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Changes in TNFα plasma levels in osteoarthritic patients under balneotherapy with acratothermal water

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Abstract

Der Tumornekrosefaktor α (TNFα) ist ein Zytokin und Hauptmediator der Reaktion auf Infektionserreger. In dieser Studie wurden die Serumspiegel des TNFα und einiger akuter Phase-Reaktanten (ARPs [CRP und Haptoglobin]) untersucht, um die Wirkung von Akrothermalwasser als Vollbad auf das Immunsystem nachzuweisen. Zu diesem Zweck wurden zwei Patientengruppen mit Arthrose in die Untersuchung einbezogen. Die Patienten der ersten Gruppe wurden mit Akratothermalwasservollbädern und Elektrotherapie behandelt. Bei den Patienten der zweiten Gruppe wurde ausschließlich Elektrotherapie eingesetzt. Am Anfang und am Ende der Studie wurden die Serumspiegel von TNFα sowie von ARP und Haptoglobin gemessen. Zum Abschluß erwies sich der Anstieg der Blutspiegelwerte des TNFα sowie der ARPs in der Balneotherapiegruppe im Vergleich mit der Elektrotherapiegruppe als signifikant höher. Diese Ergebnisse zeigen, dass akrothermale Vollbäder die Schutz- und Abwehrmechanismen aktivieren. Summary Tumor Necrosis Factor α (TNFα) is a cytokine, which is one of the principal mediators of host response to infective agents. In this study TNFα and serum levels of some acute phase reactants (APRs) (CRP and Haptoglobin) were investigated to show how the immune system is affected by full bath applications with acratothermal water. With this aim, 2 groups of patients with osteoarthritis were included in the study. Group 1 patients were treated with full baths with acratothermal water and electrotherapy. Group 2 patients were treated with only electrotherapy. In the beginning and at the end of the therapies, TNFα, CRP and haptoglobin levels were measured. At the end of the therapy there was a statistically significant increase in TNFα and APRs serum levels in the balneotherapy group in comparison to the electrotherapy group. These results indicate that with acratothermal full bath applications the host organism's protective and response mechanisms are triggered.
Changes In TNFa plasma levels In osteoarthritic patients
under balneotherapy with acratothermal water
"
.
Z. N. Tütüllcü', i\tf.Turanl, A. Bart/t3, N. 'tii=baslUg/Ii', ii'f. Z. KaragüUe'
i Lehrstuhl mr Medizinische Ökologie und Hydroklimatologie der Medizinischen Fakultat der Universimt Istanbul
(Leiterin: Prof Dr. N. Özer), Istanbul, 1ürkei .
2Lehrstuhl mr Medizinische Ökologie und Hydroklimatologie der Medizinischen Akademie Gülhane (GATA), Ankara. Türkei
3Lehrstuhlmr Infektionskronkheitenund KlinischeMikrobiologiederMedizinischenAkademieGülhane,GATAAnkara. .
Tiirkei
Veriinderungen des TNFa-Blutspiegels
bei Arthrose unter Balneotherapie
mit Akratothermahvasser
DerTumornekrosefaktora (TNFa) ist ein Zy-
tokin und Hauptmediatorder Reaktionauf [nfektionserreger.
[n dieser Studie wurdendie Serumspiegeldes TNFa und ei-
niger akuter Phase-Reaktan.ten(ARPs [CRP und Haptoglo-
bin]) untersucht,umdie WirkungvonAkrothermalwasserals
Vollbadauf das Immunsystemnachzuweisen.
Zu diesem Zweck wurden zwei Patientengrup-
pen mit Arthrose in die Untersuchung einbeiogen. Die Patien-
ten der ersten Gruppe wurden mit Akratothermalwasservollbii-
dem und Elektrothempie behandelt Bei den Patienten der
zweiten Gruppe wurde ausschlieBlich Elektrotherapie einge-
setzt. Am-Anfang und am Ende der Studie wurden die Serum-
spiege:l von TNFa sowie von ARP und Haptoglobin gemessen.
