RESUMEN
The immune response is a central process during wound healing. Malfunctions often lead to chronic inflammation, barrier disorders, and ulcerations of the skin. The underlying pathomechanisms are complex and the subject of current dermatological research. The care of wound healing disorders is still inadequate and urgently needs improved therapy concepts. For several years now, the development of modern immunomodulators has enabled the targeted regulation of specific signaling cascades, and their effectiveness in the treatment of wound healing disorders has been proven in numerous case studies. Thus, their use not only leads to more efficient therapeutic approaches, but also provides deeper insight into the pathomechanistic importance of specific signaling pathways in inflammatory and degenerative diseases of the skin, which are poorly understood so far. Pyoderma gangrenosum, an autoinflammatory disease, provides a good example to illustrate the progress in therapy and pathomechanistic understanding through the use of new immunomodulators and is explained in more detail in the following article.
Asunto(s)
Piodermia Gangrenosa , Manejo de la Enfermedad , Humanos , Factores Inmunológicos/uso terapéutico , Inflamación , Piodermia Gangrenosa/diagnóstico , Piodermia Gangrenosa/tratamiento farmacológico , Cicatrización de HeridasRESUMEN
The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.
Asunto(s)
Mitocondrias/metabolismo , Neoplasias/patología , Neovascularización Patológica/patología , Neovascularización Fisiológica , Cicatrización de Heridas/fisiología , Adenosina Trifosfato/metabolismo , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Animales , Línea Celular Tumoral/trasplante , Respiración de la Célula , Modelos Animales de Enfermedad , Embrión de Mamíferos , Desarrollo Embrionario/fisiología , Células Endoteliales/fisiología , Endotelio Vascular/citología , Endotelio Vascular/fisiología , Femenino , Técnicas de Inactivación de Genes , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Mitocondrias/genética , Neoplasias/irrigación sanguínea , Fosforilación OxidativaRESUMEN
Macrophages are critical mediators of injury-associated corneal hemangiogenesis (HA) and lymphangiogenesis (LA). Yet, molecular regulators of the hem- and lymphangiogenic potential of corneal wound macrophages are poorly understood. Using two different mouse models of acute (perforating corneal incision injury) and chronic (corneal suture placement model) corneal injury, here we identified distinct functions of early- versus late-phase corneal wound macrophages in corneal HA and LA. Whereas early-phase wound macrophages are essential for initiation and progression of injury-mediated corneal HA and LA, late-phase wound macrophages control maintenance of established corneal lymphatic vessels, but not blood vessels. Furthermore, our findings reveal that the hem- and lymphangiogenic potential of corneal wound macrophages is controlled by the type of the corneal damage. Whereas perforating corneal incision injury induced primarily wound macrophages with lymphangiogenic potential, corneal suture placement provoked wound macrophages with both hem- and lymphangiogenic potential. Our findings highlight a previously unrecognized injury-context dependent role of early- versus late-phase corneal wound macrophages with potential clinical impact on therapy development for sight-threatening corneal neovascular diseases.
Asunto(s)
Lesiones de la Cornea/fisiopatología , Neovascularización de la Córnea/fisiopatología , Linfangiogénesis/fisiología , Macrófagos/fisiología , Animales , Lesiones de la Cornea/patología , Lesiones de la Cornea/terapia , Modelos Animales de Enfermedad , Vasos Linfáticos/fisiopatología , Ratones , Factores de TiempoRESUMEN
Fibrosis is a common symptom of a variety of skin disorders of diverse entity. The cellular and molecular pathophysiology of fibrosis development is unresolved and current treatment options are not sufficient. Tissue fibrosis leads to increased tissue stiffness, impaired organ function, decline of quality of life and ultimately increased morbidity and mortality. Epidemiologic studies indicate that nearly 45% of all deaths in the western world are associated with tissue fibrosis in diverse organs. Only few recently approved treatment options specifically target the process of fibrogenesis. The development of novel and efficient therapies is urgently needed, and at the same time provides a major challenge but also an opportunity to contribute to the advancement of this unresolved medical problem. This article highlights recent insights in the developments on tissue fibrosis with a focus on immunoregulatory mechanisms.
