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

Under conditions of sickness behavior and anorexia without uptake of energy-rich substrates but an increased sickness-related metabolic rate, the total amount of stored energy would only last for 19 to 43 days in females and 28 to 41 days in males.

“Depending on the amount of stored energy, this time point can be calculated to be 19–43 days.”

• Also stated in: § From acute to chronic inflammatory disease—where is the boundary? · hedged

  “Under conditions of sickness behavior and anorexia without uptake of energy-rich substrates but an increased sickness-related metabolic rate (Tables 1 and 6), the total amount of stored energy would only last for 19 to 43 days in females and 28 to 41 days in males (Table 6).”

• cites [11] Rolfe DF, Brown GC (1997) Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 77:731–758 sourceNot checked yet

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• cites [12] Blaxter K (1989) Energy metabolism in animals and man. Cambridge University Press, CambridgeNot checked yet

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The number of days of total energy consumption is relatively similar for domestic fowl, which have an evolutionary distance to Homo sapiens of 300 million years.

“The number is relatively similar for domestic fowl which have an evolutionary distance to Homo sapiens of 300 million years (Table 6).”

HLA DR4 (DRB1*04) homozygous individuals are 12 times less likely to develop dengue hemorrhagic fever.

“HLA DR4 (DRB1*04) homozygous individuals are 12 times less likely to develop dengue hemorrhagic fever [21].”

• cites [21] LaFleur C et al (2002) HLA-DR antigen frequencies in Mexican patients with dengue virus infection: HLA-DR4 as a possible genetic resistance factor for dengue hemorrhagic fever. Hum Immunol 63:1039–1044 sourceNot checked yet

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Disease sequelae of chronic inflammatory disease can be explained by redirection of energy-rich fuels from storage organs to the activated immune system.

“According to this theory, disease sequelae can be explained based on redirection of energy-rich fuels from storage organs to the activated immune system.”

• Also stated in: § The framework of evolutionary biology and neuroendocrine immune energy regulation in pathophysiology of chronic inflammatory diseases · plain

  “As a common denominator, the redirection of energy-rich fuels from energy stores to the activated immune system can explain systemic disease sequelae [9].”

• cites [9] Straub RH, Cutolo M, Buttgereit F, Pongratz G (2010) Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med 267:543–560 sourceNot checked yet

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An acute consuming infectious disease that uses all energy stores can only last until the stores are empty, say 19 to 43 days.

“In other words, an acute consuming infectious disease that uses all energy stores can only last until the stores are empty, say 19 to 43 days.”

Due to the physical restrictions of energy storage under natural paleolithic conditions, an acute infectious disease may not last much longer than 3 to 6 weeks.

“Due to the physical restrictions of energy storage under natural paleolithic conditions, an acute infectious disease may not last much longer than 3 to 6 weeks.”

Typical disease-related sequelae that are very common in chronic inflammatory diseases have been linked to transient inflammatory episodes, where they support the transiently activated immune system and tissue inflammation.

“On the basis of these considerations, typical disease-related sequelae that are very common in chronic inflammatory diseases have been linked to transient inflammatory episodes [9, 10]. Here, these sequelae have an important function in supporting the transiently activated immune system and tissue inflammation (Table 4).”

• cites [9] Straub RH, Cutolo M, Buttgereit F, Pongratz G (2010) Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med 267:543–560 sourceNot checked yet

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• cites [10] Straub RH (2011) Concepts of evolutionary medicine and energy regulation contribute to the etiology of systemic chronic inflammatory diseases. Brain Behav Immun 25:1–5 sourceNot checked yet

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Antagonistic pleiotropy can explain why genes positively selected at younger ages can have disease-supporting roles in later life independent of the selection process.

“Antagonistic pleiotropy can explain why genes positively selected at younger ages can have disease-supporting roles in later life independent of the selection process.”

Uptake of energy-rich substrates has an upper threshold of 20,000 kJ per day (the absorptive capacity in the gut).

“Since uptake of energy-rich substrates has an upper threshold of 20,000 kJ per day (the absorptive capacity in the gut) [11, 12], it is important for the organism to partition energy-rich substrates according to fine-tuned mechanisms of energy regulation.”

• cites [11] Rolfe DF, Brown GC (1997) Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 77:731–758 sourceNot checked yet

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• cites [12] Blaxter K (1989) Energy metabolism in animals and man. Cambridge University Press, CambridgeNot checked yet

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The point of transition from acute disease to chronic disease can represent a range in time because the consumption curve depends on stored energy reserves.

