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All sentences and ideas below conceived from (1).
To understand the sequelae of chronic inflammatory disease, pathophysiology, neuroendocrine immunology and evolutionary biology has been used.
Using these theory, sequelae can be explained in various redirection of energy-rich fuels from storage organs to the activated immune system.
The sequelae can be seen in many mammals with chronic inflammatory disease.
So the mechanism can be understood by evolutionary approach.
But we need to care two points below when observing chronic inflammatory disease. The time point when an acute inflammatory disease becomes chronic, and in acute inflammation disease, water loss is observed but in chronic state, no water loss is observed. In contrast there is increased water generation.
Evolutionary biology and medicine has a strong power to explain disease and age related problems including chronic inflammatory disease. But until recently these discipline did not contribute to the current research fields.
We should consider go back to 400 million years ago to understand the mechanism of neuroendocrine immune network.
The framework of evolutionary biology and neuroendocrine immune energy regulation in pathophysiology of chronic inflammatory disease.
Activated immune system has an urgent need for energy-rich substances from internal and external energy stores.
And studies in number of systems showed that circadian rhythms of neuronal, endocrine, and immune systems can regulate energy metabolism and partition fuels to daytime and nighttime consumers.
These energy regulation system might be created by positive selection pressure under no chronic inflammatory disease, because chronic inflammatory disease can give an extensive negative selection pressure. However, many chronic inflammatory disease only become manifested at old age, our ancestors did not suffer from the inflammatory disease as we know today.
So it has been hypothesized that genes relevant to the chronic inflammatory diseases has positively selected for effects on normal host defense.
'Antagonistic pletiotropy' is a theory that many genes has positive effect on host defense but include increased risk of severe form of chronic inflammatory disease, for example, HLA polymorphism.
'Antagonistic pletiotropy' example is below
・HLA DR4(DRB1*04) is a well known risk factor of rheumatoid arthrists and other chronic autoimmune disease, but have a strong negative association with dengue hemorrhagic fever (デング出血熱).
（patients who have homozygous HLA DR4 is 12 times less likely to infected with dengue hemorrhagic fever）
・HLA DR4 polymorphism helps hosts live in roductive period, but give autoimmune disease in later ife.
Other examples are showed below
sited from (1)
Genes, signaling pathways and networks relates to chronic inflammatory disease have been developed in non-life-threating episodes of inflammation .
sited from (1)
(Acute) systemic response results from an appeal of energy rich substances.
In light of altered energy regulation, sequelae and their pathophysiological elements can be described below.
sited from (1)
If such systemic response prolonged sometimes it become pathogenic such as chronic inflammation.
So "systemic response" can be added to etiologic factors of chronic inflammatory disease.
sited from (1)
Adaptive immune response lasts 3~4 weeks, but why it does not last more longer?
Self-limiting infectious disease include disease-induced sickness behavior and related anorexia, inhibitation of intake of energy-rich substrates.
It can be proposed that such sickness behavior is one of the adaptive program positively selected, in order to limit energy utilization for such activities as foraging and courtship. And also, sickness behavior will let individual keep safe.
Under conditions of sickness behavior and anorexia, in addition to increased sickness-related metabolic rate, the total amount of stored energy will run out for about 19 to 43 days in females and 28 to 41 days in males.
sited from (1)
Taking this into consideration, under paleolithic conditions, acute infectious disease may not last longer than 3 to 6 weeks, because stored energy will be consumed in 38 to 41 days.
If immune system lasted longer than period of energy consumption, infected person would have died.
But immune system won the infection and ended shorter than energy consumption period, infected person survived and transfer favorable gene to next generations.
So time point when an acute inflammatory disease becomes chronnic considered to be 19-43days, complete energy consumption time.
Persistent inflammatory disease might be not existed long time ago. But if a disease is progressive and longstanding, and a therapy is available to stop lethal emaciation, a chronic stage can be developed.
Acute inflammation often accompanied by local and systemic water loss.
Local water loss mainly results from wounded skin, outer and inner surface.
And systemic water loss results from hydrolysis of metabolic reaction that degrade energy-rich substrates.
Also, proliferation of B cells, T cells, and other immune cells needs a lot of amount of water.
To overcome local and systemic water loss, SNS system, sympathetic nervous system, activates the renin-angiotensin-aldosterone pathway and hypothalamic-pituitary-adrenal (HPA) axis with ACTH, aldosterone and cortisol.
SNS system and HPA axis can activate immune system and water retention system, and redirect energy-rich substrates from energy stores.
SNS system and HPA axis are supported by other alarm hormones, vasopressin, growth hormone and insulin.
Thus, it is hypothesized that some hormones have pro-inflammation effects.
For example, Angiotensin Ⅱ is a water retention hormone and may have such effects.
Angiotensin Ⅱ uses NF-kB signaling cascade, as well as TNF.
Water retention system has similarities to energy provision system, and it is important that considering water retention in sight of a and chronic inflammation, such as rheumatic and autoimmune diseases undergo madical treatments.
In aging and in chronic inflammatory diseases, both SNS and HPA axis are chronically activated.
As noted above, energy appeal reaction and water retention reaction appear to be resulted from selection in evolution.
Such reaction is useful for survival, if a disease symptom ended in short period.
However, prolonged operation of such reaction, such as chronic inflammatory disease and aging of today can become pathogenic, because no counteracting mechanism is incorporated.
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
sited from (1)
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
sited from (1)
insulin resistance with hyperinsulinemia（高インスリン血症）
increase of adipose（脂肪）
elevated sympathetic tone（交感神経緊張）
decreased parasympathetic tone（副交感神経緊張）
Cori cycle（コリ回路（Cori cycle）、嫌気呼吸の過程において、赤血球や筋肉でグルコースから乳酸を作り、肝臓で乳酸からグルコースに戻すまでの経路のこと（２））
(1) Rainer H. Strau, Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology