ArticlePDF Available

Effect of Avène Spring Water on the Activation of Rat Mast Cell by Substance P or Antigen

  • Centre de Recherche Pierre Fabre Toulouse

Abstract and Figures

The biological activity of Avène water from two different springs ('Sainte Odile' and 'Val d'Orb') was studied in vitro on rat peritoneal mast cell activation. A dilution-dependent inhibition of both histamine and prostaglandin D2 antigen-induced release was observed when cells were preincubated with both Avène spring waters. They also inhibited histamine release triggered by substance P. The ability of Avène water to inhibit mast cell activation in vitro may be related with its antiallergic and anti-inflammatory properties and its use in hydrotherapy.
Content may be subject to copyright.
Original Research Article
Skin Pharmacol Appl Skin Physiol 1998;11:111–116
Effect of Avène Spring Water on the
Activation of Rat Mast Cell by
Substance P or Antigen
F. Joly
M. Charveron
M.F. Ariès
J. Bidault
L. Kahhak
F. Beauvais
Y. Gall
SEPhRA (Société d’Etudes en
Pharmacologie: Recherche,
Applications), Paris;
Institut de Recherche
Pierre-Fabre, Faculté de Médecine
de Rangueil, Toulouse, and
CNRS URA 1159,
Les Plessis Robinson, France
Key Words
Peritoneal mast cell
Avène spring water
Substance P
Prostaglandin D
The biological activity of Avène water from two different
springs (‘Sainte Odile’ and ‘Val d’Orb’) was studied in vitro on
rat peritoneal mast cell activation. A dilution-dependent inhi-
bition of both histamine and prostaglandin D
induced release was observed when cells were preincubated
with both Avène spring waters. They also inhibited histamine
release triggered by substance P. The ability of Avène water to
inhibit mast cell activation in vitro may be related with its
antiallergic and anti-inflammatory properties and its use in
Avène spring water, known for its thera-
peutic properties in dermato-allergology, has
long been used to treat a variety of skin dis-
eases including atopic dermatitis, psoriasis,
eczema and urticaria. In vitro, Avène water
inhibits human basophil and mast cell aller-
gen-induced activation [1, 2]. Recently, it
was shown that incubation of cultured hu-
man skin fibroblasts with Avène water in-
creased the fluidity of the plasma membrane
suggesting that its primary impact is at this
level [3].
Mast cells play an important role in the
pathophysiological changes observed in cuta-
neous allergic and inflammatory reactions.
They release preformed mediators such as his-
tamine, hydrolytic enzymes and synthesize,
after antigenic challenge, the newly formed
mediator derived from membrane phospho-
lipids, prostaglandin D
) [4, 5]. Fur-
thermore, recent studies indicate that the ner-
vous system may also influence cutaneous
Received: July 18, 1997
Accepted: Dec. 4, 1997
Fax + 41 61 306 12 34
© 1998 S. Karger AG, Basel
This article is also accessible online at:
F. Joly
SEPhRA (Société d’Etudes en Pharmacologie: Recherche, Applications)
41, avenue du Général Sarrail
F–75016 Paris (France)
Tel. +33 01 46 32 70 47, Fax +33 01 46 31 02 77
Downloaded by:
Universite Rene Descartes - 7/1/2015 9:07:55 PM
Skin Pharmacol Appl Skin Physiol
Table 1.
Composition of the two Avène waters
Val d’Orb Sainte Odile
pH 7.7 7.8
Resistivity ø/cm 2,915 2,353
Silica mg/l 12.1 14.0
mg/l 59.0 42.7
mg/l 26.0 21.2
mg/l 4.6 4.8
K+ mg/l 0.8 0.8
mg/l 281 227
mg/l 4.2 5.4
mg/l 25.3 13.1
mg/l 1.0 1.4
mg/l ! 0.02 ! 0.01
mg/l ! 0.05 0.3
mg/l ! 0.1 0.1
mg/l ! 0.1 0.3
Arsenic Ìg/l 8 10
Bore Ìg/l 38 220
Cadmium Ìg/l ! 12
Chrome Ìg/l ! 5 ! 2
Copper Ìg/l ! 20 ! 5
Lead Ìg/l ! 5 ! 5
Iron Ìg/l 70 ! 5
Lithium Ìg/l ! 20 ! 0.1
Manganese Ìg/l ! 5 ! 2
Zinc Ìg/l ! 20 45
Strontium Ìg/l 110 100
inflammatory events through the activation
of immune cells by substance P, a neurotrans-
mitter [6, 7]. Substance P is a peptide which is
released by skin C fibers which are in the
immediate vicinity of mast cells. It can bind
to and activate mast cells of the serosal type
resulting in histamine release [5, 8].
The aim of the present study was to inves-
tigate the effect of Avène spring water on sub-
stance P- and antigen-induced degranulation
of PGD
release in rat peritoneal mast cells
which present the same functional character-
istics as human cutaneous mast cells.
