Salt water and skin interactions: new lines of evidence

Abstract

In Health Resort Medicine, both balneotherapy and thalassotherapy, salt waters and their peloids, or mud products are mainly used to treat rheumatic and skin disorders. These therapeutic agents act jointly via numerous mechanical, thermal, and chemical mechanisms. In this review, we examine a new mechanism of action specific to saline waters. When topically administered, this water rich in sodium and chloride penetrates the skin where it is able to modify cellular osmotic pressure and stimulate nerve receptors in the skin via cell membrane ion channels known as “Piezo” proteins. We describe several models of cutaneous adsorption/desorption and penetration of dissolved ions in mineral waters through the skin (osmosis and cell volume mechanisms in keratinocytes) and examine the role of these resources in stimulating cutaneous nerve receptors. The actions of salt mineral waters are mediated by a mechanism conditioned by the concentration and quality of their salts involving cellular osmosis-mediated activation/inhibition of cell apoptotic or necrotic processes. In turn, this osmotic mechanism modulates the recently described mechanosensitive piezoelectric channels.

Full text

1 23
International Journal of
Biometeorology
ISSN 0020-7128
Int J Biometeorol
DOI 10.1007/s00484-018-1545-z
Salt water and skin interactions: new lines
of evidence
Jose Manuel Carbajo & Francisco
Maraver

1 23
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REVIEW PAPER
Salt water and skin interactions: new lines of evidence
Jose Manuel Carbajo
1
&Francisco Maraver
1,2
Received: 28 February 2018 /Revised: 8 April 2018 /Accepted: 10 April 2018
#ISB 2018
Abstract
In Health Resort Medicine, both balneotherapy and thalassotherapy, salt waters and their peloids, or mud products are mainly
used to treat rheumatic and skin disorders. These therapeutic agents act jointly via numerous mechanical, thermal, and chemical
mechanisms. In this review, we examine a new mechanism of action specific to saline waters. When topically administered, this
water rich in sodium and chloride penetrates the skin where it is able to modify cellular osmotic pressure and stimulate nerve
receptors in the skin via cell membrane ion channels known as BPiezo^proteins. We describe several models of cutaneous
adsorption/desorption and penetration of dissolved ions in mineral waters through the skin (osmosis and cell volume mechanisms
in keratinocytes) and examine the role of these resources in stimulating cutaneous nerve receptors. The actions of salt mineral
waters are mediated by a mechanism conditioned by the concentration and quality of their salts involving cellular osmosis-
mediated activation/inhibition of cell apoptotic or necrotic processes. In turn, this osmotic mechanism modulates the recently
described mechanosensitive piezoelectric channels.
Keywords Health resort medicine .Salt water .Skin .Spa therapy .Mud therapy .Review
Abbreviations
AVD Apoptotic volume decrease
C-TEAB C-tetraethylammonium bromide
HaCaT Adult human keratinocyte cell line
HSC Human stratum corneum
KCl Potassium chloride
K
ow
Octanol/water partition coefficient
MS Mechanosensitive
MT Mechanotransduction
NaCl Sodium chloride
NHEs Na
+
-H
+
-exchangers
NMF Natural moisturizing factor
NVI Necrotic volume increase
P
ow
Participation coefficient
QSPR Quantitative structure permeability relationships
RVD Regulatory volume decrease
RVI Regulatory volume increase
TEA Triethanolamine
TEWL Transepidermal water loss
UVR Ultraviolet radiation
Introduction
Among the core elements used in Health Resort Medicine, we
find mineral waters whose physical-chemical composition
plays a key role in their therapeutic properties (Gutenbrunner
et al. 2010; Morer et al. 2017b). The use of salt waters is
common in balneology and these waters are defined as those
with a mineral content of at least 1 g/L of dry residue consisting
of over 20% mEq/L of both chloride and sodium ions
(Maraver and Armijo 2010). Derived products such as mud
peloids are also used, and these have been defined as a
suspension/dispersion with therapeutic and/or cosmetic prop-
erties composed of a complex mixture of fine-grained geolog-
ical and/or biological materials matured in these waters
(Gomes et al. 2013; Maraver et al. 2015).
Among the numerous balneology studies and reviews ex-
amining the use of salt waters or peloids matured in these
waters, we should highlight those performed in France
(Chary-Valckenaere et al. 2018;Constantetal.1995;
Léauté-Labrèze et al. 2001), Germany (Brockow et al.
2007a,2007b; Schiener et al. 2007), Greece (Nastos 2010;
*Francisco Maraver
fmaraver@ucm.es
1
Department of Radiology, Rehabilitation and Physiotherapy, Faculty
of Medicine, Universidad Complutense de Madrid, Plaza Ramon y
Cajal, s/n, 28040 Madrid, Spain
2
Professional School of Medical Hydrology, Faculty of Medicine,
Universidad Complutense de Madrid, 28040 Madrid, Spain
International Journal of Biometeorology
https://doi.org/10.1007/s00484-018-1545-z
Author's personal copy

Spilioti et al. 2017), Hungary (Bálint et al. 2007;Benderetal.
2014;Hanzeletal.2018; Kulisch et al. 2009; Tefner et al.
2012), Iran (Mahboob et al. 2009); Israel (Halevy and
Sukenik 1998;Katzetal.2012;Matzetal.2003), Italy
(Bazzichi et al. 2013;Bellomettietal.1997a,1997b,2000,
2002,2007; Bellometti and Galzigna 1999; Capurso et al.
