A TGF-beta1-dependent autocrine loop regulates the structure of focal adhesions in hypertrophic scar fibroblasts.
(17/85)
Following injury, fibroblasts migrate into wounds and differentiate into alpha smooth muscle cell actin (SMCA)-positive cells, termed myofibroblasts, that assemble and remodel the scar. Cultured myofibroblasts assemble larger focal adhesions than do normal dermal fibroblasts and these focal adhesions attach to alpha SMCA-rich stress fibers. Following severe traumatic or thermal injury to the dermis, hypertrophic scars (HTSs) often develop and these scar fibroblasts (HTSFs) express alpha SMCA persistently. We now report that HTSFs stably display large focal adhesions as a consequence of both the autocrine production and activation of transforming growth factor beta1 (TGF-beta1). We also observe that myofibroblasts elaborating larger focal adhesions adhere more tightly to fibronectin. Conditioned medium from HTSFs induces focal adhesion growth in normal fibroblasts and this is blocked by pre-incubation with a soluble TGF-beta1 receptor mimetic. Human foreskin fibroblasts transduced with a retrovirus encoding active TGF-beta1 elaborate large focal adhesions, whereas fibroblasts overexpressing normal, latent TGF-beta1 do not. We conclude that the large focal adhesions found in pathogenic myofibroblasts arise through an autocrine loop involving the production and activation of TGF-beta1; these adhesions likely mediate both tighter adhesion to wound matrix and the exuberant wound contraction observed in pathogenic scars. (+info)
Ischaemic necrosis of subcutaneous colonic neoesophagus: an unusual complication of presternal hypertrophic scar.
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Hypertrophic scars and keloids not only pose aesthetic problems but also cause functional and anatomical dysfunction by leading to contractures and sometimes by compression of underneath structures. A 76-year-old man presented with progressive dysphagia of two months duration. Examination showed the unusual complication of a presternal hypertrophic scar, causing ischaemic necrosis of a subcutaneously-transposed colon, used for oesophageal reconstruction in a patient with inoperable carcinoma of the oesophagus. Such a complication of hypertrophic scar has never been reported in the literature. (+info)
Safety and efficacy of local administration of contractubex to hypertrophic scars in comparison to corticosteroid treatment. Results of a multicenter, comparative epidemiological cohort study in Germany.
(19/85)
OBJECTIVES: To investigate the safety and efficacy of Contractubex administration to hypertrophic scars in routine out-patient practice and to compare it to corticosteroid treatment. PATIENTS AND METHODS: This was a multicenter, retrospective cohort study, based on 38 randomly selected practices representatively distributed in Germany, including dermatologists and general practitioners. Data from 859 patients fulfilling the inclusion criteria were assessed and analyzed. Of these, 771 patients were eligible for the per protocol treatment with Contractubex (n=555) and corticosteroid (n=216). The safety and efficacy of local administration of Contractubex to hypertrophic scars was compared to corticosteroid treatment. RESULTS: At the end of defined treatment periods (minimum 28 days for local therapy with 1 intralesional corticosteroid application), normalization of the pre-treatment pathological parameters (erythema, pruritus, consistency) of hypertrophic scars was more frequent (42.5%) after Contractubex per protocol treatment as compared to corticosteroid per protocol treatment (22.2%). After adjusting imbalances of baseline characterisics between the treatment groups by the propensity score, the odds ratio was 2.274, demonstrating a significant superiority (p<0.001) of Contractubex treatment as compared to corticosteroid treatment. The time to normalization of erythema, pruritus and consistency was significantly (p=0.034) shorter with Contractubex treatment (median 344 days) than with corticosteroids (median 507 days). No unexpected or severe adverse events occurred in the Contractubex-treated patients. Apart from moderate pruritus (10% Contractubex vs. 1% corticosteroids), adverse events were significantly (p<0.001) more frequent in corticosteroid-treated patients (teleangiectasias 15% vs. 7% Contractubex; cutaneous atrophy of scars 10% vs. 2% Contractubex; cutaneous atrophy of scar surrounding skin tissue 11% vs. 1% Contractubex). CONCLUSION: For the primary aim of this study (assessment of normalization of erythema, pruritus, and consistency of hypertrophic scars) and for time to normalization, local administration of Contractubex was significantly more effective than corticosteroid treatment. Concerning safety, Contractubex treatment was associated with significantly less adverse events (e.g. teleangiectasias, cutaneous atrophy of scars and surrounding skin tissue) than topical corticosteroid application. (+info)
Upregulation of the Wnt/beta-catenin pathway induced by transforming growth factor-beta in hypertrophic scars and keloids.
(20/85)
Hypertrophic scars and keloids represent a dysregulated response to cutaneous wounds, which results in an excessive deposition of collagen. Transforming growth factor-beta (TGF-beta) is the key regulator in the pathogenesis of fibrosis. Accumulating evidence suggests that Wnt signalling and its effector beta-catenin also play an important role in wound healing. The role of Wnt/beta-catenin signalling in TGF-beta induced collagen deposition in hypertrophic scars and keloids was studied. Transcriptional assays and Western blotting was performed using fibroblast cell lines established from normal skin and hypertrophic scar tissue. Immunohistochemical studies were performed using scar tissues. We provide evidence that TGF-beta induces activation of beta-catenin mediated transcription in human dermal fibroblasts via the Smad3 and p38 MAPK pathways. Immunohistochemical studies demonstrated that beta-catenin protein levels are elevated in hypertrophic scar and keloid tissues. This finding may be relevant to the pathogenesis of hypertrophic scars and keloids. (+info)
Histology of the thick scar on the female, red Duroc pig: final similarities to human hypertrophic scar.
