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Molecular Mechanisms Related to Burns, Burn Wound Healing and Scarring 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 29194

Special Issue Editors


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Guest Editor
Sunnybrook Hlth Sci Ctr, Ross Tilley Burn Ctr, 2075 Bayview Ave, University of Toronto, Toronto, ON M4N 3M5, Canada
Interests: burn; trauma; stress response; inflammation; hypermetabolism, including insulin resistance; cell regeneration; gene transfer; stem cells
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria
2. COREMED—Cooperative Centre for Regenerative Medicine, Joanneum Research GmbH, Neue Stiftingtal Str., 2, A-8010 Graz, Austria
Interests: plastic surgery; burn care; tissue engineering; regenerative medicine; wound healing; outcome measures; high-impact leadership; circular economy; sustainability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Burn injury is a complex traumatic event with various local, regional and systemic effects. The pathophysiology of the burn patient shows the full spectrum of the complexity of inflammatory response reactions. In the acute phase, the inflammation mechanism may have negative effects because of capillary leak, the propagation of inhalation injury, and the development of multiple organ failure. Attempts to mediate these processes remain a central subject of burn care-related research. Conversely, inflammation is a necessary component in the later-stage processes of wound healing. Improvements in acute burn care have enabled patients to survive massive burns that would have once been fatal. Now, up to 70% of patients develop hypertrophic scars after burns. The functional and psychosocial sequelae remain a major rehabilitative challenge, decreasing quality of life and delaying reintegration into society. Approaches to optimizing the healing potential of burn wounds use targeted wound care and surgery to minimize the development of hypertrophic scarring. Such approaches often fail, and modulation of the established scar is continued, although the optimal indication, timing, and combination of therapies have yet to be established. The need for novel treatments is paramount, and future efforts to improve outcomes and quality of life should include optimization of wound healing to attenuate or prevent hypertrophic scarring, well-designed trials to confirm treatment efficacy, and further elucidation of molecular mechanisms to allow development of new preventive and therapeutic strategies. In this issue of the journal, we are looking for articles which deliver a profound insight into the current science of burn wound pathophysiology, burn wound healing, and scarring.

Prof. Dr. Marc Jeschke
Prof. Dr. Lars-Peter Kamolz
Guest Editors

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Keywords

  • burn injury
  • wound healing
  • scarring
  • pathophysiology
  • molecular mechanism

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Published Papers (7 papers)