1999; Ciprian et al. 2013; Cozzi et al. 2007,2015;
Fioravanti et al. 2007,2011; Guidelli et al. 2012; Miraglia
Del Giudice et al. 2011; Staffieri et al. 1998; Tsoureli-Nikita
et al. 2002), Japan (Agishi et al. 2010; Nasermoaddeli and
Kagamimori 2005), Tunisia (Fazaa et al. 2014), Turkey
(Dönmez et al. 2005; Karagülle and Karagülle 2004,2015;
Karagülle et al. 2007,2017a,2017b,2018a,2018b;Kardeş
et al. 2018;Kesiktasetal.2012; Ozkurt et al. 2012;Özkuk
et al. 2017), Spain (Carretero et al. 2010), and Switzerland
(Moufarrij et al. 2014).
In thalassotherapy, sea water is used and characterized by
its high mineral content, high density, and its chemical com-
position rich in chlorides of mainly sodium besides magne-
sium, calcium, potassium, and iodine, along with marine
peloids known as limes. These applications include their ap-
plication with systematic methodic exposure to sun, total or
partial application of hot sea sand, and marine climatotherapy
(based on atmosphere, temperature, humidity, wind, air pres-
sure, etc.) (Lucchetta et al. 2007; Maraver et al. 2011;Morer
2016b). Among the studies that have examined the effects of
thalassotherapy, we should highlight those conducted in
Brazil (de Andrade et al. 2008), Bulgaria (Grozeva and
Stoicheva 2015; Kazandjieva et al. 2008), France (Bobet
1999; Duparc-Ricoux et al. 2004), Germany (Felix 1999;
Schuh 2009), Israel (Abu-Shakra et al. 2014; Codish et al.
2005; Czarnowicki et al. 2011; Elkayam et al. 1991; Flusser
et al. 2002;Halevyetal.2001;Katzetal.2012; Kopel et al.
2013;Nissenetal.1998; Sukenik et al. 1990,1992,1994,
1995,1999;Wigleretal.1995), Italy (Bonsignori 2011;
Lucchetta et al. 2007), Japan (Agishi et al. 2010), Malaysia
(MohdNanietal.2016), Russia (Rogozian et al. 2011),
Tunisia (Zijlstra et al. 2005), and Spain (Morer 2016a;
Morer et al. 2017a).
These saline water therapeutic agents have been described
to act via mechanical, thermal, and chemical mechanisms
(Bender et al. 2005; Fioravanti et al. 2011,2017; Guidelli
et al. 2012; Tenti et al. 2015).
The objective of this review was to assess a newly pro-
posed mechanism of action specific to salt waters employed
in Health Resort Medicine. When topically applied, these wa-
ters rich in Cl
−
and Na
+
act via the skin either directly or via
their mud products by modifying cell osmotic pressure, which
in turn stimulates skin nerve receptors through cell membrane
channels called BPiezos.^
To this end, we here examine models of cutaneous adsorp-
tion and desorption, dissolved ion mechanisms of penetrating
the skin (osmosis and cell volume driven mechanisms in
keratinocytes), and the behavior of salt waters as stimulators
of mechanosensitive ion channels.
Cutaneous absorption and desorption models
The human stratum corneum (HSC) is an effective barrier
against most substances, especially polar solutes such as wa-
ter, sugars, and salts (Bouwstra and Ponec 2006; Rawlings
and Harding 2004).
For skin barrier function, intercorneocyte cement is essen-
tial and is secreted by keratinocytes into intercellular spaces
during their terminal differentiation, giving rise to a Bbrick and
mortar^structure (Bouwstra et al. 2000).
Corneocytes are embedded in this intercorneal cement
which has a laminar structure, initially described by Elias
et al. (1979) and modified by Friberg and Osborne (1985),
composed of alternating hydrophilic and hydrophobic layers
which are especially capacitated to retain the organism’smois-
ture. The different types of cholesterol, ceramides, and unsat-
urated free fatty acids are responsible for this crystalline gel or
liquid crystal structure (Pappas 2009; Wertz et al. 1987).
When intact, it is practically impenetrable to ions and may
be partially or fully modified according to exogenous or en-
dogenous circumstances.
Transdermal permeation of hydrophilic solutes is usually
slow and displays various mechanisms (Kushner et al. 2007).
The main route established is through the brick and mortar
structure of the intercorneocyte cement (intercellular route),
besides absorption through pores and cutaneous follicles
(trans-appendicular route) and absorption into the interior of
corneocytes (Chen et al. 2013;Mitragotrietal.1996), or so-
called transcellular route (Mitragotri et al. 1996).
There is scarce information on hydrophilic molecules ca-
pable of crossing the stratum corneum, or on their rates of
absorption and/or desorption. However, we may reasonably
assume the absorption of hydrophilic solutes, enhanced in
specific conditions such as occlusion (Chen et al. 2006;
Tezel et al. 2003) or with the use of techniques promoting
the penetration of polar substances such as molecules that
induce cutaneous penetration (Hathout et al. 2010), electrical
fields (Kalia et al. 2004), or ultrasound (Alvarez-Román et al.
2003). In addition, we should not ignore the influence of tem-
perature and hydrostatic pressure of balneotherapy.
Small quantities of polar solutes can penetrate the HSC
in vivo (Chizmadzhev et al. 1998) and in vitro (Tang et al.
2002).
The skin permeability of various substances has been wide-
ly investigated (Mitragotri et al. 2011). Currently, the perme-
ability of more than 100 molecules has been established and
mathematical cutaneous permeability predictive models re-
main to be elucidated (Chen et al. 2013).
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Experimental studies of the skin absorption of hydrophilic
solutes have been conducted in small (Mitragotri et al. 1996)
and large (Michaels et al. 1975) molecules, and in moderately
hydrophilic (Southwell et al. 1984) and highly hydrophilic
(Anderson et al. 1988) molecules. Further studies span from
macroscopic studies that consider skin as a homogenous com-
partment (Clowes et al. 1994) to microscopy studies that con-
sider the individual cell structures of skin (Hansen et al. 2008;
Kushner et al. 2007).
Several authors have proposed mathematical models to
predict skin permeability. Among these, we should mention
the models quantitative structure permeability relationships
(QSPR) of Potts and Guy (1992) and Abraham and Martins
(2004), four pathways of Mitragotri (2003), and corneal bricks
and mortar of Wang et al. (2007) and Chen et al. (2010).
QSPR-quantitative structure-permeability
relationship
Human skin permeability data exist for over 50 hydrophilic
solutes and prediction studies of the absorption of these sol-
utes have tried to relate molecular structure to permeability.
These have been mainly statistical models fitted to experimen-
tal data (Abraham and Martins 2004).
QSPR includes simple mathematical models and mechan-
ical models that take into account the physical structure of the
corneum stratum. Most models have proved scarcely accurate
(Lian et al. 2008;Mitragotrietal.2011), though some simple
QSPR models have shown a good prediction capacity for
hydrophobic solutes while this capacity is much worse for
hydrophilic substances.
Four pathways
Mitragotri et al. (2011) considered corneocytes to be imper-
meable, and examined the skin permeability of hydrophilic
solutes through pores arising in the intercorneocyte cement.
He proposed a four pathway model, two of which were ap-
plied to lipophilic compounds (free diffusion and lateral dif-
fusion of lipids in the intercorneocyte cement) and the remain-
ing two to hydrophilic compounds (intercorneocyte pores and
shunts via skin annexes).
This model differentially includes diffusion by means of
Bshunts^through hair follicles and sweat glands, and estimates
that this contribution is practically constant due to a small
proportion of the skin surface area covered with appendages,
though it is the preferential route for hydrophilic solutes of
high molecular weight. Regarding predictions for hydrophilic
solutes, the studies of Mitragotri have provided useful results
with implications for some hydrothermal techniques
(Carretero et al. 2010; Spilioti et al. 2017).
Chen et al. (2006) also considered that corneocytes are
permeable and consequently that hydrophilic solutes are
also absorbed by HSC corneocytes via the transcellular
route. Other authors have considered other porous lipid
networks (Mitragotri et al. 2011; Potts and Francoeur
1991) related to nonspecific trans-appendicular transport
(Mitragotri et al. 2011) or have not considered this pathway
(Tezel et al. 2003).
Human stratum corneum has between 10 and 20 layers of
devitalized keratinocytes (corneocytes), elongated and
completely keratinized, embedded in a continuous intercellu-
lar lipid matrix whose goal is one of protection against the
penetration of unknown substances and the loss of body sub-
stances (Norlén 2007).
The thickness of this barrier is around 10–20 μm(Talreja
et al. 2001) and itis composed of proteins, solublesalts,water,
and the remaining of lipids. The barrier is renewed depending
on the circumstances every 8–28 days through simple detach-
ment or friction.
The HSC retains endogenous water in the skin due to the
hygroscopicity of the salts it contains both inside and out of
the cells (Polefka et al. 2012).
The amount of water present in the HSC is some 6.5 times
lower than in the basal cell layer. Thus, skin isotonicity is
achieved with a 6% aqueous solution of sodium chloride.
Accordingly, more concentrated salt solutions would lead
to water loss from corneocytes and lower salt concentra-
tions, like most mineral waters, will cause corneocyte
humidification.
The inside of the corneocyte is composed mainly of kera-
tins, water, and natural moisturizing factors (NMFs)
(Rawlings and Harding 2004). Because of their hygroscopic
nature, NMF have the role of keeping the corneocyte moist
(Nakagawa et al. 2004) and consequently they are an impor-
tant penetration route for hydrophilic solutes (Naegel et al.
2008; Nitsche et al. 2006).
Trancellular absorption has been confirmed by several
experimental lines of evidence. Thus, water enters
corneocytes very effectively (Kasting et al. 2003). The larg-
er hydrophilic molecules are found inside the corneocyte as
shown by transmission electron microscopy (Bodde et al.
1991) and two-photon excitation microscopy (Jacobi et al.
2006).
The human skin permeability of solutes can be determined
through the octanol-water partition coefficient (K
ow
), also
called the partition coefficient (P
OW
). This coefficient is the
ratio between the concentrations of the substance in a biphasic
mixture of two immiscible liquids: n-octanol and water. This
means that hydrophilic solutes have a logK
ow
<0.0,solutesof
low hydrophobia 0 ≤logK
ow
< 0.5, and hydrophobic solutes
logK
ow
≥0.5.
Skin moisturizing molecules such as butylene glycol
(logK
ow
=−0.29), glycerol (logK
ow
=−1.76), and urea
(logK
ow
=−2.11), all very hydrophilic, can promote transcel-
lular absorption (Ventura and Kasting 2017).
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Certainly, the transcellular route is an important transder-
mal permeation pathway for hydrophilic solutes and
moderately hydrophobic solutes.
Brick and mortar model
Wang et al. (2007) used the brick and mortar model to predict
the skin permeability of hydrophilic and hydrophobic solutes
through the diffusion coefficient of solutes in free water. This
model served to predict the skin permeability of hydrophobic
solutes but was unable to effectively predict the permeability
of hydrophilic solutes (Chen et al. 2010;Wangetal.2007).