Materials and Methods
Substance P (Neosystem, Strasbourg, France),
HEPES, bovine serum albumin (BSA), mouse mono-
clonal IgE anti-dinitrophenyl (DNP), p-nitrophenyl-N-
acetyl-ß-D-glucosaminide, metrizamide (Sigma Chem-
ical Co., St. Louis, Mo., USA). DNP coupled to BSA
antigen was prepared according to Eisen [9] and stored
at –20
Isolation and Purification of Rat Peritoneal Mast
Mast cells from male Wistar rats (200–300 g; Iffa-
Credo, L’Arbresle, France) were obtained following an
intraperitoneal injection of 15 ml of Tyrode’s buffer
(NaCl 137 mM, KCl 2.7 mM, glucose 5.6 mM,
0.4 mM, NaHCO
10 mM, HEPES 4.2 mM,
BSA 0.25%, pH 7.4). After injection, the peritoneal cav-
ity was massaged for 2–3 min and the fluid collected.
The cell suspension was centrifuged (400 g, 5 min, 4
and the pellet was resuspended in 2 ml of this buffer.
Mast cells were stained using toluidine blue solution
and counted. The number of peritoneal cells per rat var-
ied from 1.2 ! 10
to 1.7 ! 10
. Mast cells were puri-
fied on a metrizamide layer (22.5%) and then centri-
fuged (400 g, 20 min, 20
C). Cells at the interface were
excluded and the pellet, which contained mast cells, was
resuspended in Tyrode’s buffer. Prior to stimulation
with substance P, cells were washed by centrifugation
and resuspended in Tyrode’s buffer supplemented with
0.3 mM and MgCl
0.5 mM. Before antigenic
stimulation, cells were resuspended in Tyrode’s buffer
containing CaCl
1.3 mM and MgCl
0.5 mM.
Avène Water
Avène waters from two different springs, ‘Sainte
Odile’ and ‘Val d’Orb’, were tested. The composition
of both Avène waters is presented in table 1. They were
supplied in glass bottles (Pierre Fabre Laboratory) and
stored at 4
C. Avène water was made isotonic prior to
use by dilution (9:1, v/v) in tenfold concentrated wash-
ing Tyrode. This solution was then diluted 1/2, 1/4 and
1/10 in Tyrode’s.
Downloaded by:
Universite Rene Descartes - 7/1/2015 9:07:55 PM
Inhibition of Mast Cell Activation by
Avène Water
Skin Pharmacol Appl Skin Physiol
Mast Cell Activation and Mediator Release
Substance P stimulation: Before activation, cells
were preincubated with Avène water (stock solution or
dilutions) for 30 min at 37
C. Cell suspensions were
then incubated with substance P (30 ÌM) for 5 min.
Antigenic stimulation: Cells were suspended in
Tyrode’s buffer and sensitized with mono-
clonal IgE anti-DNP (1Ìg/ml) for 90 min, washed by
centrifugation (300 g, 5 min, 20
C), and finally resus-
pended in the control Tyrode’s buffer, Avène water
or its dilutions. Cells were stimulated with DNP-BSA
(40 ng/ml) for 10 min.
The stimulations were stopped on ice and superna-
tants and pellets were obtained by centrifugation at
C. Histamine content in supernatants and sonicated
cell pellets was assessed by ELISA (Bioadvance,
France). PGD
released in supernatants was measured
by radioimmunoassay (Amersham, France). ß-Hexo-
saminidase (ß-hex) activity (an index of degranulation)
in supernatants and sonicated cell pellets was quanti-
fied by the hydrolysis of p-nitrophenyl-N-acetyl-ß-D-
glucosaminide as previously described [10].
Statistical Analysis
Released histamine is expressed as a percentage of
total histamine content. Spontaneous histamine re-
lease was subtracted from all values to give the net
release percentage. The net percentage of ß-hex release
was calculated using the following formula: [(S – Sc) !
100]/[(S + P) – Sc], where S is the ß-hex activity in the
supernatant of antigen-challenged cells, P is the activi-
ty in the pellet of challenged cells, and Sc is the activity
in the supernatant of unchallenged cells. The Student’s
t test was used for statistical evaluation. p values ! 5%
were considered as significant.
We compared Avène waters from the
springs, ‘Sainte Odile’ and ‘Val d’Orb’, com-
paratively with a distilled water control for
their effects on mast cell degranulation, mea-
sured as histamine and ß-hex release induced
by substance P or antigen. The viability of the
cell suspensions used in all experiments in the
presence of Avène water was verified by try-
pan blue exclusion (1 95%). In addition, spon-
taneous histamine or ß-hex release (! 6%)
were not increased by the treatment with
Avène water suggesting that the cell viability
was not affected.
Incubation of mast cells with Avène water
before peptidergic or antigenic stimulation in-
duced a statistically significant and dilution-
dependent inhibition of ß-hex and histamine
release with respect to distilled water without
significant difference between Sainte Odile
and Val d’Orb spring water (fig. 1, 2). Inhibi-
tions were 35 B 4% and 40 B 4% with undi-
luted Sainte Odile and Val d’Orb spring wa-
ter, respectively. ß-hex, contained in mast cell
secretory granules, was released in a quantita-
tive relation to histamine after the stimula-
tion with antigen or substance P. Interesting-
ly, the observed inhibition of enzyme release
was related to the reduction of histamine lib-
eration (33 B 4% and 38 B 1% for Sainte
Odile and Val d’Orb, respectively).
In contrast to peptidergic activation, anti-
genic stimulation of rat mast cells resulted in
the release of the newly formed mediator
, derived from membrane phospholip-
ids. Pretreatment of mast cells with Avène
water reduced release of this mediator from
146 B 6 pg/1 ! 10
cells to 69 B 5 pg and 104
B 3 pg/1 ! 10
cells for Sainte Odile and Val
d’Orb spring water, respectively (fig. 3).