. Zum AbschluBerwies sich der Anstieg der
Blutspiegelwerte des TNFa sowie der ARPs in der Balneothe-
rapiegruppe im Vergleicl}mit der Elektrotherapiegruppe als
signifikant" höher. Diese Ergt;bnisse zeigen, da/3akrothermale
Vollbider die Schutz- und Abwehrmechanismen aktivieren.
SchIüsseiwörter
Balneothempie - Kurortbehandlung - Zytokj::'
ne - AkratothermaIwasser
Summary
Tumor Necrosis Factor a (TNFa) is':a eylo-
kine, whieh is one of the principal mediators of host responsc
to infeetive agents. In this study TNFa and serum levels of
some acute phase reactants (APRs) (CRP and Haptoglobin)
were investigated to .show how the immune system is atTcetcd
byfullbathapplieationswithacratothermalwater. .
With this aim, 2 groups of patients with os-
teoarthritis were included in the study. Group 1 patients werc
treated with full baths' with acmtothermal water and elee-
trotheiiipy. Group 2 patients were treated with only elee-
trotherapy. In the beginnin'g and' at the end of the therapies,
TNFa, CRP and haptoglobin levels were measured:.
.
At the end of the therapy there was a statisti-
eally signifieant inerease in TNFa and APRs serum levels in
the balneotherapy group in cOl1lpariso~to the electrotherapy
group. These results indicate that with aeratothermal fuii bath
applieations the bost organism's proteetive and response
mechanisms are triggered.
Key words
BaIneothempy - health resort-thempy - eyto-
kines - aeratothermal water
Introduetion
During balneothempeutic applieations, organ-
ism is under the influenec ofserial stimulations. it was'observed
by some researchers .that these stimulations mgger metabolie,
hormona! and immune meehanisms (Amehlilg et ai. 1985,
Selimidi et ai. 1987).
Cytokines is the genenc term eurrently em-
ployed to refer to' the pcptide regulatory faetors released by
aetivated cells which influcnce the behaviour of target cells
(Kus/iiier 199I). Tumor Neerosis Factor Alpha (TNFa) is a
Phys Rehab Kur Med 6 (1996) 80-82
@ Georg Thieme Verlag Stuttgart. New York
cytokine with a large ae.tivitypotentialwhieh affeets diffcrcnt
eell populations.TNFa playsan cffeetiverole in the metabolie
activitiesof manytissuesandeven in immunologicfiiiictionsof
all leukoeyte types. This is evidcnee of its immunomediatiir
funetion in immuneresponse(Abbaret ai. 1991).
Acute phase response is the setting of niany of
the normal homeostatic mechanisl1ls in response to inflamnia-
tory stimuli. These inflammatory stimuli may be physicul.
isehemie or immunological as well as infectious (Kii.rhiier 1991,
Riclim'dr et ai. 1991). (n a narrower sense, aeute phase responsc
refers to these plasma protein changes which reflec.t reorchcs-
tmtion of the pattem of expression of plasma protein gene!; iii
hcpiitoeytcs. CRP is one of the two major human acule phasc
proteins. While it is normally present in plasma only in trncc
Changes in TNFa.plasma level.. in osteoarthritic pa tierits l/nder balneotherapy
p'hysReJiabKurMed 6 (1996) 81_
amounts, there maybe dramatic.increases in the rates of syn-
ihesi:;and conseqiicniplasma concentrations of these proteins
Iiillowing siimulus. Haptoglobin is an acute phase protein
wliichmanifestslessspectacularresponse (Kusliner 1991).Ex-
periments revealed that these changes in biosynthesis are
\:mi:;edby alterationsin gene transcription regulated primarily
byinterleukin-6(IL-6),afteninconjunctionwith[L-I andTNF
(../bbCls et ai. i 99 i).