Chen et al. (2010) also applied the brick and mortar model
according to the intracellular cement absorption route, the
transcellular route, and to published data of the binding capac-
ity of the different solutes to lipids, stratum corneum keratins,
and obtained accurate predictions about hydrophilic solutes
for the lipid-corneocyte interface.
Current art state and cutaneous desorption
Both the four pathway model of Mitragotri (2003) and the
brick and mortar model of Chen et al. (2010) offer the best
predictions and a similar precision for the absorption of solu-
ble solutes in water despite considering the hydrophilic path-
way in a fairly different way.
Hydrophilic solutes show low skin permeability, approxi-
mately one time lower than any hydrophobic solute. In gen-
eral, the skin permeability of hydrophilic solutes decreases as
hydrophilic behavior and molecular weight increases (Chen
et al. 2010).
Consequently, the transcellular pathway is important for
the transdermal permeation of hydrophilic solutes and may
contribute to more than 95% of the total skin permeability of
these molecules (Chen et al. 2013).
Recently, Miller et al. (2017) reported that small polar com-
pounds, whether charged or not charged, may be dispersed in
the moist HSC as if in an amount of water similar to the
tissue’s water content, and once absorbed, can be desorbed
in two phases: a rapid phase of some minutes and a slower
phase lasting several hours.
When validating this model, the authors determined
capture/desorption on HSC of radiolabeled solutes of three
inorganic salts,
22
NaCl, Na
36
Cl, and
14
C-tetraethylammonium
bromide (14C-TEAB), and a polyalcohol,
14
C-mannitol.
Desorption measurements are an adequate complementary
method to permeability measurements and give an idea of the
skin permeation of solutes. From the findings of Miller et al.
(2017) shown in Fig. 1, we can deduce that desorption rates
for water, 1-propanol, testosterone, and sucrose in the HSC are
much faster than for the other molecules. This could indicate a
greater facility of the former to cross the HSC.
Highly and moderately lipophilic compounds like testos-
terone and propanol respectively, as well as the hydrophilic
molecules water and sucrose have clear desorption profiles,
and two time constants are not needed to describe the desorp-
tion process which occurs as a single phase.
For the remaining hydrophilic molecules (Na
+
,Cl
−
,TEA
+
,
mannitol, and glycerin), the second slow desorption phase was
very parsimonious and lengthy with cycles of longer than
3.74 h.
These determinations provide evidence that HSC allows
small hydrophilic solutes access to inside the corneocytes
and show that most of the water and salts dissolved in the
hydrated HSC are found in the corneocytes.
The specific characteristics of this desorption can be pre-
dictive of the absorption capacity of the different molecules.
The rapid desorption process lacks importance for lipid com-
pounds, yet the slow desorption phase is selective of size, and
thus large molecules show a much slower desorption than
smaller molecules.
Osmosis and cell volume mechanisms
in keratinocytes
The cell plasma membrane is permeable to water and semi-
permeable to inorganic and organic solutes. To maintain their
viability, keratinocytes have semipermeable membranes sen-
sitive to external osmotic pressure. Hydration and cell volume
are regulated, adaptingto the external osmotic pressure via the
accumulation/elimination of low molecular weight inorganic
ions (Carbajo 2014) and some organic molecules called
osmolytes (Hoffmann et al. 2009).
Aqueous flow through animal cell membranes occurs by
simple diffusion, although some specialized membrane pro-
teins exist. These are transmembrane selective pores called
aquaporines, which considerable increase aqueous permeabil-
ity in cell membranes (Agre and Kozono 2003; Verkman and
Mitra 2000).
In addition, changes in volume and cell hydration represent
an essential process for life (Lang and Waldegger 1997).
Besides playing a role in cell shape and ion transport, cell
volume regulates several cell functions such as growth and
differentiation, metabolism, epithelial transport, hormone re-
lease, excitability, migration, and even cell death (Wehner
et al. 2003).
Cells respond to changes in their volume mainly through
two mechanisms. The process through which swollen cells in
hypotonic medium recover their normal volume is called reg-
ulatory volume decrease (RVD), while the opposite process
whereby they increase their volume to recover from a hyper-
tonic medium is regulatory volume increase (RVI) (Hoffmann
et al. 2009).
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Cell volume can only be regulated through the gain or loss
of osmotically active solutes. These active solutes are mainly
ions such as Na
+
,K
+
,Cl
−
, or organic osmolytes that act
through a membrane transport mechanism (Lang et al. 1998;
O'Neill 1999).
Animal cells, which have thin cytoplasmic membranes,
respond to a hypotonic environment by undergoing an acute
increase in cell volume, and them via RVD (Okada et al.
2001), losing KCl through activation of K
+
and Cl
−
channels
or activation of the K
+
/Cl
−
cotransporter (Fig. 2).
Conversely, after acute shrinkage in a hypertonic medium,
volume recovers via RVI (Hoffmann and Dunham 1995). This
process is mainly mediated by the intracellular build-up of
salts (predominantly NaCl and KCl) and by the water dragged
by these electrolytes through cellular interchange of hydrogen
with sodium (Na
+
/H
+
) and chlorides and bicarbonates (Cl
−
/HCO
3
−
) that regulate pH or through the Na
+
/K
+/
2Cl
cotransporter and Na
+
channels (Fig. 2).
These transport mechanisms through channels are rapid
and electrolyte transporters are activated from seconds to
some minutes after the cell volume modification takes place.
This activation is this fast because ion channels and
cotransporters occur on the plasma membrane or are stored
in vesicles on cytoplasmic submembranes and not only par-
ticipate in the transport of salts and water but also play a role in
controlling intracellular pH (Strange 2004).
Fig. 1 Desorption through the
skin of different substances.
Absorption/desorption
measurements made in
hydrophilic compounds on
isolated human stratum corneum
indicate that substantial amounts
of these compounds are absorbed
into the keratinocyte interior and
are desorbed very slowly,
especially mineral salts. Other
molecules that may be absorbed
through the skin show slow
overall desorption times.
Modified from Miller et al. (2017)
Fig. 2 Mechanism of the loss and
gain of solutes that occurs in
keratinocytes when they adapt to
hypo- and hypertonic
environments (Carbajo 2014)
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Sodium is the main extracellular ion and the main element
that maintains total body water volume and contributes to the
ratio of extracellular to intracellular fluid (Häussinger 1996).
It is now known that mechanotransduction (De Palma et al.
2017) and the transcription/translation of genes can also be
controlled through signaling pathways triggered by the intra-
cellular sodium/potassium ratio. Specifically, a sodium ion
increase on the endothelium is influential on the tonicity
enhancer-binding protein (TonEBP, NFAT5), which contrib-
utes to the transcriptomic changes caused by an elevated in-
take of common salt, an effect that is enhanced by an increase
in the production of endogenous Na/K-ATPase (Orlov and
Hamet 2015).
Epidermal defense against salts
Cell defense against osmotic stress takes place in two stages: a
rapid first stage involving inorganic salts, or electrolytes, and a
second slower stage in which organic osmolytes participate
that requires enzyme synthesis and the translation and tran-
scription of genetic codes in the transporters (Strange 2004).
These osmolytes are able to ensure the constant cell volume
that keratinocytes need at each level of the epidermis and thus
prevent cell metabolism alterations, even in high salt concen-
trations. These molecules have proved effective against salin-
ity, heat, dehydration, and freezing (Welch and Brown 1996),
and even against oxidative stress (Yancey et al. 1982), ultra-
violet radiation (UVR) damage (Rosette and Karin 1996), or
in wound repair processes (Değim et al. 2002).
Osmolytes do not affect cell metabolism even at high con-
centrations. Their biophysical and biochemical properties are
unique such that cells may accumulate them in large quantities
and over long time periods without modifying their structure
and functions. The build-up of organic osmolytes is mediated
both by a transport mechanism requiring external energy and
by regulation of their synthesis/destruction processes (Burg
et al. 1997; Chamberlin and Strange 1989).
The maintenance of a constant cell volume in isotonic con-
ditions, or steady state volume, is achieved through balance
between passive flow routes and the Na
+
/K
+
/ATPase pump,
otherwise known as the pump and leak mechanism (Hallows
and Knauf 1994). On this mechanism depends the cotransport
and build-up of the proteins, sugars, and amino acids needed
for cell metabolic functions. Its correct functioning maintains
the electrochemical gradient via the membrane, which is offset
by the expulsion of Na
+
and a higher osmotic pressure inside
the cell conferred by the concentration of these organic
osmolytes.
Kleinewietfeld et al. (2013) showed that increased concen-
trations of sodium chloride drastically stimulate the induction
of murine and human Th17 cells. Under these hyperosmotic
conditions, the p38/MAPK pathway involving sensitization
via interleukin 17 (IL-17) is activated, which increases the
production of CD4
+
T cells (Th17), which plays a fundamen-
tal role in autoimmune diseases. It has been shown that Th17
cells dependent on pathogenic IL-23 are essential for the de-
velopment of experimental autoimmune encephalomyelitis,
an animal model for multiple sclerosis and the genetic risk
factors associated with MS that are related to the IL23/Th17
pathway.
The skin is also a reservoir of excess Na
+
and Cl
−
in salt-
sensitive hypertension. Cells of the phagocytic mononuclear
system (MPS) are recruited into the skin, detect NaCl hyper-
tonicity as a chemotactic stimulus (Müller et al. 2013), migrate
in the direction of excess salt concentration, and activate the
tonicity enhancer-binding protein (TonEBP) to initiate the ex-
pression and secretion of vascular endothelial growth factor C
(VEGFC). These mechanisms, which favors the elimination
of electrolytes through the cutaneous lymphatic vessels, in-
creases the expression of endothelial nitric oxide synthase
(eNOS) in blood vessels (Wiig et al. 2013), suggesting that
electrolyte homeostasis in the body cannot be achieved by
renal excretion alone.
It is not clear whether this local response of the MPS to
osmotic stress is important for the systemic control of blood
pressure, but it seems that the interstitium/extracellular matrix
of the skin has a hypertonic behavior in which the MPS cells
exert their homeostatic and regulatory control. Blood pressure
through TonEBP and subsequent alteration of cutaneous lym-
phatic capillary function through VEGFC/VEGFR3. (Wiig
et al. 2018).
Necrosis and apoptosis via a mechanism of cell
volume
Cells can detect small variations in volume, even lower than
3%, through a wide array of volume sensors that respond to
the magnitude and nature of the perturbation (MacLeod
1994).
In extreme conditions, a process of cell destruction takes
place through different mechanism so that their viability is
lost.
The mechanism through which RVD occurs seems simple:
a hypotonic medium leads to the expulsion of KCl and exit of
osmolytes, mainly sorbitol, inositol, and taurine, until normal
volume is recovered. However, the different cells show a num-
ber of characteristic complex molecular mechanisms (Jakab
et al. 2002). The activation of the RVD mechanism occurs via
the expulsion of NaCl (Wright and Rees 1998). This activa-
tion could lead to a loss of plasma membrane integrity, follow-
ed by the release of enzymes and unspecific DNAdegradation
(Taimor et al. 1999).
