[Targeted therapies in Pyoderma gangrenosum: deciphering pathophysiology and improving disease management]. / Pyoderma gangraenosum: durch zielgerichtete Therapieansätze besser verstehen und behandeln können.

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.

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth.

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.

Phase-specific functions of macrophages determine injury-mediated corneal hem- and lymphangiogenesis.

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.

[Current pathophysiological developments in fibrosing diseases: insights into novel treatment concepts]. / Aktuelle pathophysiologische Entwicklungen bei fibrosierenden Erkrankungen: Ansatzpunkte für neue Konzepte in der Therapie.

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.

Skin fibrosis: Models and mechanisms.

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.

[Wound healing in the elderly]. / Wundheilung im Alter.

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.

[Parallels between wound healing, chronic inflammatory skin diseases and neoplasia: clinical aspects]. / Parallelen zwischen Wundheilung, chronisch entzündlichen Dermatosen und Neoplasien: Wissenswertes für die Praxis.

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.

Protease-modulating polyacrylate-based hydrogel stimulates wound bed preparation in venous leg ulcers--a randomized controlled trial.

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.

[Delayed wound healing during therapy of cutaneous graft-versus-host disease with everolimus]. / Wundheilungsstörung bei kutaner Graft-versus-Host-Disease unter Therapie mit Everolimus.

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.

[Autoinflammatory diseases as cause of wound healing defects]. / Autoinflammatorische Erkrankungen als Ursache von Wundheilungsstörungen.

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.

[Chronic wounds. Novel approaches in research and therapy]. / Chronische Wunde. Neue Wege in Forschung und Therapie.

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.

[Growth factors]. / Wachstumsfaktoren.

Growth factors such as PDGF, VEGF and TGF-beta play a pivotal role in the regulation and differentiation of different cell types in the connective tissue, for example fibroblasts and endothelial cells, and in the immune system. Pathophysiologically, these growth factors are thought to play a central role in tumorigenesis, and the use of their inhibitors has led to substantial improvements in tumor therapy. Recent findings also support an important role for growth factors in inflammatory rheumatoid diseases. New developments in the understanding and potential role of these factors in the pathophysiology of rheumatic diseases will be discussed.

Early increase in serum levels of the angiogenesis-inhibitor endostatin and of basic fibroblast growth factor in melanoma patients during disease progression.

BACKGROUND: Increased serum levels of angiogenesis-related factors such as endostatin, vascular endothelial cell growth factor (VEGF) or basic fibroblast growth factor (bFGF) have been demonstrated for a variety of solid and nonsolid tumours. Therefore, these factors have been suggested as diagnostic and in some studies as prognostic tumour markers. OBJECTIVES: The purpose of the present study was to investigate a possible correlation of endostatin, VEGF or bFGF serum levels with disease progression in melanoma. Especially, we compared these factors to the established melanoma marker S-100 B, which increases in advanced disease but often fails to indicate early metastatic spread to regional lymph nodes. PATIENTS AND METHODS: Sera from 197 melanoma patients and 35 healthy controls were measured by enzyme-linked immunosorbent assay; 72 patients had primary tumours (American Joint Committee on Cancer stages I and II), 55 had regional lymph node metastasis (stage III) and 70 patients had distant organ metastasis (stage IV). RESULTS: Endostatin, VEGF and bFGF serum levels were significantly elevated in stage IV disease, compared with the control group. In stage III, endostatin and bFGF, but not VEGF or S-100 B, were significantly increased. However, follow-up of this patient group did not show a correlation with the future clinical course including time until progression or overall survival, arguing against a role of endostatin, VEGF or bFGF as prognostic markers. CONCLUSIONS: These data indicate that endostatin or bFGF might be useful as diagnostic markers for the early detection of locoregional metastasis.