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Research

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16 pages, 3719 KiB  
Article
The Role of Local Inflammation and Hypoxia in the Formation of Hypertrophic Scars—A New Model in the Duroc Pig
by Sebastian P. Nischwitz, Julia Fink, Marlies Schellnegger, Hanna Luze, Vladimir Bubalo, Carolin Tetyczka, Eva Roblegg, Christian Holecek, Martin Zacharias, Lars-Peter Kamolz and Petra Kotzbeck
Int. J. Mol. Sci. 2023, 24(1), 316; https://doi.org/10.3390/ijms24010316 - 24 Dec 2022
Cited by 5 | Viewed by 1891
Abstract
Hypertrophic scars continue to be a major burden, especially after burns. Persistent inflammation during wound healing appears to be the precipitating aspect in pathologic scarring. The lack of a standardized model hinders research from fully elucidating pathophysiology and therapy, as most therapeutic approaches [...] Read more.
Hypertrophic scars continue to be a major burden, especially after burns. Persistent inflammation during wound healing appears to be the precipitating aspect in pathologic scarring. The lack of a standardized model hinders research from fully elucidating pathophysiology and therapy, as most therapeutic approaches have sparse evidence. The goal of this project was to investigate the mechanisms of scar formation after prolonged wound inflammation and to introduce a method for generating standardized hypertrophic scars by inducing prolonged inflammation. Four wound types were created in Duroc pigs: full-thickness wounds, burn wounds, and both of them with induced hyperinflammation by resiquimod. Clinical assessment (Vancouver Scar Scale), tissue oxygenation by hyperspectral imaging, histologic assessment, and gene expression analysis were performed at various time points during the following five months. Native burn wounds as well as resiquimod-induced full-thickness and burn wounds resulted in more hypertrophic scars than full-thickness wounds. The scar scale showed significantly higher scores in burn- and resiquimod-induced wounds compared with full-thickness wounds as of day 77. These three wound types also showed relative hypoxia compared with uninduced full-thickness wounds in hyperspectral imaging and increased expression of HIF1a levels. The highest number of inflammatory cells was detected in resiquimod-induced full-thickness wounds with histologic features of hypertrophic scars in burn and resiquimod-induced wounds. Gene expression analysis revealed increased inflammation with only moderately altered fibrosis markers. We successfully created hypertrophic scars in the Duroc pig by using different wound etiologies. Inflammation caused by burns or resiquimod induction led to scars similar to human hypertrophic scars. This model may allow for the further investigation of the exact mechanisms of pathological scars, the role of hypoxia and inflammation, and the testing of therapeutic approaches. Full article
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13 pages, 2570 KiB  
Article
Pioglitazone Modifies Kupffer Cell Function and Protects against Escherichia coli-Induced Bacteremia in Burned Mice
by Hiromi Miyazaki, Manabu Kinoshita, Hiroyuki Nakashima, Shingo Nakamura and Daizoh Saitoh
Int. J. Mol. Sci. 2022, 23(21), 12746; https://doi.org/10.3390/ijms232112746 - 22 Oct 2022
Cited by 2 | Viewed by 1858
Abstract
Infectious complications and subsequent sepsis in severely burned patients lead to high morbidity and mortality in response to uncontrolled innate immune responses mediated by macrophages. Peroxisome proliferator-activated receptor gamma (PPARγ) has anti-inflammatory activity and acts as a master regulator of macrophage polarization. In [...] Read more.
Infectious complications and subsequent sepsis in severely burned patients lead to high morbidity and mortality in response to uncontrolled innate immune responses mediated by macrophages. Peroxisome proliferator-activated receptor gamma (PPARγ) has anti-inflammatory activity and acts as a master regulator of macrophage polarization. In this study, we investigated whether the administration of a PPARγ agonist could modulate the Kupffer cell phenotype and thereby ameliorate the dysregulated innate response during post-burn bacterial infection. C57BL/6 mice were subjected to severe burns and randomized to receive either the PPARγ agonist, pioglitazone, or the vehicle control five days after injury, followed by the subsequent analysis of hepatic macrophages. Survival from the bacterial infection was monitored for seven days. Pioglitazone protected burned mice against bacterial infection. A single treatment with pioglitazone significantly enhanced phagocytosis, phagosome acidification, bacterial clearance, and reduction in inflammatory mediators in Kupffer cells. In conclusion, PPARγ activation by pioglitazone prevents clinical deterioration due to post-burn bacterial infection and improves survival. Our findings suggest that pioglitazone may be an effective therapeutic candidate for post-burn infectious complications. Full article
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16 pages, 3700 KiB  
Article
