Journal of Theoretical Biology 363 (2014) 164–168
Contents lists available at ScienceDirect
Journal of Theoretical Biology journal homepage: www.elsevier.com/locate/yjtbi
Hypothesis: Possible respiratory advantages for heterozygote carriers of cystic fibrosis linked mutations during dusty climate of last glaciation Vladimir Borzan a, Boris Tomašević b, Sven Kurbel c,n a
Osijek University Hospital, Dept. of Internal Medicine, Osijek, Croatia Zagreb University Hospital, Dept. of Anesthesiology, Zagreb, Croatia c Osijek Medical Faculty, Dept. of Physiology, Osijek, Croatia b
H I G H L I G H T S
Airway fluid is lost through evaporation, particularly when breathing cold and arid air. Fluid reabsorption depends on active CFTRs that allow ENaCs to absorb salt and water. The cystic fibrosis (CF) mutation is common in north Europe and probably near 52 ky old. Between 50 and 10 kya, the European climate was arid, cold, with a dust-laden atmosphere. Individuals with one CF mutation due to slower fluid reabsorption might have better clearance of inhailed dust.
art ic l e i nf o
a b s t r a c t
Article history: Received 2 January 2014 Received in revised form 4 August 2014 Accepted 9 August 2014 Available online 21 August 2014
This paper puts forward a new hypothesis to interpret the high carrier frequency of CFTR mutations in individuals of European descent. The proposed heterozygote advantage factor is related to the specific climate conditions in Europe during the last 50 ky that might have heavily compromised the respiratory function of our ancestors in Eurasia. A large part of the last 50 ky was cold, and the coldest period was the Last Glacial Maximum (LGM) (26.5 to 19 kya). The global climate was dry with a dust-laden atmosphere (20 to 25 times more dust than the present level). High levels of atmospheric dust started more than 40 kya and ended less than 10 kya. Secretion of airway fluid is usually related to the submucosal tissue hydration, while salt reabsorption relies on activation of CFTRs that allow ENaCs to absorb salt and water. The water loss by evaporation depends on the air humidity and flow rate. Salt accumulation in the mucus is normally prevented by reabsorption of Na þ and Cl by epithelial cells if the presence of functional CFTRs is normal. If one gene for CFTR is mutated, the number of functional CFTRs is reduced and this limits the capacity of salt reabsorption by epithelial cells. This means that evaporation makes the airway fluid more hypertonic, and osmotic forces bring more water from the interstitial space, thus leading to a new balance in mucosal fluid traffic. Increased osmolarity and volume of airway fluid can be more moveable in cases when evaporation and dust exposure is increased. If both CFTR genes are mutated, low number of functional CFTRs diminishes salt resorption of epithelial cells. Salt accumulated in the mucous fluid within respiratory ducts, as previously described. The hypertonic ductal content forces more water and some electrolytes to enter the airway fluid from the interstitial fluid, and evaporation leads to further concentration of thick immobile mucus. The proposed interpretation is that CFTR mutations have spread among our ancestors that roamed the central Eurasia after the LGM. The heterozygote individuals might have benefitted from the limited water resorption in their respiratory mucosa that allowed improved airway cleansing. & 2014 Elsevier Ltd. All rights reserved.
Keywords: ENaC function CFTR function Mucus transport Membrane potential Airways
1. Introduction n
Corresponding author to: Osijek Medical Faculty, J Huttlera 4, 31000 Osijek, Croatia. Tel.: þ 385 31 512800; fax: þ 385 31 512833. E-mail address: [email protected] (S. Kurbel). http://dx.doi.org/10.1016/j.jtbi.2014.08.015 0022-5193/& 2014 Elsevier Ltd. All rights reserved.
A puzzling question is what makes the prevalence of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) mutations
V. Borzan et al. / Journal of Theoretical Biology 363 (2014) 164–168
so common among Europeans, particularly in people from northern Europe (estimated mutation incidences are 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark (Wennberg and Kucinskas, 1994)). Besides that, the highest disease incidence was reported in Italy, France, Switzerland, British Isles, Germany and Greece (Bobadilla et al., 2002). It is puzzling that Saamis and Finnish have the lowest rates in Europe (Wennberg and Kucinskas, 1994), while the highest incidences have been found in some disparate locations such as Ireland, Romania, Slovakia and Bulgaria (Farrell, 2008). Although the geographical distribution of the disease is key to judge the suitability of any hypothesis aiming to explain its etiology, in the described setting of CFTR mutations, the overall information is blurred by continuous human migrations during the last 50 ky. The situation became even more complex during the Neolithic period when improved climates opened new routes for animal migration (Pinhasi et al., 2012) thus forcing hunter-gatherers to cover new and longer distances that helped gene spreading. An early interpretation of high prevalence of CFTR mutations in Caucasian population was that it had resulted from a fertility advantage in CF carriers. Despite early small supportive studies, this hypothesis was not supported by data of 143 grandparent couples of Utah CF patients compared with 20 replicate sets of matched control couples from the Utah Genealogical Database (Jorde and Lathrop, 1988). More recently, the same idea of increased fertility was tested in the Hutterites of South Dakota, a genetic isolate with a relatively high CF carrier frequency (M1101K and F508 mutations) (Gallego Romero and Ober, 2008). Again, with no evidence of nonrandom transmission of mutations, skewed sex ratios in children of carrier parents or of altered overall fertility of carriers. These data clearly suggest that other, fertility unrelated mechanisms are more likely to be responsible for the prevalence of CF related genes. Other possible advantages of being a CFTR mutation carrier include improved resistance to cholera toxin and other diarrhea disorders, including lactose