The usefulness of Avène spring water in
the treatment of skin diseases, particularly
atopic dermatitis, urticaria and psoriasis,
have long been recognized. Due to their re-
lease of mediators, mast cells are involved in
many different cutaneous and inflammatory
disorders [11]. We studied this spring water in
a pharmacological assay using rat serosal mast
cells as a representative model of human cuta-
neous mast cells. Both cell types can be stimu-
lated not only via the classical antigenic IgE-
Downloaded by:
Universite Rene Descartes - 7/1/2015 9:07:55 PM
Skin Pharmacol Appl Skin Physiol
Fig. 2.
Effect of Avène spring water on histamine
release induced by antigen. Sensitized mast cells,
preincubated (30 min, 37
C) with Avène water for
indicated dilutions or control buffer were stimulated
with DNP-BSA (40 ng/ml, 5 min). Results are ex-
pressed in percentages of histamine release in compari-
son to the total cell histamine content and are means of
duplicate determinations. They represent the mean B
SEM of 4 experiments. * p ! 0.05.
Fig. 1.
Effect of Avène spring water on histamine
release induced by substance P. Mast cells, preincu-
bated (30 min, 37
C) with Avène water for indicated
dilutions or control buffer were stimulated with sub-
stance P (30 ÌM, 5 min). Results are expressed in per-
centages of histamine release in comparison to the
total cell histamine content and are means of duplicate
determinations. They represent the mean B SEM of
4 experiments. * p ! 0.05; ** p ! 0.01; *** p ! 0.001.
Downloaded by:
Universite Rene Descartes - 7/1/2015 9:07:55 PM
Inhibition of Mast Cell Activation by
Avène Water
Skin Pharmacol Appl Skin Physiol
dependent pathway but also by the peptider-
gic pathway [5, 8].
Avène spring water was effective in inhib-
iting mast cell activation, i.e. degranulation
and PGD
release induced by antigen or sub-
stance P. The ability of Avène spring water to
inhibit optical basophil degranulation and
mast cell histamine release has been reported
[1, 2]. In addition to studying histamine re-
lease, we have measured PGD
release and
mast cell activation by peptidergic stimula-
tion. The inhibitory effect of Avène spring
water on degranulation induced by substance
P is of particular interest because the mecha-
nisms underlying the neurogenic inflamma-
tion might be implicated in numerous patho-
logical processes such as chronic idiopathic,
cholinergic, heat and cold urticaria [12]. Fur-
thermore, the cutaneous proinflammatory ef-
fects of PGD
are well documented [13], and
in vivo studies demonstrated the presence of
histamine and PGD
in the different types of
urticaria mentioned above [14, 15]. Different
steps may constitute potential sites of cell per-
turbation leading to an inhibition of the stim-
ulation: primary interaction of substance P
(positively charged) with sialic acid residues
(negatively charged) or the cell membrane,
IgE receptor-ligand bridging, Ca
entry fol-
lowing activation of membrane phospholi-
pases, etc. These hypotheses are consistent
with previous studies showing that Avène wa-
ter modified changes in the hydrodynamic
properties of cell membranes leading to an
increase in fluidity [3]. Furthermore, numer-
ous pathological processes, such as atopic ec-
zema and psoriasis, are linked to membrane
fluidity abnormalities [16]. The inhibitory ef-
fect of the thermal Avène spring water on
mast cell activation provides a physiological
mechanism that could explain its therapeutic
usefulness in controlling allergic or inflamma-
tory skin diseases.
Fig. 3.
Effect of Avène spring water on PGD
release induced by antigen. Sensitized mast cells,
preincubated (30 min, 37
C) with Avène water for
indicated dilutions or control buffer were stimulated
with DNP-BSA (40 ng/ml, 5 min). Results are ex-
pressed in pg per 1 ! 10
cells and represent the mean
B SEM of 4 experiments. * p ! 0.05.
Downloaded by:
Universite Rene Descartes - 7/1/2015 9:07:55 PM
Skin Pharmacol Appl Skin Physiol
1 Sainte-Laudy J, Sambusy JL: Inhibi-
tion of basophil degranulation by
Avène spring water. Int J Immu-
nother 1987;4:307–312.
2 Sainte-Laudy J, Gall Y, Soto P: Inhi-
bition of human basophil and rat
mast cell activation by Avène spring
water. Agents Actions 1993;38:228–
3 Cézanne L, Gaboriau F, Charveron
M, Morlière P, Tocanne JF, Duber-
tret L: Effects of the Avène spring
water on the dynamics of lipids in
the membranes of cultured fibro-
blasts. Skin Pharmacol 1993;6:231–
4 Christopher BR, Lowan MA, Mar-
tin KC: Human skin mast cells:
Their dispersion, purification, and
secretory characterization. J Immu-
nol 1987;138:861–867.
5 Church MK, Lowman MA, Rees
PH, Benyon RC: Mast cells, neuro-
peptides and inflammation. Agents
Actions 1989;27:8–16.
6 Matsuda H, Kawakita K, Kiso Y,
Nakano T, Kitamura Y: Substance
P induces granulocyte infiltration
through degranulation of mast cells.
J Immunol 1989;142:927–931.
7 Hagermark O, Hokfelt T, Pernow B:
Flare and itch induced by substance
P in human skin. J Invest Dermatol
8 Ebertz JM, Hirshman CA, Kettel-
kamp NS, Uno H, Hanifin JM: Sub-
stance P-induced histamine release
in human cutaneous mast cells. J
Invest Dermatol 1987;88:682–685.