“In this regard, the point can represent a range in time because the consumption curve depends on stored energy reserves (Table 6).”

Sickness behavior represents an element of an adaptive program that has been positively selected for transient immune and inflammatory reactions to limit energy utilization for activities such as foraging and courtship behavior.

“To explain these seemingly disparate observations, it can be proposed that sickness behavior represents an element of an adaptive program that has been positively selected for transient immune and inflammatory reactions to limit energy utilization for such activities as foraging and courtship behavior [8, 26, 27].”

• cites [8] Straub RH, Besedovsky HO (2003) Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases. FASEB J 17:2176–2183 sourceNot checked yet

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• cites [26] Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160 sourceNot checked yet

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• cites [27] Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56 sourceNot checked yet

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The energy appeal reaction has been positively selected for transient inflammatory episodes.

“In this scenario, the energy appeal reaction has been positively selected for transient inflammatory episodes.”

The time point of total energy consumption marks the upper threshold of an acute disease period for which genes, signaling pathways, and networks can be subject to positive selection.

“These considerations thus suggest that the time point of total energy consumption marks the upper threshold of an acute disease period for which genes, signaling pathways, and networks can be subject to positive selection.”

If an acute inflammatory response lasted longer than the time point at which energy stores were exhausted, the affected person would probably have died due to inanition and starvation, preventing transfer of genes to any offspring.

“If an acute inflammatory response lasted longer than the time point at which energy stores were exhausted, the affected person would probably have died due to inanition and starvation, preventing transfer of genes to any offspring.”

Prolonged operation of these adaptive programs such as in chronic inflammatory diseases of today can in itself become pathogenic.

“However, prolonged operation of these adaptive programs such as in chronic inflammatory diseases of today can in itself become pathogenic.”

An activated immune system has an urgent need for energy-rich substrates that must be allocated from internal and external energy stores.

“To meet the challenges of infection and other environmental stress, an activated immune system has an urgent need for energy-rich substrates that must be allocated from internal and external energy stores (glycogen, proteins, triglycerides, or free fatty acids) [9].”

• cites [9] Straub RH, Cutolo M, Buttgereit F, Pongratz G (2010) Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med 267:543–560 sourceNot checked yet

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The response of the adaptive immune system with a maximum of proliferation until days 12 to 14 and subsequent contraction until days 21 to 28 is surprisingly constant in various acute infectious diseases.

“The response of the adaptive immune system with a maximum of proliferation until days 12 to 14 and subsequent contraction until days 21 to 28 is surprisingly constant in various acute infectious diseases [24].”

• cites [24] Murphy KM, Travers P, Walport M (2011) Janeway’s immunobiology. Taylor & Francis, OxfordNot checked yet

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Circadian rhythms of neuronal, endocrine, and immune systems can regulate energy metabolism and partition fuels to daytime and nighttime consumers.

“Studies in a number of systems have demonstrated that circadian rhythms of neuronal, endocrine, and immune systems can regulate energy metabolism and partition fuels to daytime and nighttime consumers [9, 13–15].”

• cites [9] Straub RH, Cutolo M, Buttgereit F, Pongratz G (2010) Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med 267:543–560 sourceNot checked yet

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• cites [13] Le Magnen J (1988) Lipogenesis, lipolysis and feeding rhythms. Ann Endocrinol (Paris) 49:98–104Not checked yet

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• cites [14] Lange T, Dimitrov S, Fehm HL, Westermann J, Born J (2006) Shift of monocyte function toward cellular immunity during sleep. Arch Intern Med 166:1695–1700 sourceNot checked yet

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• cites [15] Lange T, Dimitrov S, Bollinger T, Diekelmann S, Born J (2011) Sleep after vaccination boosts immunological memory. J Immunol 187:283–290 sourceNot checked yet

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The combination of no increased water loss, increased water generation in inflamed tissue and inflammatory cells, and persistent activation of the water retention system leads to a net increase of the systemic fluid volume.

“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”

• AssumptionRests on an assumption: In chronic smoldering inflammation, there is no increased water loss.
• AssumptionRests on an assumption: In chronic smoldering inflammation, there is increased water generation in inflamed tissue and inflammatory cells.
• AssumptionRests on an assumption: In chronic smoldering inflammation, the activation of the water retention system persists.

Acute inflammatory episodes are often accompanied by local and systemic water loss.

“Acute inflammatory episodes require abundant energy and are often accompanied by local and systemic water loss (Table 7).”