intolerance (Modiano et al., 2007). Besides that, the heterozygotes seem to have better resistance to typhoid fever (Pier et al., 1998). Another interesting proposition is that the distribution of CF genes results from the development of the cattle pastoralism in the recent Neolithic period (Alfonso-Sánchez et al., 2010). These combined seasonal migrations of men and their cattle helped spreading of infectious disease that imposed a new survival pressure favoring certain traits, possibly even the CF related genes in heterozygote individuals. These authors propose that an increased resistance to the diseases caused by pathogens transmitted by dairy cattle would have constituted a definite selective advantage. A single copy of mutated CFTR gene might provide additional resistance to chloride secreting diarrheas. This attractive interpretation is based on similar distributions of the lactase persistence and of the most common CF mutation (Delta F508). An even more complex physiological interpretation of CFTR spreading, is proposed by Lubinsky (2012) and, involves the question of resistance to tuberculosis (Poolman and Galvani, 2007; Williams, 2006). The core idea is that complex interaction between climate, pathogens and human physiology can explain the CFTR mutation carrier distribution. The climate factors that are considered are temperature, latitude and altitude, the probable pathogen is tuberculosis while the physiological mechanisms involve vitamin D availability and arterial hypertension. The basic idea is that altered Cl transport suppresses tuberculosis and alleviates the risk of hypertension caused by salt ingestion. On the other hand, low vitamin D availability, due to scarce sun exposure, increases the chances for tuberculosis and hypertension. This vitamin D and CFTR mutation link is based on the distribution of CF mutations with a high incidence among people from northern latitudes with low
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vitamin D food levels and low insolation, except among Inuits on the vitamin D reach sea food diet. On the other hand, cold climate, high altitude and vitamin D deficiency can all increase risk of arterial hypertension that becomes a very strong selective pressure during pregnancy. Thus, the heterozygote individuals for the CF mutation might have been more resistant to hypertension in this setting due to increased salt losses. This complex interpretation seems plausible and in concordance with a large part of epidemiological data. The idea that CFTR mutations have something to do with seemingly unrelated physiological mechanisms (vitamin D deficiency, hypertension etc.) is in several ways related to interpretation presented here that spreading of CFTR mutations might have been an adaptation to survival pressures in continental Eurasia. The other important piece of evidence is the estimate that the most common CF linked mutation is possibly no more than 52 ky old (Wiuf, 2001), clearly suggesting that any paleophysiological explanation of this rapid spreading of CFTR mutations needs to be focused on the last 50 ky of European climate and its impact on human health.
2. The climate setting in Europe during last 50 ky A large part of the last 50 ky was much colder in Europe than the present climate (Spielhagen et al., 2004). The coldest period was the Last Glacial Maximum (LGM) (26.5 to 19 kya), when the global climate was cold and dry with a dust-laden atmosphere. Reported levels of dust in ice cores were 20 to 25 times greater than the present dust levels (Lambert et al., 2012; Kohfeld and Harrison, 2001; Claquin et al., 2003). This increased dust exposure started more than 40 kya and ended less than 10 kya. Probable causes for this long lasting dustiness include glacial erosion, scarce vegetation, aridity with little precipitation and strong winds. This heavy dust exposure lasting for thousands of years has formed the European loess ridges aligned with the prevailing winds during the last glacial period (Haase et al., 2007; Frechen et al., 2003). Estimated periods of atmospheric dust lasted from 360 to 340 kya, 270 to 255 kya, 170 to 130 kya, 80 to 60 and finally 40 to 10 kya. Some of them coincide with migrations of the Neanderthals and H. sapiens out of Africa, suggesting that the harsh climate with reduced daily light might have been important for in making our ancestors migrate. The most convincing link between human locomotion, sun exposure, pregnancy and nakedness of our ancestors was proposed by Jablonski and Chaplin (2000, 2010). They have postulated that skin pigmentation possibly increased after our African ancestors have lost their body hair. This new dark skin protected folate in the blood stream from harmful African UV exposure that was particularly important during pregnancy. Pale skin was then interpreted as a later adaptation to reduced sun exposure when our ancestors moved to continental Eurasia. Insufficient vitamin D formation in the skin due to northern latitudes might compromise bone growth and locomotion of young adults. Noting that sustained exposure to atmospheric dust might have been the decisive factor in adapting both skin pigmentation and respiratory function to this harsh climate is important. During long periods of drought, drinkable water sources were scarce and the lack of water might have forced our ancestors to follow animals from the Eurasian coast to the central continent, near the south edge of the belt of glaciers. The lack of sea food and exposure to dim light in dusty atmosphere might have resulted in a strong pressure toward lighter skin pigmentation, eventually leading to the Caucasian phenotype. This possible link between sun exposure and hominid evolution is supported by new evidences that skin pigmentation genes in our genome came from the Neanderthals (Sankararaman et al.,
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2014; Vernot and Akey, 2014). These hominids have survived more than 400 ky years in Eurasia and it seems probably that during that long period Neanderthals might have developed thicker, and possibly less pigmented skin, thus making vitamin D availability essential for their mobility.