9 Eisen H: Preparation of purified
anti-2,4-dinitrophenyl antibodies;
in Eisen HN (ed): Methods in Medi-
cal Research. Chicago, Yearbook
Medical, 1964, vol 10, p 94.
10 Schwartz LB, Austen KF, Wasser-
man SI: Immunological release of ß-
hexosaminidase and ß-glucuroni-
dase from purified rat serosal mast
cells. J Immunol 1979;123:1445–
11 Bienenstock J, Tomioka M, Stead R,
Ernst P, Jordana M, Gauldie J, Do-
lovich J, Denburg J: Mast cell in-
volvement in various inflammatory
processes. Am Rev Respir Dis 1987;
12 Landry Y: Mastocytes cutanés et in-
flammation neurogène. Rev Eur
Dermat 1990;2:79–84.
13 Maurice M: The effects of PGD
the response of human skin to hista-
mine. J Invest Dermatol 1987;89:
14 Kaplan AP, Gray L, Shaff RE, Hora-
kova Z, Beaven MA: In vivo studies
of mediator release in cold urticaria
and cholinergic urticaria. J Allergy
Clin Immunol 1975;55:458–461.
15 Heavey DJ, Kobza-Black A, Barrow
SE, Chappell CG, Greaves MW,
Dollery CT: Prostaglandin D
histamine release in cold urticaria. J
Allergy Clin Immunol 1986;78:458–
16 Ferreti G, Offidani AM, Simonetti
O, Valentino M, Curatola G, Bossi
G: Changes in membrane properties
of erythrocytes and polymorphonu-
clear cells in psoriasis. Biochem
Med Metab B 1989;41:132–138.
Downloaded by:
Universite Rene Descartes - 7/1/2015 9:07:55 PM
... With the increased interest of cosmetic industry in commercialized SPA waters as cosmeceuticals, an effort has been made to prove cellular effects, especially in France 33 . Well recognized European thermal centers as Avène and La Roche Posay have already promoted scientific studies validating their TW effects 27,[33][34][35][36][37] . However, in Portugal and to the best of our knowledge, only one study reporting the health benefits of a Portuguese TW has been published 38 . ...
... From the 14 TW studied, 11 promoted a reduction in NO production and/or iNOS expression, and/or exhibited NO scavenging activity in macrophages exposed to LPS, supporting their anti-inflammatory properties. In Europe, important thermal centers as Avène and La Roche Posay have already promoted scientific studies validating their TW effects [33][34][35][36][37] . Avène TW was shown to protect cell membranes, genomic DNA and proteins of human keratinocytes in a UVA-induced oxidative stress cell model, as mentioned by Merial-Kieny et al. 35 , supporting its antioxidant properties. ...
... Avène TW was shown to protect cell membranes, genomic DNA and proteins of human keratinocytes in a UVA-induced oxidative stress cell model, as mentioned by Merial-Kieny et al. 35 , supporting its antioxidant properties. Anti-allergic effect was also assessed, in which Avène TW inhibited histamine and prostaglandin D 2 release by rat mast cells exposed to substance P-or antigen-induced cells degranulation 36 . The anti-inflammatory effect was also demonstrated in a model of human skin explants stimulated by VIP (vasoactive intestinal peptide), a neurotransmitter that induces vessel dilation. ...
Full-text available
In light of Medical Hydrology, thermal waters (TW) are all-natural mineral waters that emerge inside a thermal resort and have therapeutic applications. Their beneficial effect has been empirically recognized for centuries, being indicated for symptom alleviation and/or treatment of several diseases, almost all associated with inflammation. Indeed, an anti-inflammatory effect has been attributed to many different Portuguese TW but there is no scientific validation supporting this empiric knowledge. In the present study, we aimed to investigate the anti-inflammatory properties of 14 TW pertaining to thermal centers located in the Central Region of Portugal, and grouped according to their ionic profile. Mouse macrophage cells stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 agonist, were exposed to culture medium prepared in TW. Metabolism, nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression levels and the scavenging capacity of TW, were investigated in vitro. 11 out of 14 TW reduced NO production and/or iNOS expression, and/or scavenging activity, in macrophages exposed to LPS. The sulphated/calcic TW did not show any effect on at least one of the inflammatory parameters evaluated. Two sulphurous/bicarbonate/sodic TW and the sulphurous/chlorinated/sodic TW promoted an increase in NO production and/or iNOS expression. Our results validate, for the first time, the anti-inflammatory properties of Portuguese TW, supporting their therapeutic use in the treatment of inflammation-related diseases and promoting their putative application in cosmetic products and medical devices.
... Moreover, when mast cells were preincubated in an Av ene TSW-based buffer, production of prostaglandin D 2 and histamine was decreased. 26,27 The ability of Av ene TSW to dampen mast cell degranulation may be important in reducing symptoms associated with skin inflammation. Indeed, mast cell granules contain a huge array of mediators (histamine, tryptase, chymase, TNF, etc.) able to initiate or to sustain inflammation. ...
... Effect of Av ene TSW on mast cell degranulation following substance P or IgE/Ag stimulation (see ref26) ...
