Euromedica 2011 Alexander Pukhalsky Galina Shmarina Vladimir Alioshkin metabolic syndrome and the complex adaptive system exhaustion: modern approachesto their prevention and treatment"

Alexander Pukhalsky Galina Shmarina Vladimir Alioshkin	METABOLIC SYNDROME AND THE COMPLEX ADAPTIVE SYSTEM EXHAUSTION: MODERN APPROACHES TO THEIR PREVENTION AND TREATMENT
	Research Centre for Medical Genetics, Moscow, Russia G.N. Gabrichevsky Institute of Epidemiology and Microbiology, Moscow, Russia

Ability to respond to environmental changes is a fundamental property of all living things from bacteria to human society. If life is an ability to adapt, a loss of such ability brings the threat of death. In the course of biological evolution, the ancient adaptive mechanisms do not disappear but become an integrated part of a complex adaptive system presented in mammalia as a triad including the brain, immune and endocrine systems. The body is secured against stressors, chemical agents, and infection until the work of all three systems is well equalized. Such balance may be disturbed by age due to repeated episodes of stress and hypothalamic-pituitary-adrenal (HPA) axis activation. Multiple episodes of stress, which are survived by an individual throughout his life lead to gradual depletion of HPA axis that is manifested by both basal cortisol level decrease and the reduction of stress-induced cortisol response. As a result, the cells (dendritic cells, macrophages, endothelial and epithelial cells, as well as adipocytes) deprived of glucocorticoid control begin to produce high amounts of pro-inﬂammatory factors. Thus, the development of such symptoms as chronic fatigue, fever, ﬁbromialgia, joint pains, and skin disorders is a consequence of central and/or local imbalance of cytokines including the pain mediator IL-8 and pro-inﬂammatory cytokines TNF-, IL-1β, and IL-6. So, cortisol presenting in the blood in low concentration is not able any more to control inﬂammation, and regulatory T cells (Tregs) become a principal antiinﬂammatory instrument of the immunity. This mode of regulation of inﬂammatory reaction being more slow and rough does not allow to ﬁne tune immune system and each new environmental challenge promotes further Treg accumulation that leads to stable immunosuppression. It is quite possible that this fact may hold the key why old age is the greatest cancer-risk factor in humans.

Another consequence of stress may be obesity associated both with alteration of feeding behaviour and decrease of sex and thyroid hormone production. Lipid metabolism disorder is accompanied by overload of adipocytes with fat. Such adipocytes produce high amount of pro-inﬂammatory cytokines and the immune system begin to perceive adipose tissue as an inﬂammatory focus. Consequently adipose tissue is inﬁltrated by macrophages, which particularly produce TNF-α. The latter binds with TNF receptor on the surface of adipocyte and owing to competition with insulin receptors for secondary messengers makes the cell insulin resistant. Such adipocytes loss the ability to glucose utilization and in consequence of energy deﬁciency they are incapable of further fat accumulation. A part of the adipocytes undergoes lipolysis creating favourable conditions for visceral obesity. The alterations described above are signiﬁcant components of metabolic syndrome, which predisposes individuals to an increased risk of developing many diseases, including atherosclerosis, coronary disease, diabetes, and non-alcoholic fatty liver disease.

For the purpose of the prevention and/or damping of unfavourable effects of permanent stress modern pharmacology proposes a number of approaches, which are based on following principles: (1) elimination of surplus Treg number; (2) compensation of HPA axis exhaustion; (3) lipid metabolism normalization. Different methods of Treg depletion have been proposed. In our opinion the therapy with low (non-cytototoxic) doses of alkylating drugs are most promising among them. With the view of supporting depleted HPA axis replacement hormone therapy in the form of alternated course of prednisolone (0.3 mg/kg body weight every other day) may be recommended. Chronic treatment with 14-membered ring macrolide antibiotics may be also used. We believe that the restoration of HPA axis and decrease of surplus activity of Tregs may promote lipid metabolism normalization. With the same purpose the treatment with angiotensin-converting enzyme blockers such as prestarium or enalapril may be worthwhile