Other studies have shown that the activation of a non-
selective cation channel sensitive to Ca
2+
by the hydroxyl
radical is involved in the necrotic death of cells with a thin
membrane (necrotic volume increase, NVI). Although this
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channel is also permeable to Na
+
,K
+
,Rb
+
,andCs
+
and im-
permeable to Ca
2+
, its activity depends on intracellular Ca
2+
concentrations (Simon et al. 2004).
Severe cell shrinkage caused by a hypertonic environment
can recover its shape through RVI and can trigger, already in
isotonic conditions, apoptotic cellular processes known as ap-
optotic volume decrease (AVD) (Okada et al. 2001).
The main defense mechanism against AVD occurs via Na
+
/H
+
exchangers (NHE) which are common in animal cells.
Their activity is mainly regulating homeostasis and cell vol-
ume, and controlling cell surface pH and ion transport
(Alexander and Grinstein 2006). It has been shown that when
AVD is induced, cytochrome C release precedes caspase-3
activation and DNA fragmentation.
Thus, NHE are essential for cell functions such as migra-
tion, vesicle trafficking, growth, proliferation, and cell death.
Cell survival is especially dependent on NHEs and their ab-
sence or abnormality leads to multiple diseases.
NHE1 are activated by RVI and inhibited by cell swelling
(Elsing et al. 2007). This constitutes a mechanism of volume
regulation of homeostasis.
Salt water and skin nerve receptors
The immediate sensation to the mechanical stimuli is mediat-
ed fundamentally by the mechanosensitive ion channels. Its
activity is based on conformational changes induced by me-
chanical forces that cause a selective membrane permeation
and subsequent electrical signaling.
Mechanosensitive ion channels are being identified at a
prodigious rate, including some traditional ones that are
assigned new functions.
The three most representative mechanosensitive channels
are the transient receptor potential channels (TPR), where the
TRPV4 is also known as the vanilloid receptor-related osmot-
ically activated channel, the voltage-dependent potassium
channel Kv1.1 (Kv), and Piezo channels.
TRPV4 is a non-selective cation channel, first described as
an osmo-sensor that detects hypotonic stimuli, and shares ap-
proximately 40% amino acid identity with TRPV1. The open-
ing of the TRPV4 channel to hypotonic stress but not to iso-
tonic stasis or hypertonic stress occurs in a few seconds to
2min.
They have been implicated in various osseous and nervous
system diseases in humans. The Kv1.1 channel can detect
mechanical stimuli and are widely expressed in the nervous
system and other tissues.Altogether, the alteration/mutation in
the Kv1 channels causes multiple human neurological dis-
eases (Gu and Gu 2014).
In 2010, a variety of skin nerve receptors were described
(Coste et al. 2010) which we feel could shed new light on
therapeutic mechanisms in Health Resort Medicine. These
noci-propioreceptors are identified by a series of functional
and anatomical characteristics of sensory neurons and also
play a key role in non-neuronal cells such as Merkel cells
and keratinocytes (Woo et al. 2015b).
Cell mechanotransduction (MT), known for decades, con-
sists of the transformation into biological signals of cell me-
chanical forces whereby mechanosensitive (MS) ion channels
play an essential role in detecting such mechanical forces.
However, their true identity was not revealed until the discov-
ery of cell membrane channels designated BPiezos^(Chalfie
2009;Kungetal.2010).
This discovery of Piezo channels as a new family of MS
ion channels has helped unveil new molecular functions that
mediate MTin mammalian touch receptors (Bagriantsev et al.
2014;Gengetal.2017;Xu2016; Zhang et al. 2017)through
the identification of the new proteins, Piezo1 and Piezo2, and
of their MS cation channels (Coste et al. 2010; Coste et al.
2012).
Piezo proteins form ion channel pores that open in response
to mechanical stimuli, allowing positive ions including calci-
um, to be taken up by the cell (Walsh et al. 2015). However, it
has not yet been confirmed that Piezo channels are only in-
duced mechanically and are not also spontaneously or chem-
ically induced (Wu et al. 2017)(Fig.3).
Piezo1 and Piezo2 are expressed in several human organs
and tissues: brain, optic nerve head, periodontal ligament, tri-
geminal ganglion, dorsal root ganglion, skin, lungs, cardiovas-
cular system, red blood cells, gastrointestinal system, kidney,
colon, bladder, and joint cartilage (Bagriantsev et al. 2014).
The importance of Piezo proteins as physiological (Murthy
et al. 2017) and pathophysiological (Murthy et al. 2017;
Ranade et al. 2015;Suchyna2017) mechanotransducers has
been stressed in a wide variety of MT processes, as shown by
the link between mutations in the human Piezo1 or Piezo2
genes and a series of genetic diseases (Ranade et al. 2015).
Mechanotransduction has important roles in somatosensation
(touch perception, pain, propioception, hearing, and lung respi-
ration), red blood cell volume regulation, the physiology of vas-
cular tone, and in muscle and tendon stretching (Nilius 2010),
and has been linked to several human genetic disorders includ-
ing abnormal embryonic development. Thus, in theory, salt wa-
ter baths could have indirect effects on internal organs or
processes.
In this line of research, it has been shown that Piezo1 af-
fects several physiological systems (Gottlieb and Sachs 2012).
Clear effects of this protein have been observed on the blood
system as a blood flow sensor (Davies 1995), in the develop-
ment of blood vessel endothelium, and in regulating blood
pressure (Li et al. 2014; Retailleau et al. 2015). Further roles
assigned to Piezo1 include modulating the red blood cell in-
dex (Cahalan et al. 2015; Faucherre et al. 2014), cell migration
(McHugh et al. 2012), and the development of epithelial cells
(Eisenhoffer et al. 2012;Gudipatyetal.2017). In addition,
Int J Biometeorol
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Piezo1 participates in MT in cartilage and chondrocytes (Lee
et al. 2014; Servin-Vences et al. 2017), in urine osmolarity
(Martins et al. 2016), in neural stem cells (Pathak et al.