The hydrotherapy centre in Avène, France, is used extensively to treat inflammatory skin diseases. Nevertheless, the immune mechanisms targeted by Avène Thermal Spring Water (TSW) are not fully understood. Here, we review the main results reported regarding the effects of Avène TSW on the immune system. In particular, mast cells, dendritic cells (DCs) and CD4+ T cells have been shown to be modulated by Avène TSW. All in all, the studies carried out on the effects of Avène TSW on leucocytes indicate that this water is endowed with a tolerogenic potential.
... Several in vitro studies were performed during the last twenty years, mainly in AD. Joly et al. [7] studied two different thermal spring waters ("Sainte Odile" and "Val d'Orb") from Avène on rat peritoneal mast cell activation. In this study, cells were preincubated with both Avène spring waters. ...
Full-text available
Background: Thermal waters have been showing different beneficial effects on the skin due to their physicochemical composition. The beneficial effect of thermal water in the treatment of some skin diseases may thus justify its use as an active ingredient in cosmetic formulations. The main objective of this work was to demonstrate the potential of incorporating thermal water as an active ingredient in cosmetic formulations. (2) Methods: A descriptive literature review was carried out by the analysis of scientific articles in PubMed and Google Scholar databases. Twelve thermal spring waters were found (Avène, Blue Lagoon, Comano, Cró, Dead Sea, La Roche-Posay, Monfortinho, Saint-Gervais, Salies-de-Béarn, São Pedro do Sul, Uriage and Vichy) with potential as an active in cosmetic products, demonstrated through in vitro studies evaluating the different activities/properties and clinical trials in healthy volunteers or with skin pathologies. (3) Results: For these studies, in natura thermal water as well as incorporated in cosmetic formulations were used. In in vitro studies, most thermal waters have been shown to have activities on membrane fluidity, skin barrier repair, antiradical, antioxidant, anti-inflammatory and immunomodulatory properties, proliferative activity, regulation of processes involved in ageing and moisturizing properties. In clinical trials, cosmetic thermal waters reduced skin discomfort through their soothing and exhibited moisturizing and anti-irritant properties. (4) Conclusions: The effect of thermal waters on the skin and the absence of side effects reported in different studies allows them to be used as an adjuvant or in the treatment of various skin disorders and may play an important role in the cosmetics industry. However, further clinical trials are needed to assess their effectiveness and safety.
... The main anions present in the TSW are chlorides, sulfates and bicarbonates. TSW's differ in the proportions among those bulk minerals as well as in the content of trace elements, such as zinc, copper, strontium, selenium, iron, manganese, silica, fluoride, bromide, etc. (de Raimbouville, 1898;Joly et al., 1998;Seite, 2013). Since the Antiquity, bathing was regarded as more than a simple cleansing procedure. ...
Skin constitutes a barrier protecting the organism against physical and chemical factors. Therefore, it is constantly exposed to the xenobiotics, including inorganic ions that are ubiquitous in the environment. Some of them play important roles in homeostasis and regulatory functions of the body, also in the skin, while others can be considered dangerous. Many authors have shown that inorganic ions could penetrate inside the skin and possibly induce local effects. In this review, we give an account of the current knowledge on the effects of skin exposure to inorganic ions. Beneficial effects on skin conditions related to the use of thermal spring waters are discussed together with the application of aluminium in underarm hygiene products and silver salts in treatment of difficult wounds. Finally, the potential consequences of dermal exposure to topical sensitizers and harmful heavy ions including radionuclides are discussed.
... As reported in a review by Khalilzadeh et al. [23], salty thermal sources highest in minerals can reduce: (i) the human leukocyte elastase enzyme (involved in PSO), (ii) the transforming growth factor (TGF)-β (which is increased in psoriatic patients), (iii) the LCs of the skin, (iv) the aging markers, and (v) the skin infections, through the removal of yeasts and bacteria which classically contribute to seborrheic dermatitis (SD). Regarding spring thermal sources, the regulation of immunomodulatory parameters by spa water-supplemented media was observed in human psoriatic keratinocytes (Comano Thermal Water-CTW, Italy) [60], LCs (La Roche Posay-LRP, France) [61], mast cells (Avène Spa Water-ASP, France) [62], and CD4+ T lymphocytes (ASP, France) [63]. Most notably, TNF-α and IL-8 production was reduced in psoriatic keratinocytes by CTW [60], and a partial shift from a Th2 to a Th1 cytokine profile was observed by ASW [63], offering a rationale for the treatment of PSO and AD, respectively. ...
Full-text available
The benefits of thermal water in different diseases have been known since ancient times. Over the past decades, a re-assessment of the use of mineral water for the treatment of several pathologic conditions has taken place around the world. Today, water therapy is being practiced in many countries that have a variety of mineral springs considerably different in their hydrogeologic origin, temperature, and chemical composition. Thermal water and balneotherapy offer several advantages: this approach needs no chemicals or potentially harmful drugs; there are almost no side effects during and after treatment, and there is a low risk to the patient's general health and well-being. However, it is difficult to evaluate the efficacy of this therapeutic approach in clinical practice due to the complexity of molecular mechanisms underlying its efficacy. Here we review the current knowledge of the chemical, immunological, and microbiological basis for therapeutic effects of thermal water with a specific focus on chronic inflammatory skin diseases. We also describe recent evidence of the major dermatologic diseases that are frequently treated by balneotherapy with a remarkable rate of success. Moreover, we discuss the potential role of balneotherapy either alone or as a complement to conventional medical treatments.