Asunto(s)
Enfermedades del Tejido Conjuntivo , Enfermedades de la Piel , Fibrosis , Humanos , Calidad de VidaAsunto(s)
Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Enfermedad de Papillon-Lefevre/diagnóstico , Catepsina C/genética , Catepsina C/metabolismo , ADN/genética , Análisis Mutacional de ADN , Humanos , Mutación , Neutrófilos/patología , Enfermedad de Papillon-Lefevre/genética , Enfermedad de Papillon-Lefevre/metabolismoRESUMEN
Matrix synthesis, deposition and remodeling are complex biological processes that are critical in development, maintenance of tissue homeostasis and repair of injured tissues. Disturbances in the regulation of these processes can result in severe pathological conditions which are associated with tissue fibrosis as e.g. in Scleroderma, cutaneous Graft-versus-Host-Disease, excessive scarring after trauma or carcinogenesis. Therefore, finding efficient treatments to limit skin fibrosis is of major clinical importance. However the pathogenesis underlying the development of tissue fibrosis is still not entirely resolved. In recent years progress has been made unraveling the complex cellular and molecular mechanisms that determine fibrosis. Here we provide an overview of established and more recently developed mouse models that can be used to investigate the mechanisms of skin fibrosis and to test potential therapeutic approaches.
Asunto(s)
Matriz Extracelular/metabolismo , Piel/patología , Animales , Bleomicina/toxicidad , Citocinas/fisiología , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrosis , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inflamación , Péptidos y Proteínas de Señalización Intercelular/fisiología , Péptidos y Proteínas de Señalización Intercelular/toxicidad , Ratones , Ratones Transgénicos , Modelos Biológicos , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/patología , Enfermedades de la Piel/prevención & control , Estrés Mecánico , Cloruro de Vinilo/toxicidadRESUMEN
Restoration of tissue integrity is essential for host defense and protection of the organism. The efficacy and quality of skin repair varies significantly over a person's lifetime. Whereas prenatal wound healing is characterized by regeneration and scarless healing, scarring, fibrosis, and loss of function are features of postnatal repair. In fact, aging is the prominent risk factor for chronic wounds, skin fragility, infections, comorbidities, and decreased quality of life. Current strategies for restoration of tissue integrity and wound therapy are not sufficient and require further investigation of the underlying pathomechanisms and the development of causal-based concepts.
Asunto(s)
Envejecimiento , Laceraciones/patología , Laceraciones/fisiopatología , Piel/patología , Piel/fisiopatología , Cicatrización de Heridas/fisiología , Anciano , Anciano de 80 o más Años , Femenino , Evaluación Geriátrica , Humanos , Masculino , Modelos BiológicosRESUMEN
Chronic wounds, scars, burns and recalcitrant chronic inflammatory skin lesions can give rise to malignancy. These neoplasias are usually squamous cell carcinomas but basal cell carcinomas can also develop. Tumorigenesis is a severe complication of chronic ulcers as well as certain inflammatory skin diseases; early diagnosis is critical for prognosis. This article describes parallels between wound healing, chronic inflammatory skin diseases and carcinogenesis and provides advice on practical aspects of diagnosis and therapy.
Asunto(s)
Dermatitis/diagnóstico , Dermatitis/terapia , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/terapia , Úlcera Cutánea/diagnóstico , Úlcera Cutánea/terapia , Cicatrización de Heridas , Enfermedad Crónica , HumanosRESUMEN
BACKGROUND: Stringent control of proteolytic activity represents a major therapeutic approach for wound-bed preparation. OBJECTIVES: We tested whether a protease-modulating polyacrylate- (PA-) containing hydrogel resulted in a more efficient wound-bed preparation of venous leg ulcers when compared to an amorphous hydrogel without known protease-modulating properties. METHODS: Patients were randomized to the polyacrylate-based hydrogel (n = 34) or to an amorphous hydrogel (n = 41). Wound beds were evaluated by three blinded experts using photographs taken on days 0, 7 and 14. RESULTS: After 14 days of treatment there was an absolute decrease in fibrin and necrotic tissue of 37.6 ± 29.9 percentage points in the PA-based hydrogel group and by 16.8 ± 23.0 percentage points in the amorphous hydrogel group. The absolute increase in the proportion of ulcer area covered by granulation tissue was 36.0 ± 27.4 percentage points in the PA-based hydrogel group and 14.5 ± 22.0 percentage points in the control group. The differences between the groups were significant (decrease in fibrin and necrotic tissue P = 0.004 and increase in granulation tissue P = 0.0005, respectively). CONCLUSION: In particular, long-standing wounds profited from the treatment with the PA-based hydrogel. These data suggest that PA-based hydrogel dressings can stimulate normalization of the wound environment, particularly in hard-to-heal ulcers.
Asunto(s)
Resinas Acrílicas , Hidrogeles , Úlcera de la Pierna/terapia , Péptido Hidrolasas/administración & dosificación , Úlcera Varicosa/terapia , Heridas y Lesiones/terapia , Resinas Acrílicas/efectos adversos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Graft-versus-host-disease (GvHD) is despite improvement in transplantation medicine the major cause for morbidity and mortality after allogeneic stem cell transplantation. We describe a patient with chronic cutaneous GvHD who developed massive skin ulcerations after changing the immunosuppressive therapy to a mammalian target of rapamycin (mTOR)-inhibitor.
Asunto(s)
Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Sirolimus/análogos & derivados , Úlcera Cutánea/inducido químicamente , Trasplante de Células Madre/efectos adversos , Everolimus , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Úlcera Cutánea/prevención & control , Resultado del TratamientoRESUMEN
Ulcerations of the skin and mucosal membranes are a common feature of autoinflammatory diseases. They can give raise to chronic wound healing defects and should be considered in the differential diagnosis of chronic skin ulcers. The increased activation of the innate immune system in the absence of an apparent provocation for inflammation is a hallmark of autoinflammatory diseases. Mutations and alterations of signaling pathways regulating the innate immune response to physical trauma/tissue damage result into an unrestrained activation of the inflammasome, which leads to increased activation of Interleukin-1. Uncontrolled recruitment and activation of myeloid effector cells within the wound site lead to the release of potent proteases that cause the degradation of structural components of the skin. The majority of these diseases respond well to immunosuppressive and immunomodulatory treatment regimes. Therapeutic resistance converts the acute inflammatory response into a chronic and non-resolving inflammatory process that leads to tissue degeneration. In this article we will focus on the review of those autoinflammatory diseases that often display ulcerative cutaneous and aphthous lesions including pyoderma gangrenosum, Behçet disease, PAPA syndrome and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). Furthermore, the article will be complemented by an overview of those inflammatory diseases that are associated with non-ulcerative cutaneous manifestations.
Asunto(s)
Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Úlcera Cutánea/diagnóstico , Cicatrización de Heridas/inmunología , Acné Vulgar/diagnóstico , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/genética , Acné Vulgar/inmunología , Artritis Infecciosa/diagnóstico , Artritis Infecciosa/tratamiento farmacológico , Artritis Infecciosa/genética , Artritis Infecciosa/inmunología , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamiento farmacológico , Síndrome de Behçet/genética , Síndrome de Behçet/inmunología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Enfermedades Autoinflamatorias Hereditarias/tratamiento farmacológico , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/inmunología , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Inflamasomas/sangre , Interleucina-1/sangre , Deficiencia de Mevalonato Quinasa/diagnóstico , Deficiencia de Mevalonato Quinasa/tratamiento farmacológico , Deficiencia de Mevalonato Quinasa/genética , Deficiencia de Mevalonato Quinasa/inmunología , Piodermia Gangrenosa/diagnóstico , Piodermia Gangrenosa/tratamiento farmacológico , Piodermia Gangrenosa/genética , Piodermia Gangrenosa/inmunología , Úlcera Cutánea/tratamiento farmacológico , Úlcera Cutánea/genética , Úlcera Cutánea/inmunología , Estomatitis Aftosa/diagnóstico , Estomatitis Aftosa/genética , Estomatitis Aftosa/inmunología , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Underlying disease may impair normal wound healing, leading to chronic, poorly healing wounds. Efficient treatment strategies require identification and treatment of the underlying disease as well as directed correction of the wound healing defect. A thorough knowledge of tissue repair mechanisms at the cellular and molecular level will help to achieve these goals. This review focuses on new developments in wound healing research and the resulting non-operative therapeutic implications.