3. Normal respiratory defense mechanisms During respiration, the outside air enters the mouth or nose, passes through the pharynx into the trachea, bronchi and bronchioles, until the inhaled air reaches alveoli. Alongside the gas traffic that happens in alveoli, the exhaled air is warmed to the body temperature and saturated with water vapor (Barrett et al., 2012). Air conditioning along airways makes the inhaled cold and dry air warm and humid in alveoli. While exhaling, some warmth is recuperated by mucosa, but the humidity is lost, particularly if the surrounding air is dry. Dust protection in airways is active and all solid particles from the inhaled air easily stick to the layer of mucus secreted by goblet cells in respiratory ducts. The epithelial cells have mobile cilia that continuously move the mucus layer toward the oropharynx (Barrett et al., 2012). This movement of mucus depends on the fluid secreted by epithelial cells. All these components are fine tuned to provide an efficacious system for airway cleansing, able to resist even heavy cigarette smoking. Sufficient water content in the mucus layer is even more important if dust particles are abundant. The last lines of defense are macrophages that engulf bacteria and other inhaled particles. 3.1. Ion and fluid traffic in respiratory ductal cells Ion traffic in epithelial ductal cells is important for the maintenance of ductal cleansing, since the transepithelial potential in the respiratory tract is among the diagnostic tests for cystic fibrosis. In CF patients, this potential is of increased negativity, suggesting that the altered apical membrane potential of ductal cells is caused by dysfunctional CFTR channels (Rosenstein and Zeitlin, 1998). A description of the apical ductal cell permeability, presented here, is based on several assumptions: Membrane ion traffic is governed by electric fields, concentration gradients and the ion specific membrane permeability. All cell membranes act as diffusion bottlenecks and if ions accumulate near the membrane, their electric charges alter diffusion of other ions (Wright, 2004; Ding et al., 2014). If a membrane allows only one ion to diffuse along its concentration gradient, the diffusion will continue until the membrane reaches the Nernst value for that ion. Further ion traffic depends on Brownian kinetic that washes away ions adjacent to the membrane, suggesting importance of body temperature. Cell membranes are permeable to more than one ion and the actual membrane potential can be calculated by the Goldman equation (http://www.nernstgoldman.physiology.arizona.edu/). Cells permeable to potassium (K þ ) and chloride (Cl ) ions normally have membrane potential somewhere between the respective Nernst values for these ions (Kurbel, 2011). An example: the resting potential in neurons is near the potassium Nernst potential and further traffic of K þ is opposed by a strong electric force. Traffic of ions across the membrane becomes intensive only during the action potential due to increased permeability to sodium ions. The momentary altered membrane potential (between the sodium and potassium Nernst values)
allows both ions to follow their concentration gradients since none of them is fully opposed by the electric force. The apical membranes of ductal epithelial cells face the ductal lumen. Due to the presence of the epithelial sodium channels (EnaC), the membrane is permeable for Na þ ions. Activation of CFTRs by cAMP (Gadsby et al., 2006) makes the apical membrane also permeable to chloride. This means that the actual apical potentials in ductal cells depend mainly on Na þ and Cl entering the cell along their concentration gradients. Since these two ions, due to their opposed charges, have very different Nernst values in all membranes, the expected intermediary apical membrane potential (between the sodium and the chloride Nernst value) allows both ions to enter these epithelial cells. This influx of sodium and chloride ions makes the transepithelial potential (measured between the lining of respiratory ducts and extraductal interstitial potential) negative. Chloride ions that enter through activated CFTRs maintain an intermediary apical membrane potential that allows rapid absorption of both ions from the ductal fluid. Without the chloride influx, the apical membrane potential would become close to the sodium Nernst potential and thus the sodium influx would be diminished. In this way, cAMP activation of CFTRs modulates the salt reabsorption by ductal cells. Due to osmosis, water follows salt and intraductal fluid can be reabsorbed with little residues. Epithelial cells in exocrine glands of patients with cystic fibrosis are in a specific situation. Their apical membranes cannot modulate the Cl permeability via CFTRs and only the small potassium permeability keeps the membrane potentials from reaching the sodium Nernst value that would diminish further influx of sodium ions. This means that much more salt (NaCl) is left in the ductal fluid. Due to osmotic forces, some intraductal water remains trapped in sodium reach residues and this reduced salt and water transport leaves more of the ductal fluid unabsorbed. When the apical membrane potential is compared with the potential of the submucosal interstitial fluid, abnormally increased negativity of their apical membrane potential is expected. Due to low chloride influx through the apical membrane, its potential is close to the sodium Nernst potential (the inner membrane side is positive, so the outer side of the apical membrane is negative). Basolateral membranes are positive on the outer side in healthy individuals and in CF patients. This means that in CF patients, when compared with healthy individuals, the intraductal potential is expected to be more negative in comparison to the basolateral potential that equals the interstitial fluid potential. This difference of potential is measured as increased intraductal negativity. 3.2. Physiological balance of water in respiratory mucus Respiratory mucosa has a unique exposure to a bidirectional air flow that leads to excessive evaporation. It is estimated that in a normal adult, the daily insensible water loss is close to 400 ml of pure water. Nearly one half is lost through water evaporation from the respiratory airways (Barrett et al., 2012). Air is saturated with water vapor during inspiration, so dry outside air evaporates fluid secreted in airways. The pure water evaporation leaves residues on the ductal lining and only quick absorption of sodium and chloride ions via combined actions of ENaCs and CFTRs can prevent the accumulation of hypertonic residues inside airways. One liter of initially isotonic mucosal fluid contains close to nine grams of NaCl. If in CF patients this sodium and chloride absorption is compromised due to altered membrane potential, some secreted salt remains on the mucosal surface as a part of the hypertonic ductal content. This salty, thick, semiliquid microenvironment is
V. Borzan et al. / Journal of Theoretical Biology 363 (2014) 164–168
prone to infection and biofilm formation by respiratory bacteria (Goldman et al., 1997). It can be argued that the volume of water in respiratory mucus (V H2 O ), at anytime, depends on these relations: V H2 O ¼ SH2 O RH2 O EH2 O SH2 O ICF volume CFTR ENaC V air EH2 O Humidityair RH2 O
where SH2 O stands for the secretion of water, RH2 O water reabsorption by ductal cells and EH2 O for water evaporation by the dry air entering airways. It is presumed here that the secretion rate depends on the submucosal tissue hydration (ICFvolume) and reabsorption depends on activation of CFTRs that allow ENaCs to absorb salt and water through the apical membrane. The water loss by evaporation depends on the air flow rate and dryness of the inhaled air (Vair and Huminidityair in the previous formulas). We can try to quantify this topic by using the reference data (http://www.engineeringtoolbox.com/index.html): One cubic meter of dry air at a normal pressure has a mass of 1.293 kg at 0 1C and 1.127 kg at 40 1C. Outside air: If the air has only 10% of relative humidity, at 1 1C, one cubic meter contains only 0.517 g of water vapor. Exhaled air: If the air has 90% of relative humidity, at 32 1C, one cubic meter contains only 30.65 g of water vapor. Conditioning of the described outside air evaporates near 27 ml/m3: During moderate exercise, respiration of 40 l/min evaporates 1.1 ml/min of water from the alveoli and airways to the exhaled air. If the outside air has an average temperature just above 0 1C with less than 30% of relative humidity, the airways have to heat the inspired air to the body temperature. Heating the air from 0 1C to 35 or 37 1C does not change the moisture content, but the saturation pressure increases, making the relative humidity very low. This forces even more water evaporation from airways. The whole water traffic in respiratory mucosa is outlined in Table 1. The evaporation makes mucosal fluid lightly hypertonic, and this draws more water and some electrolytes from the mucosal interstitial fluid. The salt accumulation in the mucus is prevented by reabsorption of Na þ and Cl by epithelial cells in the presence of functional CFTRs.