... Moreover, the soothing and protective properties of thermal spring waters in sensitive skin (antioxidant or anti-ageing) are enhanced by the presence of trace elements such as selenium, strontium (Celerier et al., 1995). These properties have been demonstrated in many studies using human keratinocytes, fibroblasts or other response-appropriate cell lines (Seite et al., 2013;Joly et al., 1998). Furthermore, a recent study demonstrated the activity of salso-bromo-iodine water on mucous-secretory disorders, in particular it helped to improve the relationship between the mucous-protein complexes and the water: initially, this action was congestive, subsequently, it became an anti-catarrhal, anti-inflammatory, antiseptic and immunostimulant action (La Mantia et al., 2018). ...
... The main anions present in the TSW are chlorides, sulfates and bicarbonates. The waters differ in the proportions among those bulk minerals as well as in the content of trace elements, such as zinc, copper, strontium, selenium, iron, manganese, silica, fluoride, bromide, etc. [82][83][84]. Since the Antiquity, bathing was regarded as more than a simple cleansing procedure. ...
Human skin forms a unique interface between the body and the external environment. Its main role is to protect the internal organs from external factors. Its highly hydrophobic outermost layer, stratum corneum, has long been believed impermeable for highly hydrophilic compounds, including ions. Several studies proved this concept wrong, and recent research by Paweloszek et al. demonstrated the important contribution of facilitated transport in permeation of halide anions. Skin penetration of anions classified in Hofmeister series (of F-, Br-, I-, SCN, ClO4-) alone and in bi- and ternary mixtures in two experimental series was studied in vitro. All tested ions permeated viable skin within 24h. Among halides, the presence of F- reduced the penetration of Br- and I- in mixtures, and synergy between Br- and I- was observed. Within the second group (I-, SCN-, ClO4-) the inhibition of ClO4- penetration in the presence of other ions was observed. Finally, the impact of formulation of marketed thermal spring water (TSW) into emulsions (TSW/O, O/TSW, TSW/O/W) and liposomes on skin absorption of Ca2+ and Mg2+ was evaluated. Liposomes and emulsions promoted retention of Ca2+ and Mg2+ in skin layers as compared to TSW. Our results prove that the beneficial effects observed during treatment with TSW are associated with penetration of the minerals into and through the skin and are not only a surface action. In this thesis, we demonstrate the possibility of both anions and cations to penetrate viable skin in vitro, and we disclose the effects of mixing and formulating on skin penetration profiles
... Moreover, they have soothing and protective properties in sensitive skin (antioxidant or anti-ageing) that are enhanced by the presence of trace elements such as selenium, strontium and zinc [22][23][24]. These properties have been demonstrated in many studies using human keratinocytes, fibroblasts or other response-appropriate cell lines [6,25,26]. Therefore, they are considered as active substances when used in a cosmetic product. Skincare products such as emulsions or lotions containing TSW as aqueous phase are present on the market, which claim soothing and hydration properties. ...
Objective: Thermal spring waters (TSW) are commonly used as active ingredients in cosmetics. Their biological activities directly depend on the ionic composition of the spring. However, in order to exhibit beneficial properties, the minerals need to reach viable skin layers. The present study addresses the incorporation of marketed TSW in model cosmetic formulations and the impact of the formulation on skin absorption of magnesium and calcium ions that are known to improve skin barrier function. Methods: Marketed TSW was introduced into five formulations. Liposomes were prepared using saturated or unsaturated phospholipids mixed with cholesterol by the thin layer evaporation technique. Emulsions water-in-oil (W/O), oil-in-water (O/W) or double: water-in-oil-in-water (W/O/W) were prepared by high shear mixing. Skin absorption of Mg2+ and Ca2+ from those formulations was studied in vitro using static Franz diffusion cells under infinite dose condition and under occlusion of the apparatus. Results: Mg2+ and Ca2+ penetrate skin samples from TSW. Encapsulating TSW into double emulsion (TSW/O/W) increased skin absorption of both cations of interest and kept the Ca2+ /Mg2+ ratio equal to that of TSW in each skin layer. The dermal absorption of Mg2+ from the double emulsion departs from both single emulsions. Application of liposome suspension improved the skin absorption of Ca2+ while keeping constant that of Mg2+ , leading to unbalanced Ca2+ /Mg2+ ratio inside skin. Conclusion: The beneficial effects of TSW are not only due to their action on the skin surface. Their active components, especially Ca2+ and Mg2+ cations reach viable skin layers in a formulation-dependent manner. The distribution of ions inside skin depends on the type of formulation.
The classical description of psoriasis does not include any of the subjective symptoms that accompany skin manifestations (pruritus, burning, tingling, pain), which is surprising especially for pruritus, a symptom present in the majority of patients with this disease, in a variable proportion between 60% and more than 90%. For the last two decades, the scientific interest for this symptom has increased. Many studies are evaluating the potential positive effect of various classes of drugs. No therapy is totally free of side effects. Psoriasis is an indication of the thermal treatment. The thermal water from Avène Hydrotherapy Center is known for its anti-inflammatory and immunomodulatory properties, as shown by many scientific studies. In this context, from the year 2016, in the Thermal Center, we studied the prevalence and characteristics of pruritus in patients with psoriasis, who came for a thermal treatment, but also the effect of hydrotherapy. In 2016, a study based on a dedicated questionnaire, administered at the entrance of the thermal station, revealed the presence of pruritus for 92% of patients who responded. In the period 2017-2018, the evaluation of pruritus associated with psoriasis on a numerical scale, in parallel with the evaluation of the severity of the disease by the thermal physician, showed the improvement of the psoriatic pruritus by 42% after the hydrotherapy cure. Recent results suggest that treatment in Avène Hydrotherapy Center might be considered for managing psoriasis accompanied by subjective symptoms, especially pruritus. © 2020 Elsevier Masson SAS. All rights reserved. Copyright © 2020 Elsevier Masson SAS. Tous droits réservés.