Asunto(s)
Cicatrización de Heridas , Heridas y Lesiones/terapia , Investigación Biomédica , Western Blotting , Enfermedad Crónica , Predicción , Humanos , Mediadores de Inflamación/fisiología , Úlcera de la Pierna/fisiopatología , Úlcera de la Pierna/terapia , Mutación , Cicatrización de Heridas/genética , Cicatrización de Heridas/fisiología , Heridas y Lesiones/tratamiento farmacológico , Heridas y Lesiones/genética , Heridas y Lesiones/metabolismo , Heridas y Lesiones/fisiopatologíaAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/complicaciones , Úlcera de la Pierna/tratamiento farmacológico , Adalimumab , Adulto , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Proteínas de Neoplasias/uso terapéutico , Receptores Tipo II del Factor de Necrosis Tumoral , Receptores Señuelo del Factor de Necrosis TumoralAsunto(s)
Acrodermatitis/etiología , Erupciones por Medicamentos/diagnóstico , Inhibidores Enzimáticos/efectos adversos , Enfermedad Injerto contra Huésped/diagnóstico , Hidroxiurea/efectos adversos , Erupciones Liquenoides/inducido químicamente , Acrodermatitis/diagnóstico , Acrodermatitis/patología , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/patología , Inhibidores Enzimáticos/uso terapéutico , Enfermedad Injerto contra Huésped/inducido químicamente , Enfermedad Injerto contra Huésped/patología , Humanos , Hidroxiurea/uso terapéutico , Erupciones Liquenoides/diagnóstico , Erupciones Liquenoides/patología , Trastornos Mieloproliferativos/tratamiento farmacológico , Piel/patologíaRESUMEN
Degradation of angiogenic mediators might be an underlying cause of chronic wounds. To test this hypothesis, we evaluated the expression and integrity of vascular endothelial growth factor, a potent angiogenic mediator, and its receptors, Flt-1 and KDR, in chronic venous leg ulcerations. Immunohisto- chemical, in situ hybridization, and semiquantitative reverse transcriptase polymerase chain reaction analyses all indicate that expression of vascular endothelial growth factor is elevated in ulcerative tissue, with vascular endothelial growth factor mRNA being especially pronounced in the hyperplastic epithelium of the wound margin. Flt-1 and KDR protein and mRNA were detected in the papillary vessels in close vicinity to the lesional epithelium of chronic wounds. Although increased expression of vascular endothelial growth factor protein was detected in the epidermis, the intensity of this staining was weak compared with the epidermal staining in psoriatic lesions and compared with the strong vascular endothelial growth factor mRNA signal in chronic wounds and psoriasis. To analyze whether this apparent decrease in immunoreactivity could be the result of degradation of vascular endothelial growth factor by proteolytic activities from the wound environment, we examined the stability of recombinant vascular endothelial growth factor in wound fluid from chronic leg ulcers. As demonstrated by sodium dodecyl sulfate polyacrylamide gel electrophoresis, incubation of rVEGF165 with chronic, but not acute, wound fluid resulted in rapid proteolytic degradation of rVEGF165. Protease inhibitor studies indicate that serine proteases, such as plasmin, are involved in this degradation. Together, our data show that, although vascular endothelial growth factor expression is elevated in chronic wounds, increased proteolytic activity in this environment results in its degradation, which may contribute to an impaired wound healing response.