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The etiology and treatment of hypertrophic scar remain puzzles even after decades of research. A significant reason is the lack of an accepted animal model of the process. The female, red Duroc pig model was described long ago. Since the skin of the pig is similar to that of humans, we are attempting to validate this model and found it to be encouraging. In this project we quantified myofibroblasts, mast cells and collagen nodules in the thick scar of the Duroc pig and compared these to the values for human hypertrophic scar. We found the results to be quite similar and so further validated the model. In addition, we observed that soon after wounding an inflammatory cell layer forms. The thickness of the inflammatory layer approaches the thickness of the skin removed as if the remaining dermis "knows" how much dermis is gone. In deep wounds this inflammatory layer thickens and this thickness is predictive of the thickness of the ultimate scar. (+info)
Low-dose enalapril in the treatment of surgical cutaneous hypertrophic scar and keloid--two case reports and literature review.
(22/85)
Hypertrophic scars and keloids are 2 forms of excessive cutaneous scarring that occur in predisposed individuals. The healing process varies greatly among patients, and the risk of a bad scar evolution is unpredictable. Keloids create disfiguring scars with associated erythema and pain or pruritus or restricted range of motion, and are a major cause of morbidity. A fortuitous observation was made by the first author of this study who, at age 54, developed an erythematous and painful postsurgical abdominal keloid scar after undergoing left colectomy for colon adenocarcinoma. Four months later, after treatment with low-dose enalapril (10 mg, once a day) for mild arterial hypertension, her keloid scar rapidly improved and she eventually made a complete recovery. second case involved a 70-year-old female with diabetes who was affected by a long-standing postsurgical abdominal keloid scar of 2 years' duration. She was intentionally treated with the same low dose of enalapril, and, after 6 months of therapy, the bad scar showed marked improvement. We conducted an exhaustive search of the literature pertaining to the wound healing process, specifically to determine whether angiotensin-converting enzyme (ACE) inhibitors have a healing effect on wounds. ACE inhibitors are known to induce reduction of left ventricular collagen content and to attenuate remodeling during the postinfarctual period (thus improving ventricular function), and they have been shown to exert a pulmonary antifibrotic effect. After conducting this literature search, it became apparent that no data on cutaneous scars and ACE inhibitors are available. During the posttraumatic or postoperative stage, it is useful to achieve the best possible aesthetic results and to decrease the risk of a disfiguring keloid scar, thereby avoiding revision surgery; to this purpose, an early treatment with a low dose of enalapril is a possible solution, even if further confirmatory observations are needed. (+info)
Hypertrophic scars occur following cutaneous wounding and result in severe functional and esthetic defects. The pathophysiology of this process remains unknown. Here, we demonstrate for the first time that mechanical stress applied to a healing wound is sufficient to produce hypertrophic scars in mice. The resulting scars are histopathologically identical to human hypertrophic scars and persist for more than six months following a brief (one-week) period of augmented mechanical stress during the proliferative phase of wound healing. Resulting scars are structurally identical to human hypertrophic scars and showed dramatic increases in volume (20-fold) and cellular density (20-fold). The increased cellularity is accompanied by a four-fold decrease in cellular apoptosis and increased activation of the prosurvival marker Akt. To clarify the importance of apoptosis in hypertrophic scar formation, we examine the effects of mechanical loading on cutaneous wounds of animals with altered pathways of cellular apoptosis. In p53-null mice, with down-regulated cellular apoptosis, we observe significantly greater scar hypertrophy and cellular density. Conversely, scar hypertrophy and cellular density are significantly reduced in proapoptotic BclII-null mice. We conclude that mechanical loading early in the proliferative phase of wound healing produces hypertrophic scars by inhibiting cellular apoptosis through an Akt-dependent mechanism. (+info)
TNF-alpha suppresses alpha-smooth muscle actin expression in human dermal fibroblasts: an implication for abnormal wound healing.
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Abnormal wound healing encompasses a wide spectrum, from chronic wounds to hypertrophic scars. Both conditions are associated with an abnormal cytokine profile in the wound bed. In this study, we sought to understand the dynamic relationships between myofibroblast differentiation and mechanical performance of the collagen matrix under tissue growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) stimulation. We found TGF-beta increased alpha-smooth muscle actin (alpha-SMA) and TNF-alpha alone decreased the basal alpha-SMA expression. When TGF-beta1 and TNF-alpha were both added, the alpha-SMA expression was suppressed below the baseline. Real-time PCR showed that TNF-alpha suppresses TGF-beta1-induced myofibroblast (fibroproliferative) phenotypic genes, for example, alpha-SMA, collagen type 1A, and fibronectin at the mRNA level. TNF-alpha suppresses TGF-beta1-induced gene expression by affecting its mRNA stability. Our results further showed that TNF-alpha inhibits TGF-beta1-induced Smad-3 phosphorylation via Jun N-terminal kinase signaling. Mechanical testing showed that TNF-alpha decreases the stiffness and contraction of the lattices after 5 days in culture. We proposed that changes in alpha-SMA, collagen, and fibronectin expression result in decreased contraction and stiffness of collagen matrices. Therefore, the balance of cytokines in a wound defines the mechanical properties of the extracellular matrix and optimal wound healing. (+info)