• cites [28] Davies JW, Lamke LO, Liljedahl SO (1974) A guide to the rate of non-renal water loss from patients with burns. Br J Plast Surg 27:325–329 sourceNot checked yet

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• cites [29] Jacob M, Chappell D, Hofmann-Kiefer K, Conzen P, Peter K, Rehm M (2007) Determinants of insensible fluid loss. Perspiration, protein shift and endothelial glycocalyx. Anaesthesist 56:747–758, 760–764 sourceNot checked yet

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In aging and chronic inflammatory diseases, the overall stimulus might be strong enough to induce a mild systemic water retention and energy appeal reaction.

“the overall stimulus might be strong enough to induce a mild systemic water retention and energy appeal reaction (responses shown for low IL-6 serum concentrations in ref. [42, 43]).”

• cites [42] Tsigos C, Papanicolaou DA, Defensor R, Mitsiadis CS, Kyrou I, Chrousos GP (1997) Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology 66:54–62 sourceNot checked yet

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• cites [43] Tsigos C, Papanicolaou DA, Kyrou I, Raptis SA, Chrousos GP (1999) Dose-dependent effects of recombinant human interleukin-6 on the pituitary-testicular axis. J Interferon Cytokine Res 19:1271–1276 sourceNot checked yet

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Many metabolic reactions that degrade storage forms of energy-rich substrates need water for hydrolysis.

“many metabolic reactions that degrade storage forms of energy-rich substrates need water for hydrolysis (Fig. 1) [30–32].”

• cites [30] Berg JM, Tymoczko JL, Stryer L (2002) Biochemistry. Freeman, New YorkNot checked yet

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• cites [31] Michal G (1999) Biochemical pathways. Spektrum Akademischer Verlag, HeidelbergNot checked yet

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• cites [32] Rassow J, Hauser K, Netzker R, Deutzmann R (2008) Biochemistry. Georg Thieme, StuttgartNot checked yet

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Under normal conditions in adults, insensible perspiration through skin and respiratory tract can reach 0.5 ml/kg/h.

“Under normal conditions in adults, insensible perspiration through skin and respiratory tract can reach 0.5 ml/kg/h (example, 80 kg and 24 h = 960 ml/day) [29].”

• cites [29] Jacob M, Chappell D, Hofmann-Kiefer K, Conzen P, Peter K, Rehm M (2007) Determinants of insensible fluid loss. Perspiration, protein shift and endothelial glycocalyx. Anaesthesist 56:747–758, 760–764 sourceNot checked yet

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In chronic inflammation without water loss, water can recirculate between activated immune cells and the system.

“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.”

Genes, signaling pathways, and networks operative in aging and chronic inflammatory diseases are similar to those that determine acute episodes of inflammation.

“genes, signaling pathways, and networks that are operative in this setting are similar to those that determine acute episodes of inflammation (Table 2).”

During transient inflammatory episodes, lipogenic insulin most probably plays a minor role because insulin secretion activated by the presence of carbohydrates would be downregulated.

“During transient inflammatory episodes, due to sickness behavior and anorexia, lipogenic insulin most probably plays a minor role because insulin secretion activated by the presence of carbohydrates would be downregulated.”

• AssumptionRests on an assumption: Insulin is lipogenic and water retentive.

Degradation of muscle protein needs particularly many molecules of water.

“degradation of muscle protein needs particularly many molecules of water (Fig. 1, brown area in right upper corner) [31].”

• cites [31] Michal G (1999) Biochemical pathways. Spektrum Akademischer Verlag, HeidelbergNot checked yet

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In local inflammation with exposed surfaces, locally formed water can be rapidly lost via the exposed surface.

“Since the local inflammatory process leads to water loss over local surfaces, locally formed water—by degradation of energy-rich fuels in activated inflammatory cells (Fig. 1, orange area)—can be rapidly lost via the exposed surface (Fig. 2a).”

Important differences exist for water loss from the system and the generation of water from locally inflamed tissue.

“Thus, important differences exist for water loss from the system and the generation of water from locally inflamed tissue.”

Chronic inflammation accompanied by essential hypertension is a necessary consequence.

“Chronic inflammation accompanied by essential hypertension is a necessary consequence”

• AssumptionThe authors state this as an assumption: The water retention system will not induce hypertension under acute inflammatory conditions with local and systemic water loss.

Loss of water can be quite high during acute inflammatory episodes.

“These numbers show that loss of water can be quite high during acute inflammatory episodes.”