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If one gene for CFTR is mutated, the number of functional CFTRs is reduced and this limits the capacity of salt reabsorption by epithelial cells. This means that evaporation makes the airway fluid more hypertonic, and osmotic forces bring more water from the interstitial space, thus leading to a new balance in mucosal fluid traffic. Increased osmolarity and volume of airway fluid can be more moveable in cases when evaporation and dust exposure is increased. If both CFTR genes are mutated, low number of functional CFTRs diminishes salt resorption of epithelial cells. Salt accumulated in the mucous fluid within respiratory ducts, as previously described. The hypertonic ductal content forces more water and some electrolytes to enter the airway fluid from the interstitial fluid, and evaporation leads to further concentration of thick immobile mucus.
4. Possible respiratory advantages of CFTR mutations in heterozygotes Our ancestors survived the last glacial period in the small Mediterranean areas. For almost 40 ky they had to adapt to some unique climate settings of cold, dry and dusty air that compromised their respiratory function. Since our ancestors had difficulties while breathing cold, dry and dusty air, any adaptation that would help maintain the mucosal integrity of airways and clearance of inhaled particles might be advantageous in surviving these harsh conditions. Previously described constraints of our respiratory physiology are inherited from our ancestors that started to spread to the central and north Europe several ky after the LGM. When they roamed into the recently defrosted areas, physical challenges were extreme requiring frequent periods of high respiratory rates, leading to water loss. If the drinking water availability was limited, while insensible water evaporation increased, the only compensation could have been obtained through limitation of water absorption in airways by a reduced number of functional CFTRs. This would offer more water for evaporation, so the mucous layer would longer remain moveable and thus the respiratory mucosa would be protected from drying. The importance of these events is exaggerated by the sustained dust exposure, potentially leading to some form of pneumoconiosis in weaker adapted individuals. Although the occurrence of mutations that inactivate CFTRs is detrimental for homozygote individuals, the heterozygotes can benefit from the limited water resorption in respiratory mucosa. If this meant fewer respiratory problems despite ubiquitous air pollution, the spreading of the mutated genes was inevitable.
Table 1 Here proposed interpretation of the respiratory mucosa function in individuals without the CF related mutations, in heterozygotes with one mutated gene and in CF patients with two mutated genes (ANS stands for the Autonomic nervous system). The heterozygote setting is better adapted to breathing arid air, particularly if it is cold (due reduced relative humidity during air conditioning) and if dust is inhaled (due to enhanced mucus mobility). Features of the mucus homeostasis
Both CFTR genes (healthy)
One mutant CFTR gene (heterozygote setting)
Fluid secretion
Stable, modulated by ANS that changes local perfusion Proportional to the physical activity Modulated by ANS to suit the evaporation rate Slightly above normal osmolarity
Increased due to hyperosmolar fluid caused by limited salt resorption
Depends on mucosal perfusion and mucosal fluid osmolarity Fluid evaporation Depends on the air flow rate and humidity Salt resorption by Depends on activation of CFTRs epithelial cells Fluid osmolarity Balance between evaporation and sat resorption Inhaling air
Arid Humid
Maximum capacity is limited despite ANS modulation Moderately hypertonic during physical exercise due to increased evaporation
Both CFTR genes mutated (CF patient)
Diminished resorption capacity due to low Cl conductance Hypertonic due to salt accumulation in the mucosal fluid Increased evaporation partially Increased evaporation compensated by ANS CF symptoms compensated by ANS and limited salt reabsorption Air conditioning regulated by Increased presence of mucous fluid due to ANS limited salt reabsorption
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Competing interests section The authors declare that they have no competing interests regarding this paper. Acknowledgment This theoretic paper was financed through grant 219-21923822426 from Croatian Ministry of Science, Education and Sport. References Alfonso-Sánchez, M.A., Pérez-Miranda, A.M., García-Obregón, S., Pena, J.A., 2010. An evolutionary approach to the high frequency of the Delta F508 CFTR mutation in European populations. Med. Hypotheses 74 (6), 989–992 (Jun). Barrett, K.E., Barman, S.M., Boitano, S., Brooks, H.L., 2012. Ganong’s Review of Medical Physiology, (Lange Basic Science), 24th ed. McGraw-Hill Medical. Bobadilla, J.L., Macek Jr, M., Fine, J.P., Farrell, P.M., 2002. Cystic fibrosis: a worldwide analysis of CFTR mutations—correlation with incidence data and application to screening. Hum. Mutat. 19 (6), 575–606 (Jun). Claquin, T., Roelandt, C., Kohfeld, K., Harrison, S., Tegen, I., Prentice, I., et al., 2003. Radiative forcing of climate by ice-age atmospheric dust. Clim. Dyn. 20 (2–3), 193–202. Ding, Q., Hu, Y., Xu, S., Wang, J., Jin, L., 2014. Neanderthal introgression at chromosome 3p21.31 was under positive natural selection in East Asians. Mol. Biol. Evol. 31 (3), 683–695 (Mar). Farrell, P.M., 2008. The prevalence of cystic fibrosis in the European Union. J. Cyst. Fibros. 7 (5), 450–453 (Sep). Frechen, M., Oches, E.A., Kohfeld, K.E., 2003. Loess in Europe—mass accumulation rates during the Last Glacial Period. Quat. Sci. Rev. 22 (18–19), 1835–1857. Gadsby, D.C., Vergani, P., Csanády, L., 2006. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440 (7083), 477–483. Gallego Romero, I., Ober, C., 2008. CFTR mutations and reproductive outcomes in a population isolate. Hum Genet. 122 (6), 583–588 (Jan). Goldman, M.J., Anderson, G.M., Stolzenberg, E.D., Kari, U.P., Zasloff, M., Wilson, J.M., 1997. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88, 553–560. Haase, D., Fink, J., Haase, G., Ruske, R., Pécsi, M., Richter, H., Altermann, M., Jäger, K.-D., 2007. Loess in Europe—its spatial distribution based on a European Loess Map, scale 1:2,500,000. Quat. Sci. Rev. 26 (9–10), 1301–1312. Jablonski, N.G., Chaplin, G., 2000. The evolution of human skin coloration. J. Hum. Evol. 39 (1), 57–106 (Jul).
