectrometry showed a progressive increase in collagen to 13 weeks. CONCLUSION With this model, we have effectively replicated the clinical scenario, with significant pathophysiological changes occurring insidiously in otherwise healthy rats. We believe that our observed changes represent distinct phases of bladder decompensation; with an initial inflammatory response to the stress of the pBOO, smooth muscle hypertrophy to overcome the increased urethral resistance, and eventual decompensation to fibrosis. The time course of the inflammatory markers implies the need for early intervention to prevent this cascade. Novel strategies targeting these observed physiological responses could lead to improved preventative strategies, with respect to biochemical pathways and the time course of their initiation. © 2010 BJU International.


Kucera J.,Wound Healing Research Group | Kucera J.,Charles University | Sojka M.,Cell Physiology Research Group | Sojka M.,Slovak Medical University | And 6 more authors.
Journal of Microbiological Methods | Year: 2014

Wound infections represent a major problem, particularly in patients with chronic wounds. Bacteria in the wound exist mainly in the form of biofilms and are thus resistant to most antibiotics and antimicrobials. A simple and cost-effective in vitro model of chronic wound biofilms applied for testing treatments and solid devices, especially wound dressings, is presented in this work. The method is based on the well-established Lubbock chronic wound biofilm transferred onto an artificial agar wound bed. The biofilm formed by four bacterial species (Staphylococcus aureus, Enterococcus faecalis, Bacillus subtilis and Pseudomonas aeruginosa) was stable for up to 48. h post-transplant. The applicability of the model was evaluated by testing two common iodine wound treatments. These observations indicate that this method enables assessing the effects of treatments on established resilient wound biofilms and is clinically highly relevant. © 2014 Elsevier B.V.


Zhu Z.,Shantou University | Ding J.,Wound Healing Research Group | Ma Z.,Wound Healing Research Group | Iwashina T.,Wound Healing Research Group | Tredget E.E.,Wound Healing Research Group
Wound Repair and Regeneration | Year: 2016

Hypertrophic scars are caused by trauma or burn injuries to the deep dermis and can cause cosmetic disfigurement and psychological issues. Studies suggest that M2-like macrophages are pro-fibrotic and contribute to hypertrophic scar formation. A previous study from our lab showed that M2 macrophages were present in developing hypertrophic scar tissues in vivo at 3-4 weeks after wounding. In this study, the effect of systemic macrophage depletion on scar formation was explored at subacute phase of wound healing. Thirty-six athymic nude mice that received human skin transplants were randomly divided into macrophage depletion group and control group. The former received intraperitoneal injections of clodronate liposomes while the controls received sterile saline injections on day 7, 10, and 13 postgrafting. Wound area, scar thickness, collagen abundance and collagen bundle structure, mast cell infiltration, myofibroblast formation, M1, and M2 macrophages together with gene expression of M1 and M2 related factors in the grafted skin were investigated at 2, 4, and 8 weeks postgrafting. The transplanted human skin from the control group developed contracted, elevated, and thickened scars while the grafted skin from the depletion group healed with significant less contraction and elevation. Significant reductions in myofibroblast number, collagen synthesis, and hypertrophic fiber morphology as well as mast cell infiltration were observed in the depletion group compared to the control group. Macrophage depletion significantly reduced M1 and M2 macrophage number in the depletion group 2 weeks postgrafting as compared to the control group. These findings suggest that systemic macrophage depletion in subacute phase of wound healing reduces scar formation, which provides evidence for the pro-fibrotic role of macrophages in fibrosis of human skin as well as insight into the potential benefits of specifically depleting M2 macrophages in vivo. © 2016 by the Wound Healing Society.


Zuo K.J.,Wound Healing Research Group | Tredget E.E.,University of Alberta
Burns | Year: 2014

Marjolin's ulcer is an aggressive ulcerating cutaneous malignancy that may arise in chronically inflamed or traumatized skin. Frequently overlooked, this rare condition is classically associated with burn scars, with the process of malignant degeneration typically occurring over two to three decades. The most common histopathological pattern is squamous cell carcinoma; however, compared to typical squamous cell carcinomas, Marjolin's ulcers have an increased rate of metastasis. The correlation between radiotherapy for benign hypertrophic scarring and carcinogenesis is controversial, with few reports in the literature. We present a unique case of a 61 year old Caucasian male who was burned by scald at age 4, received radiotherapy for his post-burn hypertrophic scars, and later developed multiple Marjolin's ulcers on his left arm, chest, and right temporal scalp.


Ding J.,Wound Healing Research Group | Ma Z.,Wound Healing Research Group | Shankowsky H.A.,Wound Healing Research Group | Medina A.,Wound Healing Research Group | And 2 more authors.
Wound Repair and Regeneration | Year: 2013

Hypertrophic scars are a significant fibroproliferative disorder complicating deep injuries to the skin. We hypothesize that activated deep dermal fibroblasts are subject to regulation by bone marrow-derived mesenchymal stem cells (BM-MSCs), which leads to the development of excessive fibrosis following deep dermal injury. We found that the expression of fibrotic factors was higher in deep burn wounds compared with superficial burn wounds collected from burn patients with varying depth of skin injury. We characterized deep and superficial dermal fibroblasts, which were cultured from the deep and superficial dermal layers of normal uninjured skin obtained from abdominoplasty patients, and examined the paracrine effects of BM-MSCs on the fibrotic activities of the cells. In vitro, deep dermal fibroblasts were found higher in the messenger RNA (mRNA) levels of type 1 collagen, alpha smooth muscle actin, transforming growth factor beta, stromal cell-derived factor 1, and tissue inhibitor of metalloproteinase 1, an inhibitor of collagenase (matrix metalloproteinase 1). As well, deep dermal fibroblasts had low matrix metalloproteinase 1 mRNA, produced more collagen, and contracted collagen lattices significantly greater than superficial fibroblasts. By co-culturing layered fibroblasts with BM-MSCs in a transwell insert system, BM-MSCs enhanced the fibrotic behavior of deep dermal fibroblasts, which suggests a possible involvement of BM-MSCs in the pathogenesis of hypertrophic scarring. © 2013 by the Wound Healing Society.


Medina A.,Wound Healing Research Group | Medina A.,University of Alberta | Shankowsky H.,Wound Healing Research Group | Savaryn B.,Wound Healing Research Group | And 3 more authors.
Journal of Burn Care and Research | Year: 2014

Heterotopic ossification (HO) is a clinical condition of ectopic bone formation in soft tissue. This clinical entity has been associated with genetic disorders, traumatic injuries, and musculoskeletal surgeries. In this regard, functional impairments secondary to scar contractures seen in burn injuries may be exacerbated with underlying HO. The appropriate prevention or management of this complication is crucial to optimize outcome in burn patients. This clinical study reviews the incidence of HO in our burned patients, diagnostic methods, therapeutic approaches including surgical timing and techniques. Copyright © 2014 by the American Burn Association.


Medina A.,Wound Healing Research Group | Tredget E.E.,Wound Healing Research Group | Tredget E.E.,University of Alberta
Journal of Burn Care and Research | Year: 2013

Total nasal reconstruction requires the management of skin, cartilage, and nasal mucosa. This three-dimensional surgical approach is especially restricted in patients with severe deformities after deep panfacial burns. In this regard, the development of tissue fibrosis reduces the quality and reliability of surrounded donor sites, limiting the surgical options and flap survival outcomes. This report discusses the benefit of tissue protection procedures, such as flap delay and leech therapy, in the total nasal reconstruction of a patient with split-thickness skin grafts on donor sites for forehead and nasolabial flaps. © 2013 by the American Burn Association.


Knorr C.,Justus Liebig University | Marks D.,Justus Liebig University | Gerstberger R.,Justus Liebig University | Muhlradt P.F.,Wound Healing Research Group | And 2 more authors.
Neuroscience Letters | Year: 2010

We investigated whether an inflammation-dependent activation of the brain occurs in response to systemic intraperitoneal (i.p.) or local injections of macrophage-activating lipopeptide-2 (MALP-2) into a subcutaneous (s.c.) air pouch, and whether local (peripheral) or central cyclooxygenase (COX)-2-dependent formations of prostaglandin E2 (PGE2) are involved in MALP-2-induced illness responses. Body temperature, activity, food and water intake were measured telemetrically. Local (s.c.) and circulating levels of PGE2 were measured by an ELISA. Inflammatory activation of the brain in response to MALP-2 was determined by immunohistochemical detection of the transcription factors NFκB and STAT3 in cell nuclei as well as the appearance of COX-2 at the same sites. S.c. treatment with the preferential COX-2 inhibitor meloxicam attenuated, but not abolished fever induced by local injections of MALP-2 into the pouch. Local MALP-2-induced formation of PGE2 was blunted by treatment with meloxicam. In the brain, i.p. stimulation with MALP-2-induced nuclear STAT3- and NFκB-translocation in the vasculature and the sensory circumventricular organs, which was accompanied by an increase in COX-2 immunoreactivity (IR) in endothelial cells. Local MALP-2-treatment induced a moderate STAT3 activation and a small but significant increase in COX-2 IR while no NFκB-activation could be observed in the brains of these animals. We demonstrated that the activation of the brain STAT3 (NFκB)-COX-2 singling cascade seems to be involved in the manifestation of brain-controlled illness symptoms induced by systemic and local inflammatory stimulation with MALP-2. The present data further suggest a contribution of peripherally produced PGE2 to MALP-2-induced activation of brain sites implicated in fever. © 2010 Elsevier Ireland Ltd.


PubMed | Wound Healing Research Group
Type: Journal Article | Journal: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society | Year: 2016

Hypertrophic scars are caused by trauma or burn injuries to the deep dermis and can cause cosmetic disfigurement and psychological issues. Studies suggest that M2-like macrophages are pro-fibrotic and contribute to hypertrophic scar formation. A previous study from our lab showed that M2 macrophages were present in developing hypertrophic scar tissues in vivo at 3-4 weeks after wounding. In this study, the effect of systemic macrophage depletion on scar formation was explored at subacute phase of wound healing. Thirty-six athymic nude mice that received human skin transplants were randomly divided into macrophage depletion group and control group. The former received intraperitoneal injections of clodronate liposomes while the controls received sterile saline injections on day 7, 10, and 13 postgrafting. Wound area, scar thickness, collagen abundance and collagen bundle structure, mast cell infiltration, myofibroblast formation, M1, and M2 macrophages together with gene expression of M1 and M2 related factors in the grafted skin were investigated at 2, 4, and 8 weeks postgrafting. The transplanted human skin from the control group developed contracted, elevated, and thickened scars while the grafted skin from the depletion group healed with significant less contraction and elevation. Significant reductions in myofibroblast number, collagen synthesis, and hypertrophic fiber morphology as well as mast cell infiltration were observed in the depletion group compared to the control group. Macrophage depletion significantly reduced M1 and M2 macrophage number in the depletion group 2 weeks postgrafting as compared to the control group. These findings suggest that systemic macrophage depletion in subacute phase of wound healing reduces scar formation, which provides evidence for the pro-fibrotic role of macrophages in fibrosis of human skin as well as insight into the potential benefits of specifically depleting M2 macrophages in vivo.

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