Angiotensin II has proinflammatory activities.

“water retention hormones such as angiotensin II have proinflammatory activities [37].”

• cites [37] Dorffel Y, Latsch C, Stuhlmuller B, Schreiber S, Scholze S, Burmester GR, Scholze J (1999) Preactivated peripheral blood monocytes in patients with essential hypertension. Hypertension 34:113–117 sourceNot checked yet

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• AssumptionRests on an assumption: Angiotensin II is a water retention hormone.

Under conditions of local inflammation with exposed outer and inner surfaces, circulating cytokines from inflamed tissue activate the energy appeal and water retention reaction.

“Under conditions of local inflammation with exposed outer and inner surfaces, circulating cytokines from inflamed tissue activate the energy appeal and water retention reaction.”

During surgical intervention, a model of mild acute inflammatory activation, water loss by insensible perspiration can amount to 1 ml/kg/h.

“During surgical intervention, which is a model of mild acute inflammatory activation, water loss by insensible perspiration can amount to 1 ml/kg/h (example, 80 kg and 24 h = 1,820 ml/day) [29].”

• cites [29] Jacob M, Chappell D, Hofmann-Kiefer K, Conzen P, Peter K, Rehm M (2007) Determinants of insensible fluid loss. Perspiration, protein shift and endothelial glycocalyx. Anaesthesist 56:747–758, 760–764 sourceNot checked yet

  Not checked in the free run.

In aging and chronic inflammatory diseases, circulating cytokine levels can be 5 to 10 times higher than normal (e.g., IL-6 from 2 pg/ml to 10-20 pg/ml).

“In these settings, circulating cytokine levels can be 5 to 10 times higher than normal (e.g., IL-6 from 2 pg/ml to 10–20 pg/ml), and the overall stimulus might be strong enough to induce a mild systemic water retention and energy appeal reaction (responses shown for low IL-6 serum concentrations in ref. [42, 43]).”

• cites [42] Tsigos C, Papanicolaou DA, Defensor R, Mitsiadis CS, Kyrou I, Chrousos GP (1997) Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology 66:54–62 sourceNot checked yet

  Not checked in the free run.

• cites [43] Tsigos C, Papanicolaou DA, Kyrou I, Raptis SA, Chrousos GP (1999) Dose-dependent effects of recombinant human interleukin-6 on the pituitary-testicular axis. J Interferon Cytokine Res 19:1271–1276 sourceNot checked yet

  Not checked in the free run.

Water is formed when glucose, amino acids, and free fatty acids undergo degradation in the Krebs cycle and during oxidative phosphorylation in mitochondria of activated cells in inflamed tissue.

“Water is formed when glucose, amino acids, and free fatty acids undergo degradation in the Krebs cycle and during oxidative phosphorylation; these processes occur in the mitochondria of activated cells in inflamed tissue (Fig. 1, orange area).”

Breakdown of one molecule of glucose from glycogen needs two molecules of water.

“the breakdown of one molecule of glucose from glycogen needs two molecules of water (Fig. 1, pink area in left upper corner)”

• cites [31] Michal G (1999) Biochemical pathways. Spektrum Akademischer Verlag, HeidelbergNot checked yet

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Systemic hypertension could result from the continuous activation of a water retention and energy appeal reaction but without the usual water loss.

“systemic hypertension could result from the continuous activation of a water retention and energy appeal reaction but without the usual water loss (Fig. 2b).”

• AssumptionThe authors state this as an assumption: The water retention system will not induce hypertension under acute inflammatory conditions with local and systemic water loss.

Generation of the Cori cycle between lactate-producing inflamed tissue and glucose-producing liver, involving gluconeogenesis, needs five molecules of water to reactivate one molecule of lactate.

“the generation of the Cori cycle between the lactate-producing inflamed tissue and the glucose-producing liver [33], involving gluconeogenesis, needs five molecules of water to reactivate one molecule of lactate (Fig. 1, red lines with arrows) [31].”

• cites [31] Michal G (1999) Biochemical pathways. Spektrum Akademischer Verlag, HeidelbergNot checked yet

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• cites [33] Tredget EE, Yu YM (1992) The metabolic effects of thermal injury. World J Surg 16:68–79 sourceNot checked yet

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Triglyceride breakdown needs three molecules of water for three molecules of free fatty acids.