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Contents lists available at ScienceDirect
Journal of Theoretical Biology journal homepage: www.elsevier.com/locate/yjtbi
Hypothesis: Possible respiratory advantages for heterozygote carriers of cystic fibrosis linked mutations during dusty climate of last glaciation Vladimir Borzan a, Boris Tomašević b, Sven Kurbel c,n a
Osijek University Hospital, Dept. of Internal Medicine, Osijek, Croatia Zagreb University Hospital, Dept. of Anesthesiology, Zagreb, Croatia c Osijek Medical Faculty, Dept. of Physiology, Osijek, Croatia b
H I G H L I G H T S
Airway fluid is lost through evaporation, particularly when breathing cold and arid air. Fluid reabsorption depends on active CFTRs that allow ENaCs to absorb salt and water. The cystic fibrosis (CF) mutation is common in north Europe and probably near 52 ky old. Between 50 and 10 kya, the European climate was arid, cold, with a dust-laden atmosphere. Individuals with one CF mutation due to slower fluid reabsorption might have better clearance of inhailed dust.
art ic l e i nf o
a b s t r a c t
Article history: Received 2 January 2014 Received in revised form 4 August 2014 Accepted 9 August 2014 Available online 21 August 2014
This paper puts forward a new hypothesis to interpret the high carrier frequency of CFTR mutations in individuals of European descent. The proposed heterozygote advantage factor is related to the specific climate conditions in Europe during the last 50 ky that might have heavily compromised the respiratory function of our ancestors in Eurasia. A large part of the last 50 ky was cold, and the coldest period was the Last Glacial Maximum (LGM) (26.5 to 19 kya). The global climate was dry with a dust-laden atmosphere (20 to 25 times more dust than the present level). High levels of atmospheric dust started more than 40 kya and ended less than 10 kya. Secretion of airway fluid is usually related to the submucosal tissue hydration, while salt reabsorption relies on activation of CFTRs that allow ENaCs to absorb salt and water. The water loss by evaporation depends on the air humidity and flow rate. Salt accumulation in the mucus is normally prevented by reabsorption of Na þ and Cl by epithelial cells if the presence of functional CFTRs is normal. If one gene for CFTR is mutated, the number of functional CFTRs is reduced and this limits the capacity of salt reabsorption by epithelial cells. This means that evaporation makes the airway fluid more hypertonic, and osmotic forces bring more water from the interstitial space, thus leading to a new balance in mucosal fluid traffic. Increased osmolarity and volume of airway fluid can be more moveable in cases when evaporation and dust exposure is increased. If both CFTR genes are mutated, low number of functional CFTRs diminishes salt resorption of epithelial cells. Salt accumulated in the mucous fluid within respiratory ducts, as previously described. The hypertonic ductal content forces more water and some electrolytes to enter the airway fluid from the interstitial fluid, and evaporation leads to further concentration of thick immobile mucus. The proposed interpretation is that CFTR mutations have spread among our ancestors that roamed the central Eurasia after the LGM. The heterozygote individuals might have benefitted from the limited water resorption in their respiratory mucosa that allowed improved airway cleansing. & 2014 Elsevier Ltd. All rights reserved.
Keywords: ENaC function CFTR function Mucus transport Membrane potential Airways
1. Introduction n
Corresponding author to: Osijek Medical Faculty, J Huttlera 4, 31000 Osijek, Croatia. Tel.: þ 385 31 512800; fax: þ 385 31 512833. E-mail address: [email protected] (S. Kurbel). http://dx.doi.org/10.1016/j.jtbi.2014.08.015 0022-5193/& 2014 Elsevier Ltd. All rights reserved.