The biological activity of Avene spring water was studied in vitro on human basophil degranulation. For 30 patients tested who had been sensitized to respiratory allergens a highly significant inhibition of basophil degranulation triggered by the specific allergen was observed. On 7 patients with atopic dermatitis and 9 with pollinosis this inhibition effect was demonstrated to be independent of the method of sensitization of the basophils: basophils of allergic patients or basophils passively sensitized in vitro. This inhibitor activity follows a dose-effect curve which peaks for a dilution of 1/10 of Avene water. This activity is also denaturated by incubation at 100C for 15 min.
Intradermal injection of synthetic substance P (10-7–10-5 M) in humans produced flare, wheal and itching. These responses were inhibited by oral pretreatment of the subjects with an antihistaminic drug (chlorcyclizine) or by local pretreatment with Compound 48/80 administered to deplete the local stores of mast-cell bound histamine. The findings indicate that the responses induced by substance P were mainly mediated by histamine released from the dermal mast cells. In contrast to previously studied histamine liberators, substance P was less potent when acting on rat mast cells in vitro than on human skin mast cells in vivo. When incubated with rat peritoneal mast cells, about 100 times higher concentrations (10-5 M) were required to induce histamine release than in the in vivo studies on humans. It was concluded that substance P is a potent histamine liberator in human skin.
In this study the ability of Avene spring water to inhibit basophil degranulation was confirmed. The active principle is thermo-labile and inactivated by ultraviolet or gamma radiation. Inhibition of basophil degranulation occurred with immunological stimuli (e.g. antigen, anti-IgE) but not with the calcium ionophore A23187 as the secretory stimulus. Freeze drying did not impair the inhibitory properties of the spring water. Freeze dried samples were able to inhibit antigen-induced histamine release from human basophils or rat mast cells. The ability of Avene water to inhibit mast cell/basophil activation may be in part responsible for the anti-inflammatory effect of the spa water observedin vivo.
Six patients with cold urticaria were found to possess elevated plasma histamine levels after cold challenge by placing one hand in ice water for 4 minutes. A single patient became hypotensive during the procedure and had a level of 260 ng/ml. histamine in the venous effluent from his hand. No elevation of plasma serotonin or bradykinin was observed. Two patients with cholinergic urticaria possessed elevated plasma histamine levels during and after vigorous exercise for 10 minutes; these patients also gave a positive test for vibration-induced angioedema. A single patient with cholinergic urticaria possessed elevated baseline serotonin levels and elevated levels during and after exercise but no elevation of plasma histamine or bradykinin. The results suggest that histamine is the major mediator of urticaria and hypotension in cold urticaria. Histamine also appears to be released coincident with the development of urticaria in some patients with cholinergic urticaria, while elevated serotonin levels in a single atypical patient suggest that a subpopulation of patients with cholinergic urticaria possess a different pathogenesis.
The acid exoglycosidases β-hexosaminidase and β-glucuronidase are present in rat serosal mast cells at concentrations of 1.2 ± 0.5 units and 0.24 ± 0.11 units/106 cells, respectively, and are released in a dose- and time-dependent fashion in response to immunologic challenge with rabbit anti-rat F(ab′)2. The sum of the released and residual β-hexosaminidase and β-glucuronidase was no different from that of resting unchallenged cells, thereby indicating that release in physiologic buffer was sufficient for complete bioavailability of the secreted enzymes when assessed with small synthetic substrates. A comparison of the release of the acid exoglycosidases with that of histamine yields regression lines that have correlation coefficients of ≥ 0.97 for each enzyme and that intersect at the point of origin, suggesting absence of a threshold effect on the release of these mediators. The slopes of these regression lines indicate that at least 86 and 65% of the cellular content of β-hexosaminidase and of β-glucuronidase, respectively, are available for immunologic release and are therefore localized in mast cell secretory granules. The predominant isomeric form of β-hexosaminidase in the rat mast cell, as indicated by its chromatographic behavior, is type A and the A isomer is the predominant form released on immunologic activation of the cells. The only isomeric form of β-glucuronidase identified in rat serosal mast cells based upon its electrophoretic mobility is the lysosomal form, and this form was the only one released after immunologic activation of these cells. The mast cell secretory granule, based upon its content of acid hydrolases and its capacity to form phagolysosomes, is considered a modified lysosome, which also contains novel chemical mediators not generally observed in lysosomes of other cells.
