Evolutionary medicine and chronic inflammatory state--known and new concepts in pathophysiology

Abstract

During the last 10 years, a series of exciting observations has led to a new theory of pathophysiology using insights from evolutionary biology and neuroendocrine immunology to understand the sequelae of chronic inflammatory disease. According to this theory, disease sequelae can be explained based on redirection of energy-rich fuels from storage organs to the activated immune system. These disease sequelae are highly diverse and include the following: sickness behavior, anorexia, malnutrition, muscle wasting-cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, increase of adipose tissue near inflamed tissue, alterations of steroid hormone axes, elevated sympathetic tone and local sympathetic nerve fiber loss, decreased parasympathetic tone, hypertension, inflammation-related anemia, and osteopenia. Since these disease sequelae can be found in many animal models of chronic inflammatory diseases with mammals (e.g., monkeys, mice, rats, rabbits, etc.), the evolutionary time line goes back at least 70 million years. While the initial version of this theory could explain prominent sequelae of chronic inflammatory disease, it did not however address two features important in the pathogenesis of immune-mediated diseases: the time point when an acute inflammatory disease becomes chronic, and the appearance of hypertension in chronic inflammation. To address these aspects more specifically, a new version of the theory has been developed. This version defines more precisely the moment of transition from acute inflammatory disease to chronic inflammatory disease as a time in which energy stores become empty (complete energy consumption). Depending on the amount of stored energy, this time point can be calculated to be 19-43 days. Second, the revised theory addresses the mechanisms of essential hypertension since, on the basis of water loss, acute inflammatory diseases can stimulate water retention using a positively selected water retention system (identical to the energy provision system). In chronic smoldering inflammation, however, there is no increased water loss. In contrast, there is increased water generation in inflamed tissue and inflammatory cells, and the activation of the water retention system persists. This combination leads to a net increase of the systemic fluid volume, which is hypothesized to be the basis of essential hypertension (prevalence in adults 22-32%).

Fig. 1

Water fluxes in the system (blue box) and inflamed tissue (orange box). Blue box it is demonstrated that liver cells (pink box) need water for degradation of glycogen, triglycerides, amino acids in the urea cycle, and for gluconeogenesis in the context of the Cori cycle (red arrows in the blue box). Similarly, degradation of muscle proteins in muscle (brown box) and triglycerides in fat tissue (yellow box) withdraw water from the system. An enormous amount of water is needed for proliferation of immune cells in primary and secondary lymphoid organs (green box) due to generation of DNA, membranes, cytoskeletal proteins, and many others. Orange box the inflamed tissue is separated from the system. In inflamed tissue activated cells, mainly immune cells, use provided energy-rich substrates such as glucose, amino acids such as glutamine and alanine, ketone bodies, and free fatty acids to overcome the inflammatory state. In the process of complete degradation of energy-rich substrates to CO₂ and H₂O, enormous amounts of water are generated (black-edged box in orange box). In an acute inflammatory situation, both, the system and the inflamed tissue, loose water by several pathways (given as boxes below the blue and orange box). C–C bond carbon–carbon bond, FFA free fatty acids, GI tract gastrointestinal tract, HPA axis hypothalamic–pituitary–adrenal axis, Pi inorganic phosphate, SNS sympathetic nervous system. The calculations of water fluxes is derived from biochemistry literature [–32]

Fig. 2

Water fluxes between the system and inflamed tissue with water loss in a transient acute inflammatory episode (a) and without water loss in chronic inflammation (b). a Water fluxes with water loss in acute inflammatory episodes. The inflamed tissue (orange box) releases cytokines or stimulates sensory nerve endings (not shown) in order to induce an energy appeal and water retention reaction in the system (blue box). In the system, urinary water loss is inhibited and water is needed for many important reactions for provision of energy-rich substrates and immune cell proliferation (see Fig. 1). In the acute situation, water is lost from the system and from inflamed tissue via outer and inner surfaces. The water fluxes are in a balance. b Water fluxes without water loss in chronic inflammation. Similarly, as before in panel A the inflamed tissue activates water retention and energy appeal reaction. However, due to low-grade inflammation without fever and due to a lack of inflamed exposed surface areas, water is not lost from the system and from inflamed tissue. Water can recirculate between activated immune cells and the system. In this scenario, it does not matter how the inflamed tissue look like. It might be a separated tissue such as an inflamed joint or an inflamed segment of the aorta. However, it might also be the sum of disseminated activated inflammatory cells in any tissue (orange box). It might also be the sum of disseminated an activated cells in different parts of the body, which might happen during aging when different organs present higher levels of inflammatory activity. The logic behind the water flux between system and inflamed cells remains the same. It is only important that secreted cytokines of these inflammatory cells activate the energy appeal and water retention reaction, and that water loss via inner and outer surfaces is not increased. Chronic inflammation accompanied by essential hypertension is a necessary consequence