A puzzling question is what makes the prevalence of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) mutations
V. Borzan et al. / Journal of Theoretical Biology 363 (2014) 164–168
so common among Europeans, particularly in people from northern Europe (estimated mutation incidences are 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark (Wennberg and Kucinskas, 1994)). Besides that, the highest disease incidence was reported in Italy, France, Switzerland, British Isles, Germany and Greece (Bobadilla et al., 2002). It is puzzling that Saamis and Finnish have the lowest rates in Europe (Wennberg and Kucinskas, 1994), while the highest incidences have been found in some disparate locations such as Ireland, Romania, Slovakia and Bulgaria (Farrell, 2008). Although the geographical distribution of the disease is key to judge the suitability of any hypothesis aiming to explain its etiology, in the described setting of CFTR mutations, the overall information is blurred by continuous human migrations during the last 50 ky. The situation became even more complex during the Neolithic period when improved climates opened new routes for animal migration (Pinhasi et al., 2012) thus forcing hunter-gatherers to cover new and longer distances that helped gene spreading. An early interpretation of high prevalence of CFTR mutations in Caucasian population was that it had resulted from a fertility advantage in CF carriers. Despite early small supportive studies, this hypothesis was not supported by data of 143 grandparent couples of Utah CF patients compared with 20 replicate sets of matched control couples from the Utah Genealogical Database (Jorde and Lathrop, 1988). More recently, the same idea of increased fertility was tested in the Hutterites of South Dakota, a genetic isolate with a relatively high CF carrier frequency (M1101K and F508 mutations) (Gallego Romero and Ober, 2008). Again, with no evidence of nonrandom transmission of mutations, skewed sex ratios in children of carrier parents or of altered overall fertility of carriers. These data clearly suggest that other, fertility unrelated mechanisms are more likely to be responsible for the prevalence of CF related genes. Other possible advantages of being a CFTR mutation carrier include improved resistance to cholera toxin and other diarrhea disorders, including lactose intolerance (Modiano et al., 2007). Besides that, the heterozygotes seem to have better resistance to typhoid fever (Pier et al., 1998). Another interesting proposition is that the distribution of CF genes results from the development of the cattle pastoralism in the recent Neolithic period (Alfonso-Sánchez et al., 2010). These combined seasonal migrations of men and their cattle helped spreading of infectious disease that imposed a new survival pressure favoring certain traits, possibly even the CF related genes in heterozygote individuals. These authors propose that an increased resistance to the diseases caused by pathogens transmitted by dairy cattle would have constituted a definite selective advantage. A single copy of mutated CFTR gene might provide additional resistance to chloride secreting diarrheas. This attractive interpretation is based on similar distributions of the lactase persistence and of the most common CF mutation (Delta F508). An even more complex physiological interpretation of CFTR spreading, is proposed by Lubinsky (2012) and, involves the question of resistance to tuberculosis (Poolman and Galvani, 2007; Williams, 2006). The core idea is that complex interaction between climate, pathogens and human physiology can explain the CFTR mutation carrier distribution. The climate factors that are considered are temperature, latitude and altitude, the probable pathogen is tuberculosis while the physiological mechanisms involve vitamin D availability and arterial hypertension. The basic idea is that altered Cl transport suppresses tuberculosis and alleviates the risk of hypertension caused by salt ingestion. On the other hand, low vitamin D availability, due to scarce sun exposure, increases the chances for tuberculosis and hypertension. This vitamin D and CFTR mutation link is based on the distribution of CF mutations with a high incidence among people from northern latitudes with low
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vitamin D food levels and low insolation, except among Inuits on the vitamin D reach sea food diet. On the other hand, cold climate, high altitude and vitamin D deficiency can all increase risk of arterial hypertension that becomes a very strong selective pressure during pregnancy. Thus, the heterozygote individuals for the CF mutation might have been more resistant to hypertension in this setting due to increased salt losses. This complex interpretation seems plausible and in concordance with a large part of epidemiological data. The idea that CFTR mutations have something to do with seemingly unrelated physiological mechanisms (vitamin D deficiency, hypertension etc.) is in several ways related to interpretation presented here that spreading of CFTR mutations might have been an adaptation to survival pressures in continental Eurasia. The other important piece of evidence is the estimate that the most common CF linked mutation is possibly no more than 52 ky old (Wiuf, 2001), clearly suggesting that any paleophysiological explanation of this rapid spreading of CFTR mutations needs to be focused on the last 50 ky of European climate and its impact on human health.
2. The climate setting in Europe during last 50 ky A large part of the last 50 ky was much colder in Europe than the present climate (Spielhagen et al., 2004). The coldest period was the Last Glacial Maximum (LGM) (26.5 to 19 kya), when the global climate was cold and dry with a dust-laden atmosphere. Reported levels of dust in ice cores were 20 to 25 times greater than the present dust levels (Lambert et al., 2012; Kohfeld and Harrison, 2001; Claquin et al., 2003). This increased dust exposure started more than 40 kya and ended less than 10 kya. Probable causes for this long lasting dustiness include glacial erosion, scarce vegetation, aridity with little precipitation and strong winds. This heavy dust exposure lasting for thousands of years has formed the European loess ridges aligned with the prevailing winds during the last glacial period (Haase et al., 2007; Frechen et al., 2003). Estimated periods of atmospheric dust lasted from 360 to 340 kya, 270 to 255 kya, 170 to 130 kya, 80 to 60 and finally 40 to 10 kya. Some of them coincide with migrations of the Neanderthals and H. sapiens out of Africa, suggesting that the harsh climate with reduced daily light might have been important for in making our ancestors migrate. The most convincing link between human locomotion, sun exposure, pregnancy and nakedness of our ancestors was proposed by Jablonski and Chaplin (2000, 2010). They have postulated that skin pigmentation possibly increased after our African ancestors have lost their body hair. This new dark skin protected folate in the blood stream from harmful African UV exposure that was particularly important during pregnancy. Pale skin was then interpreted as a later adaptation to reduced sun exposure when our ancestors moved to continental Eurasia. Insufficient vitamin D formation in the skin due to northern latitudes might compromise bone growth and locomotion of young adults. Noting that sustained exposure to atmospheric dust might have been the decisive factor in adapting both skin pigmentation and respiratory function to this harsh climate is important. During long periods of drought, drinkable water sources were scarce and the lack of water might have forced our ancestors to follow animals from the Eurasian coast to the central continent, near the south edge of the belt of glaciers. The lack of sea food and exposure to dim light in dusty atmosphere might have resulted in a strong pressure toward lighter skin pigmentation, eventually leading to the Caucasian phenotype. This possible link between sun exposure and hominid evolution is supported by new evidences that skin pigmentation genes in our genome came from the Neanderthals (Sankararaman et al.,
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2014; Vernot and Akey, 2014). These hominids have survived more than 400 ky years in Eurasia and it seems probably that during that long period Neanderthals might have developed thicker, and possibly less pigmented skin, thus making vitamin D availability essential for their mobility.