“triglyceride breakdown needs three molecules of water for three molecules of free fatty acids (Fig. 1, pink and yellow area on the left side)”

• cites [31] Michal G (1999) Biochemical pathways. Spektrum Akademischer Verlag, HeidelbergNot checked yet

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Inhibition of the renin-angiotensin-aldosterone system by angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists exerts anti-inflammatory effects.

“Inhibition of the renin–angiotensin–aldosterone system by angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists exert anti-inflammatory effects as summarized elsewhere [39].”

• cites [39] Boos CJ, Lip GY (2006) Is hypertension an inflammatory process? Curr Pharm Des 12:1623–1635 sourceNot checked yet

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Operation of a proper adaptive immune response with proliferation of B cells, T cells, and innate immune cells in primary and secondary lymphoid organs needs enormous amounts of water.

“the operation of a proper adaptive immune response with proliferation of B cells and T cells and proliferation of innate immune cells (neutrophils, monocytes) in primary and secondary lymphoid organs needs enormous amounts of water (Fig. 1, green area in left lower corner) [31].”

• cites [31] Michal G (1999) Biochemical pathways. Spektrum Akademischer Verlag, HeidelbergNot checked yet

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In acute inflammatory episodes, water fluxes between the system and inflamed tissue are in balance due to water loss via outer and inner surfaces.

“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.”

To overcome systemic water loss during acute inflammatory episodes and events such as trauma, hemorrhage, and burns, a water retention system is activated.

“To overcome systemic water loss during acute inflammatory episodes and events such as trauma, hemorrhage, and burns, a water retention system is activated.”

• cites [34] Bader M, Ganten D (2000) Regulation of renin: new evidence from cultured cells and genetically modified mice. J Mol Med (Berl) 78:130–139 sourceNot checked yet

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In acute inflammatory episodes such as infectious disease, the energy appeal reaction and the water retention reaction support the proinflammatory process to eliminate the infectious agent.

“In the setting of acute inflammatory episodes such as infectious disease, it is important that the energy appeal reaction and the water retention reaction support the proinflammatory process to eliminate the infectious agent.”

Angiotensin II uses the proinflammatory signaling cascade of NF-κB activation similar to TNF.

“Angiotensin II uses the important proinflammatory signaling cascade of NF-κB activation similar as TNF [38].”

• cites [38] Phillips MI, Kagiyama S (2002) Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs 3:569–577Not checked yet

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If amino acids are completely degraded within the urea cycle in the liver, one molecule of water is needed for one molecule of amino acid.

“If amino acids are completely degraded within the urea cycle in the liver, one molecule of water is needed for one molecule of amino acid (Fig. 1, pink area in the left upper corner).”

• cites [31] Michal G (1999) Biochemical pathways. Spektrum Akademischer Verlag, HeidelbergNot checked yet

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The operation of the mechanisms linking inflammation to hypertension will not depend on the site of inflammation.

“The revised version of the theory predicts that the operation of these mechanisms will not depend on the site of inflammation and whether it occurs in arteries, kidneys, gastrointestinal tract, joints, or at various tissues with inflammatory cells.”

The energy appeal reaction and water retention reaction have been positively selected in evolution for their role in transient inflammatory episodes.

“the energy appeal reaction and water retention reaction appear to be the result of selection in evolution for their role in transient inflammatory episodes.”

• Also stated in: § Conclusions · plain

  “The revised theory states that energy appeal and water retention reaction have been positively selected for transient inflammatory episodes”

The magnitude of these changes determines any detrimental effect on the induction of hypertension.

“The magnitude of these changes would determine any detrimental effect on the induction of hypertension.”

Prolonged operation of these adaptive programs, such as in chronic inflammatory diseases, can in itself become pathogenic because there is no program to counteract continuous water retention and energy appeal reaction during long-term age-related inflammation and in chronic inflammatory diseases.

“prolonged operation of these adaptive programs such as in chronic inflammatory diseases of today can in itself become pathogenic because there is no program to counteract continuous water retention and energy appeal reaction during long-term age-related inflammation and in chronic inflammatory diseases.”

• Also stated in: § Conclusions · plain

  “prolonged use of these adaptive programs can in itself become pathogenic.”

Induction of energy appeal reaction and water retention reaction provides a survival value if used for a short period of time.

“Induction of energy appeal reaction and water retention reaction provide a survival value if used for a short period of time.”

Features of aging and chronic inflammatory diseases can be unified in terms of a redirection of energy-rich fuels from energy stores to the activated immune system and activation of the water retention system.

“these features can now be unified in terms of a redirection of energy-rich fuels from energy stores to the activated immune system and activation of the water retention system.”