Asunto(s)
Factores de Crecimiento Endotelial/metabolismo , Linfocinas/metabolismo , Heridas y Lesiones/metabolismo , Enfermedad Crónica , Estabilidad de Medicamentos , Factores de Crecimiento Endotelial/biosíntesis , Exudados y Transudados/metabolismo , Fibrinolisina/fisiología , Expresión Génica , Humanos , Úlcera de la Pierna/metabolismo , Linfocinas/biosíntesis , Inhibidores de Proteasas/farmacología , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/genética , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes/metabolismo , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Gene therapy is becoming a reality, and it is a particularly attractive approach for wound healing, because the wound site is often exposed, the treatment and condition should be transient, and gene products such as growth factors and cytokines suffer from problems with bioavailability and stability. Among the techniques for gene delivery to the wound site, particle-mediated bombardment with a device called the gene gun has become an important developmental tool. This instrument has been used in numerous examples of wound gene therapy with growth factors or their receptors in the last decade. Among the advantages of particle-mediated bombardment are ease and speed of preparation of the delivery vehicle, the stability of the DNA preparation, the absence of (viral) antigens, the ability to target the projectiles to different tissue depths and areas, and the rapid shedding of both particles and DNA if they are targeted to the epidermis. Clinical application of the technology remains limited by the relatively low efficiency of the method, the potential tissue damage created by impact of the particles, and the coverage area. The gene gun can also be used to facilitate the discovery and validation of gene products as wound healing agents.
Asunto(s)
Técnicas de Transferencia de Gen/instrumentación , Terapia Genética/métodos , Sustancias de Crecimiento/administración & dosificación , Sustancias de Crecimiento/genética , Cicatrización de Heridas/genética , Heridas y Lesiones/terapia , Portadores de Fármacos , Diseño de Equipo , Humanos , Sensibilidad y Especificidad , Cicatrización de Heridas/fisiologíaRESUMEN
Several techniques for cutaneous gene transfer have been investigated for either in vitro or in vivo applications. In the present study, we investigated whether the direct delivery of platelet-derived growth factor cDNA into skin results in improvement in tissue repair. Cutaneous transfections were carried out in rats using a particle-bombardment device (Accell). As revealed by reverse transcriptase-polymerase chain reaction, transgene expression in vivo was transient, with low level expression by day 5. When compared with wounds transfected with a control cytomegalovirus-luciferase plasmid, wounds transfected with platelet-derived growth factor A or B in the MFG vector showed a significant increase in wound tensile strength 7 and 14 d after transfection. At both time points platelet-derived growth factor A transfected wounds exhibited the highest increase in tensile strength over controls, resulting in a 3.5-fold increase at day 7 and a 1.5-fold increase at day 14. The degree of stimulation was not remarkably different between wounds transfected with platelet-derived growth factor B, which is predominantly cell associated, or a truncation mutant, platelet-derived growth factor B211, which is predominantly secreted. These findings demonstrate that in vivo gene transfer by particle bombardment can be used to improve the tissue repair response. This approach provides a robust tool to assess the biologic activity of various proteins and will aid in the development of therapeutic cutaneous gene delivery.
Asunto(s)
Técnicas de Transferencia de Gen , Aceleradores de Partículas , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/fisiología , Piel/lesiones , Cicatrización de Heridas/fisiología , Animales , Expresión Génica/fisiología , Isomerismo , Masculino , Mutación/fisiología , Ratas , Ratas Sprague-Dawley , Piel/fisiopatología , Resistencia a la Tracción , Transgenes/genética , Heridas y Lesiones/fisiopatologíaRESUMEN
Platelet-derived growth factor (PDGF), a mitogen and chemoattractant for mesenchymal cells, occurs as cell-associated or released isoforms. To investigate their in vivo role, human keratinocytes, which normally synthesize both types of PDGF, were genetically modified to overexpress either wild-type PDGF-B (cell-associated) or the truncation mutant PDGF-B211 (released). Cells expressing the mutant isoform released 20 times more PDGF (145 ng/hour/10(7) cells) than cells expressing the wild-type isoform (6 ng/ hour/10(7) cells). When grafted as epithelial sheets onto athymic mice, modified cells formed a stratified epithelium and induced a connective tissue response that differed depending on the PDGF isoform expressed. Expression of PDGF-B211 induced a thick connective tissue with increased numbers of fibroblasts, mononuclear cells, and blood vessels evenly distributed throughout the connective tissue layer, whereas expression of PDGF-B induced a zone of fibroblasts and mononuclear cells localized to the interface of the epidermis and connective tissue, which often disrupted the continuity of the basement membrane. Immunostaining revealed that wild-type PDGF protein was deposited in the basement membrane region. These data suggest that the different binding properties of PDGF isoforms control the spatial organization of cellular events in regenerating mesenchymal tissue in vivo.