3. Normal respiratory defense mechanisms During respiration, the outside air enters the mouth or nose, passes through the pharynx into the trachea, bronchi and bronchioles, until the inhaled air reaches alveoli. Alongside the gas traffic that happens in alveoli, the exhaled air is warmed to the body temperature and saturated with water vapor (Barrett et al., 2012). Air conditioning along airways makes the inhaled cold and dry air warm and humid in alveoli. While exhaling, some warmth is recuperated by mucosa, but the humidity is lost, particularly if the surrounding air is dry. Dust protection in airways is active and all solid particles from the inhaled air easily stick to the layer of mucus secreted by goblet cells in respiratory ducts. The epithelial cells have mobile cilia that continuously move the mucus layer toward the oropharynx (Barrett et al., 2012). This movement of mucus depends on the fluid secreted by epithelial cells. All these components are fine tuned to provide an efficacious system for airway cleansing, able to resist even heavy cigarette smoking. Sufficient water content in the mucus layer is even more important if dust particles are abundant. The last lines of defense are macrophages that engulf bacteria and other inhaled particles. 3.1. Ion and fluid traffic in respiratory ductal cells Ion traffic in epithelial ductal cells is important for the maintenance of ductal cleansing, since the transepithelial potential in the respiratory tract is among the diagnostic tests for cystic fibrosis. In CF patients, this potential is of increased negativity, suggesting that the altered apical membrane potential of ductal cells is caused by dysfunctional CFTR channels (Rosenstein and Zeitlin, 1998). A description of the apical ductal cell permeability, presented here, is based on several assumptions: Membrane ion traffic is governed by electric fields, concentration gradients and the ion specific membrane permeability. All cell membranes act as diffusion bottlenecks and if ions accumulate near the membrane, their electric charges alter diffusion of other ions (Wright, 2004; Ding et al., 2014). If a membrane allows only one ion to diffuse along its concentration gradient, the diffusion will continue until the membrane reaches the Nernst value for that ion. Further ion traffic depends on Brownian kinetic that washes away ions adjacent to the membrane, suggesting importance of body temperature. Cell membranes are permeable to more than one ion and the actual membrane potential can be calculated by the Goldman equation (http://www.nernstgoldman.physiology.arizona.edu/). Cells permeable to potassium (K þ ) and chloride (Cl ) ions normally have membrane potential somewhere between the respective Nernst values for these ions (Kurbel, 2011). An example: the resting potential in neurons is near the potassium Nernst potential and further traffic of K þ is opposed by a strong electric force. Traffic of ions across the membrane becomes intensive only during the action potential due to increased permeability to sodium ions. The momentary altered membrane potential (between the sodium and potassium Nernst values)
allows both ions to follow their concentration gradients since none of them is fully opposed by the electric force. The apical membranes of ductal epithelial cells face the ductal lumen. Due to the presence of the epithelial sodium channels (EnaC), the membrane is permeable for Na þ ions. Activation of CFTRs by cAMP (Gadsby et al., 2006) makes the apical membrane also permeable to chloride. This means that the actual apical potentials in ductal cells depend mainly on Na þ and Cl entering the cell along their concentration gradients. Since these two ions, due to their opposed charges, have very different Nernst values in all membranes, the expected intermediary apical membrane potential (between the sodium and the chloride Nernst value) allows both ions to enter these epithelial cells. This influx of sodium and chloride ions makes the transepithelial potential (measured between the lining of respiratory ducts and extraductal interstitial potential) negative. Chloride ions that enter through activated CFTRs maintain an intermediary apical membrane potential that allows rapid absorption of both ions from the ductal fluid. Without the chloride influx, the apical membrane potential would become close to the sodium Nernst potential and thus the sodium influx would be diminished. In this way, cAMP activation of CFTRs modulates the salt reabsorption by ductal cells. Due to osmosis, water follows salt and intraductal fluid can be reabsorbed with little residues. Epithelial cells in exocrine glands of patients with cystic fibrosis are in a specific situation. Their apical membranes cannot modulate the Cl permeability via CFTRs and only the small potassium permeability keeps the membrane potentials from reaching the sodium Nernst value that would diminish further influx of sodium ions. This means that much more salt (NaCl) is left in the ductal fluid. Due to osmotic forces, some intraductal water remains trapped in sodium reach residues and this reduced salt and water transport leaves more of the ductal fluid unabsorbed. When the apical membrane potential is compared with the potential of the submucosal interstitial fluid, abnormally increased negativity of their apical membrane potential is expected. Due to low chloride influx through the apical membrane, its potential is close to the sodium Nernst potential (the inner membrane side is positive, so the outer side of the apical membrane is negative). Basolateral membranes are positive on the outer side in healthy individuals and in CF patients. This means that in CF patients, when compared with healthy individuals, the intraductal potential is expected to be more negative in comparison to the basolateral potential that equals the interstitial fluid potential. This difference of potential is measured as increased intraductal negativity. 3.2. Physiological balance of water in respiratory mucus Respiratory mucosa has a unique exposure to a bidirectional air flow that leads to excessive evaporation. It is estimated that in a normal adult, the daily insensible water loss is close to 400 ml of pure water. Nearly one half is lost through water evaporation from the respiratory airways (Barrett et al., 2012). Air is saturated with water vapor during inspiration, so dry outside air evaporates fluid secreted in airways. The pure water evaporation leaves residues on the ductal lining and only quick absorption of sodium and chloride ions via combined actions of ENaCs and CFTRs can prevent the accumulation of hypertonic residues inside airways. One liter of initially isotonic mucosal fluid contains close to nine grams of NaCl. If in CF patients this sodium and chloride absorption is compromised due to altered membrane potential, some secreted salt remains on the mucosal surface as a part of the hypertonic ductal content. This salty, thick, semiliquid microenvironment is