Multiplexed Human Gene Expression Analysis Reveals a Central Role of the TLR/mTOR/PPARγ and NFkB Axes in Burn and Inhalation Injury-Induced Changes in Systemic Immunometabolism and Long-Term Patient Outcomes
by Cressida Mahung, Shannon M. Wallet, Jordan E. Jacobs, Laura Y. Zhou, Haibo Zhou, Bruce A. Cairns and Robert Maile
Int. J. Mol. Sci. 2022, 23(16), 9418; https://doi.org/10.3390/ijms23169418 - 20 Aug 2022
Cited by 4 | Viewed by 1788
Abstract
Burn patients are subject to significant acute immune and metabolic dysfunction. Concomitant inhalation injury increases mortality by 20%. In order to identify specific immune and metabolic signaling pathways in burn (B), inhalation (I), and combined burn-inhalation (BI) injury, unbiased nanoString multiplex technology was [...] Read more.
Burn patients are subject to significant acute immune and metabolic dysfunction. Concomitant inhalation injury increases mortality by 20%. In order to identify specific immune and metabolic signaling pathways in burn (B), inhalation (I), and combined burn-inhalation (BI) injury, unbiased nanoString multiplex technology was used to investigate gene expression within peripheral blood mononuclear cells (PBMCs) from burn patients, with and without inhalation injury. PBMCs were collected from 36 injured patients and 12 healthy, non-burned controls within 72 h of injury. mRNA was isolated and hybridized with probes for 1342 genes related to general immunology and cellular metabolism. From these specific gene patterns, specific cellular perturbations and signaling pathways were inferred using robust bioinformatic tools. In both B and BI injuries, elements of mTOR, PPARγ, TLR, and NF-kB signaling pathways were significantly altered within PBMC after injury compared to PBMC from the healthy control group. Using linear regression modeling, (1) DEPTOR, LAMTOR5, PPARγ, and RPTOR significantly correlated with patient BMI; (2) RPTOR significantly correlated with patient length of stay, and (3) MRC1 significantly correlated with the eventual risk of patient mortality. Identification of mediators of this immunometabolic response that can act as biomarkers and/or therapeutic targets could ultimately aid the management of burn patients. Full article
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19 pages, 3393 KiB  
Article
Characterization of the Basal and mTOR-Dependent Acute Pulmonary and Systemic Immune Response in a Murine Model of Combined Burn and Inhalation Injury
by Hannah R. Hall, Cressida Mahung, Julia L. M. Dunn, Laurel M. Kartchner, Roland F. Seim, Bruce A. Cairns, Shannon M. Wallet and Robert Maile
Int. J. Mol. Sci. 2022, 23(15), 8779; https://doi.org/10.3390/ijms23158779 - 7 Aug 2022
Cited by 3 | Viewed by 2205
Abstract
Severe burn injury leads to a cascade of local and systemic immune responses that trigger an extreme state of immune dysfunction, leaving the patient highly susceptible to acute and chronic infection. When combined with inhalation injury, burn patients have higher mortality and a [...] Read more.
Severe burn injury leads to a cascade of local and systemic immune responses that trigger an extreme state of immune dysfunction, leaving the patient highly susceptible to acute and chronic infection. When combined with inhalation injury, burn patients have higher mortality and a greater chance of developing secondary respiratory complications including infection. No animal model of combined burn and inhalation injury (B+I) exists that accurately mirrors the human clinical picture, nor are there any effective immunotherapies or predictive models of the risk of immune dysfunction. Our earlier work showed that the mechanistic/mammalian target of rapamycin (mTOR) pathway is activated early after burn injury, and its chemical blockade at injury reduced subsequent chronic bacterial susceptibility. It is unclear if mTOR plays a role in the exacerbated immune dysfunction seen after B+I injury. We aimed to: (1) characterize a novel murine model of B+I injury, and (2) investigate the role of mTOR in the immune response after B+I injury. Pulmonary and systemic immune responses to B+I were characterized in the absence or presence of mTOR inhibition at the time of injury. Data describe a murine model of B+I with inhalation-specific immune phenotypes and implicate mTOR in the acute immune dysfunction observed. Full article
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12 pages, 1603 KiB  
Article
Galunisertib Exerts Antifibrotic Effects on TGF-β-Induced Fibroproliferative Dermal Fibroblasts
by Joshua M. Peterson, Jayson W. Jay, Ye Wang, Alejandro A. Joglar, Anesh Prasai, Alen Palackic, Steven E. Wolf and Amina El Ayadi
Int. J. Mol. Sci. 2022, 23(12), 6689; https://doi.org/10.3390/ijms23126689 - 15 Jun 2022
Cited by 5 | Viewed by 9616
Abstract
Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-β, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in [...] Read more.
Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-β, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-β and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 μM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars. Full article
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19 pages, 14370 KiB  