Prostaglandin (PG) D2 and histamine concentrations have been measured in blood draining cold-challenged forearm skin in patients with cold urticaria. Local venous concentrations of both histamine and PGD2 rose in four patients who developed a whealing response. Plasma histamine concentration increased from a mean resting value of 0.24 +/- 0.09 (SD) ng/ml to peak values of 16.9 to 96.6 ng/ml. Resting concentrations of PGD2 were below the limit of detection (5 pg/ml) in three patients and 62 and 27 pg/ml in the fourth. Peak plasma PGD2 concentration after challenge ranged from 166 to 279 pg/ml. Time course of histamine and PGD2 release was similar with peak concentrations at 6 and 10 minutes, respectively. The maximum clinical response occurred between 10 and 20 minutes after challenge. Our findings demonstrate that PGD2 is produced in association with mast cell degranulation in man, but the amount, relative to histamine, is low. Despite its high potency in production of inflammatory effects, PGD2 probably has only minor direct effects in cold urticaria, although it may act to potentiate other mediators.
Digestion of human foreskin with collagenase and hyaluronidase disperses approximately 3.4 X 10(7) nucleated cells per gram of tissue, of which mast cells constitute 4.7%. These may be purified to 80% by use of density gradient centrifugation. The majority of mast cells (79%) measured between 9 and 13 micron in diameter, and the mean histamine content was 4.6 pg/cell. Viability was demonstrated by trypan blue exclusion by 93% of the cells and the low spontaneous histamine secretion of less than 7% in functional studies. Anti-IgE released up to 17.5% of cell-associated histamine within 5 to 7 min. Calcium ionophore-induced release was optimal with 0.3 microM A23187 when 28.6% histamine was released. Unlike human lung mast cells, skin mast cells released histamine in response to compound 48/80 and poly-L-lysine. This release, which was complete within 20 sec, was totally dependent on intact glycolysis and oxidative phosphorylation and partially dependent on extracellular calcium. The same characteristics were observed with secretion induced by substance P and morphine. The weak activity of eledoisin and physalaemin suggests that the substance P receptor, like that of the rat mast cell, is not of the classical types described for smooth muscle. Morphine-induced secretion was partially blocked by naloxone in a manner not compatible with competitive antagonism at a classical opioid receptor. The sensitivity of skin mast cells to nonimmunologic stimulation clearly distinguishes them from mast cells of the lung and lymphoid tissues and provides evidence of functional heterogeneity within human mast cells.
Substance P is an undecapeptide found in multiple sites throughout the central and peripheral nervous systems including small unmyelinated (type C) cutaneous nerve fibers. Previous studies demonstrated that antidromic stimulation results in substance P (SP) release from nerve endings, SP stimulates histamine release (HR) from rat mast cells in vitro, and intradermal SP in humans produces wheals identical to those induced by histamine. These studies suggest a possible role for SP as a link between neurologic events and cutaneous mast cell-mediated reactions. We therefore investigated SP-induced HR in an in vitro preparation of human skin mast cells. Human foreskin sections were incubated with varying concentrations of SP. Histamine was assayed using automated fluorimetry and release was calculated as a percentage of total tissue histamine. Substance P caused dose- dependent HR over a range from 10⁻⁵ M (1.3%) to 5 × 10⁻⁴ M (25.1%). Histamine release was optimal at 3 mM calcium and was blocked by pretreatment with calcium chelation. Naloxone failed to block HR. These studies suggest that HR from skin mast cells by SP may play a role in neural modulation of poorly understood inflammatory skin conditions.
Substance P, a potent vasodilatory neuropeptide, is released from peripheral nerve endings of sensory neurons by various stimuli. Although in vitro incubation of rat and human mast cells with substance P causes their degranulation, it is not known whether inflammatory changes induced by substance P are mediated by degranulation of mast cells. We investigated this point by using genetically mast cell-deficient WBB6F1-W/Wv and WCB6F1-Sl/Sld mice. The s.c. injection of substance P induced degranulation of mast cells in the skin of WBB6F1-+/+ mice, and then a marked eosinophil infiltration around the degranulated mast cells. However, WBB6F1-W/Wv and WCB6F1-Sl/Sld mice showed little or no eosinophil infiltration in the skin after the injection of substance P. When the mast cell deficiency of WBB6F1-W/Wv mice was rescued either systemically by bone marrow transplantation or locally by injection of cultured mast cells, injection of substance P induced the infiltration of eosinophils, suggesting that substance P-induced eosinophil infiltration was mediated through degranulation of mast cells.
We have demonstrated that, unlike mast cells of the lung, adenoids, tonsils and intestine, whose primary role is thought to be IgE-mediated host defence, human skin mast cells respond to neuropeptide stimulation with a rapid release of histamine and minimal generation of PGD2 and LTC4. This ability of skin mast cells to release mediators in response to neuropeptide stimulation is evidence in favour of a neuro-immune interaction within human skin which may have evolved to promote angiogenesis [70] or control cutaneous blood flow [71]. In this context, it is interesting to note that mast cells are found in particularly high numbers in the blush areas of the neck and face [72]. A knowledge of the functional heterogeneity of human mast cells, and of their responsiveness to neuropeptides in particular, will prove to be of great importance to our understanding of the role of mast cells in health and disease. Enhanced responsiveness of skin mast cells to neuropeptides may contribute to the aetiology of some forms of urticaria as suggested by the presence of enhanced weal responses of patients with chronic idiopathic urticaria to various non-immunological stimuli [73–76]. Furthermore, the high ratios of histamine to PGD2 (>1000∶1) [31, 32] in the venous effluent of thermally-challenged limbs of patients with heat- or cold-induced urticaria suggests mast cell activation by a neuropeptide rather than an immunological stimulus. However, the caveat applies that these two mediators may have been metabolised to different extents before reaching the sampling site.