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prone to infection and biofilm formation by respiratory bacteria (Goldman et al., 1997). It can be argued that the volume of water in respiratory mucus (V H2 O ), at anytime, depends on these relations: V H2 O ¼ SH2 O RH2 O EH2 O SH2 O ICF volume CFTR ENaC V air EH2 O Humidityair RH2 O
where SH2 O stands for the secretion of water, RH2 O water reabsorption by ductal cells and EH2 O for water evaporation by the dry air entering airways. It is presumed here that the secretion rate depends on the submucosal tissue hydration (ICFvolume) and reabsorption depends on activation of CFTRs that allow ENaCs to absorb salt and water through the apical membrane. The water loss by evaporation depends on the air flow rate and dryness of the inhaled air (Vair and Huminidityair in the previous formulas). We can try to quantify this topic by using the reference data (http://www.engineeringtoolbox.com/index.html): One cubic meter of dry air at a normal pressure has a mass of 1.293 kg at 0 1C and 1.127 kg at 40 1C. Outside air: If the air has only 10% of relative humidity, at 1 1C, one cubic meter contains only 0.517 g of water vapor. Exhaled air: If the air has 90% of relative humidity, at 32 1C, one cubic meter contains only 30.65 g of water vapor. Conditioning of the described outside air evaporates near 27 ml/m3: During moderate exercise, respiration of 40 l/min evaporates 1.1 ml/min of water from the alveoli and airways to the exhaled air. If the outside air has an average temperature just above 0 1C with less than 30% of relative humidity, the airways have to heat the inspired air to the body temperature. Heating the air from 0 1C to 35 or 37 1C does not change the moisture content, but the saturation pressure increases, making the relative humidity very low. This forces even more water evaporation from airways. The whole water traffic in respiratory mucosa is outlined in Table 1. The evaporation makes mucosal fluid lightly hypertonic, and this draws more water and some electrolytes from the mucosal interstitial fluid. The salt accumulation in the mucus is prevented by reabsorption of Na þ and Cl by epithelial cells in the presence of functional CFTRs.
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If one gene for CFTR is mutated, the number of functional CFTRs is reduced and this limits the capacity of salt reabsorption by epithelial cells. This means that evaporation makes the airway fluid more hypertonic, and osmotic forces bring more water from the interstitial space, thus leading to a new balance in mucosal fluid traffic. Increased osmolarity and volume of airway fluid can be more moveable in cases when evaporation and dust exposure is increased. If both CFTR genes are mutated, low number of functional CFTRs diminishes salt resorption of epithelial cells. Salt accumulated in the mucous fluid within respiratory ducts, as previously described. The hypertonic ductal content forces more water and some electrolytes to enter the airway fluid from the interstitial fluid, and evaporation leads to further concentration of thick immobile mucus.
4. Possible respiratory advantages of CFTR mutations in heterozygotes Our ancestors survived the last glacial period in the small Mediterranean areas. For almost 40 ky they had to adapt to some unique climate settings of cold, dry and dusty air that compromised their respiratory function. Since our ancestors had difficulties while breathing cold, dry and dusty air, any adaptation that would help maintain the mucosal integrity of airways and clearance of inhaled particles might be advantageous in surviving these harsh conditions. Previously described constraints of our respiratory physiology are inherited from our ancestors that started to spread to the central and north Europe several ky after the LGM. When they roamed into the recently defrosted areas, physical challenges were extreme requiring frequent periods of high respiratory rates, leading to water loss. If the drinking water availability was limited, while insensible water evaporation increased, the only compensation could have been obtained through limitation of water absorption in airways by a reduced number of functional CFTRs. This would offer more water for evaporation, so the mucous layer would longer remain moveable and thus the respiratory mucosa would be protected from drying. The importance of these events is exaggerated by the sustained dust exposure, potentially leading to some form of pneumoconiosis in weaker adapted individuals. Although the occurrence of mutations that inactivate CFTRs is detrimental for homozygote individuals, the heterozygotes can benefit from the limited water resorption in respiratory mucosa. If this meant fewer respiratory problems despite ubiquitous air pollution, the spreading of the mutated genes was inevitable.
Table 1 Here proposed interpretation of the respiratory mucosa function in individuals without the CF related mutations, in heterozygotes with one mutated gene and in CF patients with two mutated genes (ANS stands for the Autonomic nervous system). The heterozygote setting is better adapted to breathing arid air, particularly if it is cold (due reduced relative humidity during air conditioning) and if dust is inhaled (due to enhanced mucus mobility). Features of the mucus homeostasis
Both CFTR genes (healthy)
One mutant CFTR gene (heterozygote setting)
Fluid secretion
Stable, modulated by ANS that changes local perfusion Proportional to the physical activity Modulated by ANS to suit the evaporation rate Slightly above normal osmolarity
Increased due to hyperosmolar fluid caused by limited salt resorption
Depends on mucosal perfusion and mucosal fluid osmolarity Fluid evaporation Depends on the air flow rate and humidity Salt resorption by Depends on activation of CFTRs epithelial cells Fluid osmolarity Balance between evaporation and sat resorption Inhaling air
Arid Humid
Maximum capacity is limited despite ANS modulation Moderately hypertonic during physical exercise due to increased evaporation
Both CFTR genes mutated (CF patient)
Diminished resorption capacity due to low Cl conductance Hypertonic due to salt accumulation in the mucosal fluid Increased evaporation partially Increased evaporation compensated by ANS CF symptoms compensated by ANS and limited salt reabsorption Air conditioning regulated by Increased presence of mucous fluid due to ANS limited salt reabsorption
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