Features of Changes in Cell-Matrix Relationships in the Skin During Its Chronological and Photoinduced Aging

The dissertation by T.Yu. Vitruk is devoted to the study of features of changes in cell-matrix relationships in the skin during its chronological and photoinduced aging. The research is aimed at establishing the role of disorders of interactions between dermal fibroblasts and epidermal keratinocytes in the mechanisms of age-related changes in the skin in women. The work employed a complex of cultivation, histological, and immunohistochemical methods for the analysis of the proliferative potential of fibroblasts, structural changes in the extracellular matrix, and the expression of apoptosis marker proteins.

Relevance of the Problem. At present, there is a clear trend toward an increase in the proportion of elderly and advanced-age individuals in the population structure. Their share in the population of many countries has exceeded 20%. Prevention of aging is one of the most actively and dynamically emerging new directions in medicine in recent times. This is due to the complexity and socio-economic significance of the problem of population aging in the modern world (Anisimov V.N., 1999; Krutko V.A., 2000; Goncharova N.D. et al., 2002; Wulf N.S., 2004).

The data presented in the scientific literature regarding various hypotheses of organism aging can be grouped into several categories. The first group of theories is based on genetic factors (theories of genetic control, the "division limit" theory, the mitochondrial theory of aging, the telomerase theory, etc.). The second group of theories explains aging through the action of external factors (the theory of system wear, the free radical theory, the theory of immune system wear). The third group of theories considers, as determining factors, changes in the neuroendocrine system, energy imbalance, etc. (Fisher G.J., 2002; Turova E.A., 2007). However, all the aforementioned hypotheses regard aging as a process of structural-functional changes in the organism proceeding over a long period and unevenly, affecting both internal organs and systems and tissues that determine the external appearance of a person (Maraeva E.B., 1995).

An important role in the mechanisms of the general biological process of organism aging is played by skin aging. On the one hand, the mechanisms of skin aging are determined by the general metabolic, structural, and functional changes common to the entire organism, and the state of the organism as a whole may indicate the degree of its aging. On the other hand, the skin is an organ that is in constant contact with the external environment, as a result of which signs of its aging may appear significantly earlier than in other organs (Tkachenko S.B., Potekayev N.N., 2003; Smirnova I.O., 2004). Thus, skin aging is associated with the general process of organism aging, determined genetically (natural aging) and by the aggressive action of external environmental factors, among which the most destructive is UV radiation (photoaging) (Hertel B., 2000).

The process of skin aging involves a complex set of intercellular interactions in the skin, mediated by anatomical contacts and a wide spectrum of signaling molecules (Kosmadaki M.G., Gilchrest V.A., 2004; Smirnova I.O. et al., 2005). It is well known that the principal cell of the dermis is the fibroblast, which plays a key role in the normal functioning and state of the connective tissue matrix of the skin. The coordinated activity of fibroblasts with other components of the epidermis, dermis, and vascular bed, the regulation of the microenvironment, and cell-matrix relationships largely determine their ability to maintain skin homeostasis and respond to the action of the external and internal environment (Serov V.V., 1981; Martynov A.I. et al., 1998; Bykov V.L., 2004).

However, the features of the relationships between dermal fibroblasts and epidermal keratinocytes, as well as the dynamics of age-related morphological changes in the components of the epidermis and dermis, remain insufficiently studied (Oikarinen D., 1994; Tzaphlidou M., 2004), which justifies the expediency of a detailed examination of changes in cell-matrix relationships in the skin during chronological and photoinduced aging.

Goals and Objectives of the Research. The goal of the work is to establish the role of disorders of cell-matrix relationships in the skin in women during its chronological and photoinduced aging.

The research was focused on solving the following main tasks:

1. To determine the role of changes in the proliferative potential of dermal fibroblasts in the mechanisms of skin aging.

2. To establish the patterns of changes in the structure of the dermis and epidermis during natural and photoinduced skin aging in women.

3. To evaluate the features of expression of apoptosis marker proteins (p53, bcl-2, Bax) by keratinocytes during skin aging.

4. To identify general patterns and features of cell-matrix relationships in the skin in women during chronological and photoinduced aging.

Main Propositions to Be Defended:

1. The mechanisms of disruption of cell-matrix interactions in the skin during its chronological and photoinduced aging are associated with a decrease in the proliferative potential of dermal fibroblasts.

2. Age-related changes in the skin are characterized by structural-functional changes in the extracellular matrix — degeneration of collagen and elastic fibers, focal distribution of glycosaminoglycans in the dermis, the degree of which is most significant during photoinduced aging.

3. During skin aging, dysregulation of programmed cell death of the epidermis occurs, manifested by an increase in the level of expression of apoptosis marker proteins (p53, Bax).

Scientific Novelty. For the first time, using a complex of modern cultivation, histological, and immunohistochemical research methods, general patterns and features of disorders of cell-matrix relationships in the skin during chronological and photoinduced aging have been identified.

It has been shown that the signs of chronological, hormonal, and photoinduced skin aging are expressed in all structural components of the epidermis and dermis, the degree of expression of which is most significant during chronic insolation.

It has been established that the disruption of cell-matrix relationships in the skin during its aging is associated with a decrease in the proliferative potential of dermal fibroblasts.

It has been revealed that the degree of degeneration of dermal collagen fibers depends to a greater extent on the influence of chronic insolation than on age and reproductive system status, and that of elastic fibers — on the influence of chronic insolation and reproductive system status of the patients, rather than on age.

It has been demonstrated that age-related changes in the skin are characterized by an increase in the content of apoptosis marker proteins (p53 and Bax) in the keratinocytes of the epidermis.

Theoretical and Practical Significance of the Work. New fundamental data on complex changes in the structural components of the epidermis and dermis have been obtained, revealing new aspects of the molecular and cellular mechanisms of skin aging. It has been shown that chronic insolation is a risk factor for premature skin aging realized at the level of the epidermis and dermis. The results of the present research indicate the expediency of developing pathogenetically justified measures for the prevention of chronological and photoinduced aging of the skin, targeted at all structural components of the epidermis and dermis.

Implementation and Testing of the Dissertation. The results of the research are used in the course of lectures on pathological physiology (sections "General Pathology of the Cell," "Mechanisms of Aging," "Role of Apoptosis in Normality and Pathology"), dermatovenerology (sections "Photodermatoses," "Sun Screens and Skin Cancer Prevention," "Photoaging of the Skin"). The main provisions of the dissertation were presented at the V Siberian Physiological Congress (Tomsk, 2005) and at the All-Russian Conference "First Results of Healthcare Reform and Tasks of Dermatovenereological Institutions in the Transitional Period" (Yekaterinburg, 2005).

Volume and Structure of the Work. The dissertation is presented on 134 pages of typed text and consists of an introduction, four chapters, conclusions, and a list of references used. The work is illustrated by 23 figures and 10 tables. The bibliographic index includes 248 sources (105 domestic and 143 foreign).