Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies
TL;DR: The current understanding of the pathophysiology underlying keloid and hypertrophic scar formation is summarized and established treatments and novel therapeutic strategies are discussed.
Abstract: Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any Insult to the deep dermis. By causing pain, pruritus and contractures, excessive scarring significantly affects the patient’s quality of life, both physically and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies.
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TL;DR: This review will focus on the components of the ECM and their role in both physiological and pathological (hypertrophic and keloid) cutaneous scar formation.
Abstract: Significance: When a cutaneous injury occurs, the wound heals via a dynamic series of physiological events, including coagulation, granulation tissue formation, re-epithelialization, and extracellular matrix (ECM) remodeling. The final stage can take many months, yet the new ECM forms a scar that never achieves the flexibility or strength of the original tissue. In certain circumstances, the normal scar is replaced by pathological fibrotic tissue, which results in hypertrophic or keloid scars. These scars cause significant morbidity through physical dysfunction and psychological stress. Recent Advances and Critical Issues: The cutaneous ECM comprises a complex assortment of proteins that was traditionally thought to simply provide structural integrity and scaffolding characteristics. However, recent findings show that the ECM has multiple functions, including, storage and delivery of growth factors and cytokines, tissue repair and various physiological functions. Abnormal ECM reconstruction during wound healing contributes to the formation of hypertrophic and keloid scars. Whereas adult wounds heal with scarring, the developing foetus has the ability to heal wounds in a scarless fashion by regenerating skin and restoring the normal ECM architecture, strength, and function. Recent studies show that the lack of inflammation in fetal wounds contributes to this perfect healing. Future Directions: Better understanding of the exact roles of ECM components in scarring will allow us to produce therapeutic agents to prevent hypertrophic and keloid scars. This review will focus on the components of the ECM and their role in both physiological and pathological (hypertrophic and keloid) cutaneous scar formation.
879 citations
TL;DR: The need for novel treatments is paramount, and future efforts to improve outcomes and quality of life should include optimisation 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.
386 citations
TL;DR: Common and organ-specific pathways of tissue fibrosis are reviewed, hoping that an understanding of common fibrosis pathways will lead to development of antifibrotic therapies that are effective in all of these tissues in the future.
Abstract: Fibrosis is a pathological scarring process that leads to destruction of organ architecture and impairment of organ function. Chronic loss of organ function in most organs, including bone marrow, heart, intestine, kidney, liver, lung, and skin, is associated with fibrosis, contributing to an estimated one third of natural deaths worldwide. Effective therapies to prevent or to even reverse existing fibrotic lesions are not yet available in any organ. There is hope that an understanding of common fibrosis pathways will lead to development of antifibrotic therapies that are effective in all of these tissues in the future. Here we review common and organ-specific pathways of tissue fibrosis.
361 citations
TL;DR: This review aims to highlight the common animal models of burn injury in order to provide investigators with a better understanding of the benefits and limitations of these models for translational applications.
Abstract: Burn injury is a severe form of trauma affecting more than 2 million people in North America each year Burn trauma is not a single pathophysiological event but a devastating injury that causes structural and functional deficits in numerous organ systems Due to its complexity and the involvement of multiple organs, in vitro experiments cannot capture this complexity nor address the pathophysiology In the past two decades, a number of burn animal models have been developed to replicate the various aspects of burn injury, to elucidate the pathophysiology, and to explore potential treatment interventions Understanding the advantages and limitations of these animal models is essential for the design and development of treatments that are clinically relevant to humans This review aims to highlight the common animal models of burn injury in order to provide investigators with a better understanding of the benefits and limitations of these models for translational applications While many animal models of burn exist, we limit our discussion to the skin healing of mouse, rat, and pig Additionally, we briefly explain hypermetabolic characteristics of burn injury and the animal model utilized to study this phenomena Finally, we discuss the economic costs associated with each of these models in order to guide decisions of choosing the appropriate animal model for burn research
305 citations
Cites background from "Hypertrophic Scarring and Keloids: ..."
...Imbalance in either excessive matrix synthesis or decreased matrix catabolism can lead to keloid [34] and hypertrophic scar formation [28, 35]....
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TL;DR: How various immunological cell types and signaling molecules influence the way wounds develop, persist, and heal is reviewed, showing that the key transition point lies between the inflammatory and the proliferative phases.
Abstract: Chronic wounds are a tremendous burden on the healthcare system and lead to significant patient morbidity and mortality. Normal cutaneous wound healing occurs through an intricate and delicate interplay between the immune system, keratinocytes, and dermal cells. Each cell type contributes signals that drive the normal phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This paper reviews how various immunological cell types and signaling molecules influence the way wounds develop, persist, and heal. Concurrent with the achievement of hemostasis, neutrophils are the first cells to migrate to the wound bed, brought in by pro-inflammatory signals including IL-8. Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state, where angiogenesis occurs and granulation tissue is laid down. Myofibroblasts, activated through contractile forces and signaling molecules, then drive remodeling, where granulation tissue becomes scar. Unchecked inflammation at this stage can result in abnormal scar formation. Although the derangement of immune signals at any stage can result in impaired wound healing, recent research has shown that the key transition point lies between the inflammatory and the proliferative phases. This review summarizes the events that facilitate this transition and discusses how this process can be disrupted, leading to chronic, non-healing wounds.