2014), and acts on neurons themselves (Koser et al. 2016).
Piezo2 is an important MT channel for smooth touch sen-
sation (Ikeda et al. 2014; Maksimovic et al. 2014; Ranade
et al. 2014; Woo et al. 2014), propioception (Woo et al.
2015a), breathing volume, and pulmonary inflation
(Nonomura et al. 2017) and effects on inflammation have
been proposed (Dubin et al. 2012).
Any force that modifies cell membrane tension could in
theory activate Piezo channels (Kung et al. 2010) including
cell membrane contraction or stretching induced by osmosis.
Any stimulus affecting Piezo1 and Piezo2 activity causing
osmotic swelling, probably through increased resting mem-
brane tension, could activate ion channels (Gottlieb et al.
2012; Jia et al. 2016).
In effect, unicellular bacteria and plants and multicellular
organisms can detect and respond to both external mechanical
forces and internal ones such as osmotic pressure with the
consequence of membrane deformation (Gu and Gu 2014).
As mentioned earlier, mechanical forces have wide impacts
on cell proliferation, migration and adhesion, morphogenesis,
fluid homeostasis, and vesicle transport (Ahern et al. 2016;
Eyckmans et al. 2011; Tyler 2012).
It has been widely accepted for many years that various
mechanical stimuli can induce ion currents that cross the
plasma membrane in different cells. Many mechanically acti-
vated currents are non-selective cation channels that are per-
meable to Na
+
,K
+
,andCa
2+
among other cations (Hao and
Delmas 2010;Marotoetal.2005). These currents are
established through different ion channels in the cell mem-
brane, transforming mechanical stimuli into electrical signals
to allow cells to drive their own metabolism and communicate
with the outside environment (Lewis et al. 2017).
Piezo activity may also be regulated by other endogenous
and exogenous signals such as an acid extracellular pH. Thus,
a pH around 6.3 can trigger the inactivity of Piezo1 channels
(Bae et al. 2015).
Salt mineral water baths can have appreciable impacts on
activities driven by the nervous system added to the biochem-
ical and immune responses that have sparked a therapeutic
interest in these thermal waters (Karagülle et al. 2017a,
2018a,2018b). In any case, studies or evidences that clearly
define the role of balneotherapy on the disease and the in-
volvement of the revised mechanoreceptors are necessary.
Discussion
The thermal waters used in balneology usually have ion con-
centrations above 1 g/l and therefore behave as a hypertonic
medium for cells. The osmotic forces of sodium chloride wa-
ters play an important role in transepidermal water loss
Fig. 3 The stimulus to activate
the protein Piezo1 is tension in its
structure. The protein is really a
trimeric protein complex that
takes the form of curved blades
around a central pore crowned by
a cap or C-terminal extracellular
domain (CED). Its architecture is
such that Piezo1 is sensitive to
mechanical insult, fluid flow, and
cell membrane tension among
other factors. An overhead and a
side view of its structure are
shown. Further, graphics
mentions the release of the pore
gate (gating spring), detection of
flows (shear flow sensing), and a
possible behavior on hypotonic
and hypertonic media. Modified
from Wu et al. (2017)andMurthy
et al. (2017)
Int J Biometeorol
Author's personal copy

(TEWL), promoting the renewal capacity of skin and the re-
covery of its barrier function (van Kemenade et al. 2004). This
idea was confirmed by the observation that keratinocytes ex-
press similar sodium channels to kidney and colon epithelial
cells (Brouard et al. 1999).
In prior work, we observed using non-invasive examina-
tion techniques that the use of a mud peloid prepared with
magnesium bentonite and salt waters from the medical spa at
Cofrentes (Valencia, Spain), after 3 months of maturing, was
theoretically ideal to treat skin desquamation conditions such
as psoriasis, as blood flow is diminished and skin elasticity
and firmness improve along with dermal density, and fatigue
following repeated skin suction is reduced without affecting
skin barrier function (Carbajo et al. 2014).
The question that arises is what is responsible for this ef-
fect: the saline hypertonic medium, the magnesium bentonite,
the matured organic matter in the mud, the accompanying
microorganisms, or are we seeing the combined effect of all
of these factors?
In a report by Yoshizawa et al. (2001), it was found that
2 weeks of bathing in seawater (500 mM NaCl, 10 mM KCl)
for 20 min per day was able to improve symptoms of dryness
and itching, both in individuals with an atopic skin condition
and in those with irritant contact dermatitis caused by sodium
lauryl sulphate (SLS), which is the standard used to provoke
experimental skin irritation. Despite their improved symp-
toms, participants with atopic dermatitis, nevertheless, report-
ed a slight stinging sensation during treatment.
Theauthors(Yoshizawaetal.2003) ascribed this incon-
venience to the salt concentration and conducted a similar
experiment consisting of 2 min of immersion in three arti-
ficial salt waters and a distilled water control. Experimental
water compositions were (a) 500 mM NaCl and 10 mM de
KCl, (b) 250 mM NaCl and 10 mM KCl, and (c) 250 mM
NaCl and 50 mM de KCl. Determinations included skin
hydration by corneometry and TEWL. Results indicated
that all three compositions increased skin hydration over
the control treatment but only the (c) type water was able
to significantly reduce TEWL compared to distilled water.
The authors concluded that salt water immersion is effec-
tive to treat atopic dermatitis, though the salt water content
is a determining factor.