Article
Clostridium Collagenase Impact on Zone of Stasis Stabilization and Transition to Healthy Tissue in Burns
by Rosanne E. Frederick, Robert Bearden, Aleksa Jovanovic, Nasreen Jacobson, Rajiv Sood and Sandeep Dhall
Int. J. Mol. Sci. 2021, 22(16), 8643; https://doi.org/10.3390/ijms22168643 - 11 Aug 2021
Cited by 6 | Viewed by 3627
Abstract
Clostridium collagenase has provided superior clinical results in achieving digestion of immediate and accumulating devitalized collagen tissue. Recent studies suggest that debridement via Clostridium collagenase modulates a cellular response to foster an anti-inflammatory microenvironment milieu, allowing for a more coordinated healing response. In [...] Read more.
Clostridium collagenase has provided superior clinical results in achieving digestion of immediate and accumulating devitalized collagen tissue. Recent studies suggest that debridement via Clostridium collagenase modulates a cellular response to foster an anti-inflammatory microenvironment milieu, allowing for a more coordinated healing response. In an effort to better understand its role in burn wounds, we evaluated Clostridium collagenase’s ability to effectively minimize burn progression using the classic burn comb model in pigs. Following burn injury, wounds were treated with Clostridium collagenase or control vehicle daily and biopsied at various time points. Biopsies were evaluated for factors associated with progressing necrosis as well as inflammatory response associated with treatment. Data presented herein showed that Clostridium collagenase treatment prevented destruction of dermal collagen. Additionally, treatment with collagenase reduced necrosis (HMGB1) and apoptosis (CC3a) early in burn injuries, allowing for increased infiltration of cells and protecting tissue from conversion. Furthermore, early epidermal separation and epidermal loss with a clearly defined basement membrane was observed in the treated wounds. We also show that collagenase treatment provided an early and improved inflammatory response followed by faster resolution in neutrophils. In assessing the inflammatory response, collagenase-treated wounds exhibited significantly greater neutrophil influx at day 1, with macrophage recruitment throughout days 2 and 4. In further evaluation, macrophage polarization to MHC II and vascular network maintenance were significantly increased in collagenase-treated wounds, indicative of a pro-resolving macrophage environment. Taken together, these data validate the impact of clostridial collagenases in the pathophysiology of burn wounds and that they complement patient outcomes in the clinical scenario. Full article
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17 pages, 2279 KiB  
Review
Innate Immune System Response to Burn Damage—Focus on Cytokine Alteration
by Olga Sierawska, Paulina Małkowska, Cansel Taskin, Rafał Hrynkiewicz, Paulina Mertowska, Ewelina Grywalska, Tomasz Korzeniowski, Kamil Torres, Agnieszka Surowiecka, Paulina Niedźwiedzka-Rystwej and Jerzy Strużyna
Int. J. Mol. Sci. 2022, 23(2), 716; https://doi.org/10.3390/ijms23020716 - 10 Jan 2022
Cited by 26 | Viewed by 6694
Abstract
In the literature, burns are understood as traumatic events accompanied by increased morbidity and mortality among affected patients. Their characteristic feature is the formation of swelling and redness at the site of the burn, which indicates the development of inflammation. This reaction is [...] Read more.
In the literature, burns are understood as traumatic events accompanied by increased morbidity and mortality among affected patients. Their characteristic feature is the formation of swelling and redness at the site of the burn, which indicates the development of inflammation. This reaction is not only important in the healing process of wounds but is also responsible for stimulating the patient’s innate immune system. As a result of the loss of the protective ability of the epidermis, microbes which include bacteria, fungi, and viruses have easier access to the system, which can result in infections. However, the patient is still able to overcome the infections that occur through a cascade of cytokines and growth factors stimulated by inflammation. Long-term inflammation also has negative consequences for the body, which may result in multi-organ failure or lead to fibrosis and scarring of the skin. The innate immune response to burns is not only immediate, but also severe and prolonged, and some people with burn shock may also experience immunosuppression accompanied by an increased susceptibility to fatal infections. This immunosuppression includes apoptosis-induced lymphopenia, decreased interleukin 2 (IL-2) secretion, neutrophil storm, impaired phagocytosis, and decreased monocyte human leukocyte antigen-DR. This is why it is important to understand how the immune system works in people with burns and during infections of wounds by microorganisms. The aim of this study was to characterize the molecular pathways of cell signaling of the immune system of people affected by burns, taking into account the role of microbial infections. Full article
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