291 citations
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TL;DR: The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors.
Abstract: Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.
3,040 citations
"Hypertrophic Scarring and Keloids: ..." refers background in this paper
...An imbalance in expression of MMPs has been implicated in a number of pathological conditions such as dermal fibrosis (67) and tumor invasion and metastasis (68)....
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TL;DR: Cellular and molecular mechanisms controlling inflammation in cutaneous tissue repair are reviewed and a rationale for targeting the inflammatory phase in order to modulate the outcome of the healing response is provided.
1,874 citations
"Hypertrophic Scarring and Keloids: ..." refers background in this paper
...Mast cells are an additional leukocyte subset present in the skin, and they are an important source of a variety of proinflammatory mediators that can promote inflammation and vascular changes (63)....
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TL;DR: In this paper, the authors reported the identification of Smad7, which is related to Smad6 (ref. 13) and showed that TGF-β-mediated phosphorylation of two proteins, Smad2 and Smad3, is inhibited by Smad-7, indicating that the antagonistic effect of the protein is exerted at this important regulatory step.
Abstract: TGF-β signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins1. The activated TGF-β receptor induces phosphorylation of two such proteins, Smad2 and Smad3 (refs 2, 3, 5, 6), which form hetero-oligomeric complex(es) with Smad4/DPC4 (refs 5, 6, 7, 8, 9, 10) that translocate to the nucleus2,4,5,7, where they then regulate transcriptional responses11,12. However, the mechanisms by which the intracellular signals of TGF-β are switched off are unclear. Here we report the identification of Smad7, which is related to Smad6 (ref. 13). Transfection of Smad7 blocks responses mediated by TGF-β in mammalian cells, and injection of Smad7 RNA into Xenopus embryos blocks activin/TGF-β signalling. Smad7 associates stably with the TGF-β receptor complex, but is not phosphorylated upon TGF-β stimulation. TGFβ-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating that the antagonistic effect of Smad7 is exerted at this important regulatory step. TGF-β rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGF-β responses.
1,706 citations
TL;DR: In this article, the immunological mechanisms that initiate, sustain and suppress the fibrotic process were studied. But the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation.
Abstract: Tissue fibrosis (scarring) is a leading cause of morbidity and mortality. Current treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, hepatic fibrosis and systemic sclerosis, target the inflammatory cascade, but they have been widely unsuccessful, largely because the mechanisms that are involved in fibrogenesis are now known to be distinct from those involved in inflammation. Several experimental models have recently been developed to dissect the molecular mechanisms of wound healing and fibrosis. It is hoped that by better understanding the immunological mechanisms that initiate, sustain and suppress the fibrotic process, we will achieve the elusive goal of targeted and effective therapeutics for fibroproliferative diseases.
1,466 citations
TL;DR: This study clearly demonstrates isoform specific differences in the role of T GF-betas in wound healing and cutaneous scarring and suggests a novel therapeutic use of exogenous recombinant, TGF-beta 3 as an anti-scarring agent.
Abstract: Exogenous addition of neutralising antibody to transforming growth factor-beta 1,2 to cutaneous wounds in adult rodents reduces scarring. Three isoforms of transforming growth factor-beta (1, 2 and 3) have been identified in mammals. We investigated the isoform/isoforms of TGF-beta responsible for cutaneous scarring by: (i) reducing specific endogenous TGF-beta isoforms by exogenous injection of isoform specific neutralising antibodies; and (ii) increasing the level of specific TGF-beta isoforms by exogenous infiltration into the wound margins. Exogenous addition of neutralising antibody to TGF-beta 1 plus neutralising antibody to TGF-beta 2 reduced the monocyte and macrophage profile, neovascularisation, fibronectin, collagen III and collagen I deposition in the early stages of wound healing compared to control wounds. Treatment with neutralising antibodies to TGF-betas 1 and 2 markedly improved the architecture of the neodermis to resemble that of normal dermis and reduced scarring while the control wounds healed with scar formation. Exogenous addition of neutralising antibody to TGF-beta 1 alone also reduced the monocyte and macrophage profile, fibronectin, collagen III and collagen I deposition compared to control wounds. However, treatment with neutralising antibody to TGF-beta 1 alone only marginally reduced scarring. By contrast, wounds treated with neutralising antibody to TGF-beta 2 alone did not differ from control wounds. Interestingly, exogenous addition of the TGF-beta 3 peptide also reduced the monocyte and macrophage profile, fibronectin, collagen I and collagen III deposition in the early stages of wound healing and markedly improved the architecture of the neodermis and reduced scarring. By contrast, wounds treated with either TGF-beta 1 or with TGF-beta 2 had more extracellular matrix deposition in the early stages of wound healing but did not differ from control wounds in the final quality of scarring. This study clearly demonstrates isoform specific differences in the role of TGF-betas in wound healing and cutaneous scarring. TGF-beta 1 and TGF-beta 2 are implicated in cutaneous scarring. This study also suggests a novel therapeutic use of exogenous recombinant, TGF-beta 3 as an anti-scarring agent.
1,195 citations
"Hypertrophic Scarring and Keloids: ..." refers background in this paper
...In two studies, Shah and colleagues (50,51) found that dermal wounds of adult rats healed without scar-tissue for-...
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