Fibrosis is the production of excessive amounts of connective tissue, i.e., scar formation, in the course of reactive and reparative processes. Fibrosis develops as a consequence of various underlying diseases and presents a major diagnostically and therapeutically unsolved problem. In this review, we postulate that fibrosis is always a sequela of inflammatory processes and that the many different causes of fibrosis all channel into the same final stereotypical pathways. During the inflammatory phase, both innate and adaptive immune mechanisms are operative. This concept is exemplified by fibrotic diseases that develop as a consequence of tissue damage, primary inflammatory diseases, fibrotic alterations induced by foreign body implants, "spontaneous" fibrosis, and tumor-associated fibrotic changes.

The mechanism that may cause degenerative fibrotic skin lesions was studied in situ using skin biopsies from patients with systemic sclerosis (

As the aging population in developed countries is growing in both numbers and percentage, the medical, social, and economic burdens posed by nonhealing wounds are increasing. Hence, it is all the more important to understand the mechanisms underlying age-related impairments in wound healing. The purpose of this article is to give a concise overview of (1) normal wound healing, (2) alterations in aging skin that have an impact on wound repair, (3) alterations in the repair process of aged skin, and (4) general factors associated with old age that might impair wound healing, with a focus on the literature of the last 10 years.

Fibrosis is an important health problem and its pathogenetic principles are still largely unknown. It can develop either spontaneously or, more frequently, as a consequence of various underlying diseases. However, irrespective of the primary cause, fibrotic tissue is always infiltrated by mononuclear immune cells. In most instances the reason for the attraction of these cells to fibrotic tissue and their proliferation remains to be determined, however their cytokine profile shows clear-cut proinflammatory and profibrotic characteristics. In this review we discuss the innate and adaptive immune reactions associated with the development of fibrosis and the molecular basis of the profibrotic mechanisms taking place in systemic sclerosis (scleroderma), arteriosclerosis and peri-silicone mammary implant fibrosis. Fibrosis: a disease with an immune-mediated etiologyFibrosis, i.e. excessive extracellular matrix (ECM) formation with proliferation and activation of myofibroblasts, is a major global health problem, but its etiology, pathogenesis, diagnosis and therapy have yet to be addressed in detail in either basic or clinical research settings. In principle, fibrosis can occur as a consequence of many different pathologic conditions (Figure 1), the most important of which arise either spontaneously, from tissue damage, inflammatory disease, in response to foreign implants, or from tumors (see Table 1).Although the pathologic processes initiating and perpetuating these processes are rather diverse, from a biochemical and pathohistological view the end stage of the development of fibrosis seems to be very stereotypic. Thus, in all cases studied the early stages of fibrotic conditions are characterized by immunologic-inflammatory hallmarks, viz. a perivascular infiltration by mononuclear cells and the subsequent imbalance of anti-and profibrotic cytokine profiles. In most of these instances, the original antigenic stimuli triggering the lymphoid infiltration have not been identified. The emphasis of this review is placed on the general role of innate and adaptive immunity, and the respective cytokines involved in the development of fibrosis.

The results suggest that endothelial cell apoptosis in SSc is induced by antibody-dependent cell-mediated cytotoxicity via the Fas pathway. These data not only provide insight into the pathogenesis of SSc, but also may open new ways to rational therapy for this disease.

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Conclusion. This study is the first to demonstrate the in vivo apoptosis-inducing effects of AECAs. The findings support our hypothesis of a primary pathogenetic role of AECAs in SSc.

A well-known model of apoptosis is induction in thymocytes by injection of pharmacological doses of exogenous steroids. The aim of this study was to investigate whether this process also occurs under physiological conditions, i.e. by stimulation of endogenous glucocorticoid release, using the chicken as an experimental model. Endogenous glucocorticoid levels can be elevated by immunization with exogenous antigens or by injection of conditioned medium, e.g. supernatant of mitogen-stimulated spleen cells. This effect is mediated by so-called glucocorticoid-increasing factors, and is considered to act as an immunoregulatory principle. Thymocyte DNA of so treated birds showed a typical "ladder" pattern after electrophoresis in a 1.8% agarose gel, and degradation could be prevented by RU 38,486. This provides evidence that apoptosis can be induced by elevating endogenous corticosterone levels in vivo. By means of in situ nick translation (ISNT) and simultaneous immunofluorescence tests, it was possible to analyze various thymic subpopulations during apoptosis after treatment with exogenous glucocorticoids. Additionally, using confocal microscopical techniques, apoptosis of the same cells as analyzed by ISNT is shown. The possible role of elevated concentrations of endogenous glucocorticoids in regulating thymocyte cell death and autoimmune diseases is discussed.