Wiedow et al. (1989) demonstrated that the hyperosmotic
shock of salt waters induces the release of a leukocyte elastase
capable of inhibiting irritation processes. This enzyme prop-
erty was attributed to the water’s NaCl and KCl concentrations
irrespective of calcium and magnesium chloride concentra-
tions (Levin and Maibach 2001; Yoshizawa et al. 2001).
Sasaki et al. (2017)showedthatMg
2+
plus Si
4+
powder (a
synthetic magnesium smectite) promoted skin tissue renewal
in the rat. Further, in a study by Proksch et al. (2005), the
efficacy of bathing in a salt solution rich in magnesium chlo-
ride was shown in participants with atopic dermatitis
measured in terms of improved skin barrier function, hydra-
tion of the stratum corneum, and skin roughness and
inflammation.
Finally, Kim et al. (2010) noted that a Korean marine
mudrichinmagnesiumandhumicsubstanceswasableto
inhibit inflammatory reactions in irradiated human
keratinocytes (HaCaT) by 30%, and attributed this anti-
inflammatory effect both to the minerals and organic
molecules present in the mud. Similarly, Flusser et al.
(2002) concluded that salts have to be present for this ef-
fect, though Nicoletti et al. (2015) attributed these skin re-
newal properties to the non-pathogenic bacterial popula-
tions present in the mineral waters.
Léauté-Labrèze et al. (2001) examined the capacity of
naturally saline mineral water alone and in combination
with ultraviolet B (UVB) radiation to treat psoriasis.
These authors noted that saline waters considerably influ-
ence psoriatic whitening and also showed that greatest
whitening was produced by UVB radiation, irrespective
of its association or not with the saline waters.
Gambichler et al. (2011) compared the efficiency of salt
water in transmitting UV rays in psoriatic epidermis equiv-
alents pretreated with tap water or solutions of different
sodium chloride concentrations (3-15-30%). Greater UV
radiation, both of UVA and UVB, was detected for the salt
waters, with transmission increasing with increasing salt
concentration as a factor related to enhanced skin irritation
when the skin was irradiated. In parallel, these same au-
thors addressed the influence of salt waters on human back
skin. Determination was made of the expression of antimi-
crobial peptides and proteins (AMP) found in psoriasis and
other skin inflammation conditions. No differences were
detected in cathelicidins (LL-37) and psoriasins, but the
expression of human Beta-Defensin-2 (hBD-2) and skin
antileukoproteinase (SKALP/elafin) immunoreactivity
were significantly reduced as the salt concentration
increased.
In contrast, in a study by Zöller et al. (2015)inwhich
four hypotonic mineral waters, two thermal and two min-
eral, were compared with a control, the factors assessed
were DNA proliferation and membrane cytotoxicity along
with inflammatory variables with and without UVB radia-
tion in HaCaT keratinocytes. Results indicated that both
thermal waters led to reduced interleukin-6 and oxygen
reactive species levels. This effect was attributed to the
high selenium content of one of these waters, which is a
cofactor of glutathione peroxidase. The second thermal
water, which contained low selenium levels, showed anti-
inflammatory properties thought to be associated with its
relatively high zinc concentration. Paradoxically, both
mineral waters also led to good results in terms of all the
factors assessed due to the presence of boron, an
oligoelement that acts on keratinocytes.
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Although it has been established that other mechanical
stimuli both general and localized can activate Piezo chan-
nels (Ranade et al. 2015), these are outside the scope of this
review.
In view of all these lines of evidence, it seems clear that
the topically use of salt waters and their mud products in
Health Resort Medicine, both balneotherapy and thalasso-
therapy, has yielded good outcomes essentially in the treat-
ment of rheumatic and skin disorders. Among the former
conditions treated, we should highlight osteoarthritis
(Bálintetal.2007; Bellometti et al. 1997a,1997b,2007;
Elkayam et al. 1991; Fazaa et al. 2014; Hanzel et al. 2018;
Karagülle et al. 2007;Kardeşet al. 2018; Özkuk et al. 2017;
Wigler et al. 1995), rheumatoid arthritis (Bellometti et al.
2000;Codishetal.2005; Elkayam et al. 1991; Karagülle
et al. 2017a; Karagülle et al. 2018b), back pain or spondy-
litis (Abu-Shakra et al. 2014;Constantetal.1995;Cozzi
et al. 2007; Karagülle and Karagülle 2015;Kesiktasetal.
2012; Kulisch et al. 2009;Tefneretal.2012), and fibromy-
algia (Bazzichi et al. 2013; Bellometti and Galzigna 1999;
Fioravanti et al. 2007;Guidellietal.2012;Ozkurtetal.
2012). Among the latter treated with good results, we
would underscore psoriasis (Brockow et al. 2007a,2007b;
Halevy and Sukenik 1998;Schieneretal.2007;Tsoureli-
Nikita et al. 2002).
Conclusion
The findings of this review indicate that mineral salt waters act
via a cell osmosis mechanism conditioned by the concentra-
tion and quality of their salts that is capable of activating/
inhibiting cell apoptosis and necrosis. In turn, this osmotic
mechanism participates in mechanotransduction via piezo-
electric ion channels embedded in cell membranes. Piezo pro-
teins play important cell developmental roles such as in gene
expression, and cell volume regulation, migration, prolifera-
tion, division, and adhesion. These proteins are capable of
translating mechanical forces into the biological signals that
are pivotal for a wide range of physiological processes, includ-
ing somatosensation, red blood cell volume regulation, and
blood vessel physiology.
Funding This study was funded by grant UCM-911757 awarded to the
research group of the Universidad Complutense de Madrid (Medical
Hydrology).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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