. [n this study we investigated the changes in
plusma TNFa, CRP,and luiptoglobin Icvels in patients with
ostcoarthrosisbeforeand after acratothermal full bath applica-
iiiin:; in order to show how the immune system is affected
during balneotherapeuticapplicaiions.
Patients and Method
Arandam cohort of 32 inpatients from the
Bursa MilitaryHospital,Bursa,withgeneralised osteoarthrosis
weri}includedin thestudy.These patients were chosen among
ihuse with no other systemic disease. Patients were randamly
allocated to 2 groups.Group) (12 females,4 males; mean age:
55.5 years [SO 14.8];mean disease dUr'<ition:14.3 years [SD
7A6]) and group2 (10 females, 6 males; mean age: 57 years
[SO 7.3]; mean diseaseduraiian: 14.4years [SD 8.1)patients
wo::redaily treatedwith electrotherapy.Electrotherapy wasap-
plied either as infraredfor 20minutes (250 Watt) plus short-
\vavediathermyfor 20 minutes(27.33MHz) or inmred for 20
minutes(250 Watt)p[usTrnl1sdermalElectric Nerve Siimula-
tion (TENS) for 20 minutes (I0-1 00 present pain intensity;
minimum20mA)orultrasoiindför4 + 4 minutes (1 Watt/cm2)
plus TENS for 20 minutes (10-100 present pain iniensity;
minimum 20mA). In addition to electrotherapy modalities,
group i patients were treated with full baihs for ro-is minutes
6.times a weekfor a period of 3 weeks.
The physiochemicalanalysis of thermal water
was performedin the Medical Ecologyand HydrocIimatology
D..:purtmentand it was foundto be acratothermal waler with a
1i:l1lperuture of 44 oc.
To dCI.:rmincTNFa, CRP, haptoglobin conccn-
trations, blood samples from 32 patients were collected before
(on ihe first day) and after therapy (on the (ast day) and cen-
trifuged immediately at 1000 x g for Lo minutes. The plasma
wu:; subsequently stored at -20 oC uniil. used for the assay.
TNFa concentratjons were determined by ELJSA method, CRP
und haptoglobin levels by turbidimetric method.
Changes in serum concentraiions were statisti.
\:ully analysed by Mann-Whitney-U-test fDr intergroup analysis
unu Wilcoxon-signed rnnk test for iritragroup analysis and p.
\ulue less than 0.05 was considered statistically significant.
Results
it is observed that mean serum TNF ct concen-
initions of group i patients increased wiih a rale of 30 % at the
enu of the cure (554.38 :t269.23 pg/ml) compared to the serum
TNFa concentrntion at the beginning of the cure (477.06:t
277.98 pg/ml) (p < 0.00 I). In group 2 there was a slight de-
.:rense in TNFa. serum concentrntion although insignificanl.
\.\'l1enchanges in mean TNFa serum levels of the 2 groiips were
':lIIl1pan::dii was faund to be highly significant (p < 0.00I).
TNFa
~ Group 2
Fig. 1 Changes in the mean TNFa serum levels in percentage for
group 1 (balneotherapy and electrotherapy) and group 2 (electro-
therapy).
Changes in the mean TNFa serum levels in percentage for both
groups are summarized in 'fig. 1.
it is observedthal meanserum CRP concentra-
tionsaf group 1patientsincreased at the end of the cure (12.63
:t 5.6mg/di) comparedto the serum CRP concentraiions at the
beginningofthe cure (5.68:t 1.8mg/dl)(p < 0.005). In group 2
there was nota significantchange inCRPserum concentratton.
When changes in mean CRP serum levelsof the.2 groups were
compared it was found to be highly significant (p < 0.00I).
Changes in the mean CRP serum levels in percentage for both
groups aresummarizedinfig.2.
300
200
c
i
a.
.5 100
<ii
ci
C
iii
.s:
(J
o
-100
CRP
_ Group1
Haptoglobin
~ Group2
Fig.:Z Chang'le in the mean CAP Bnd haptoglobin serum levels
in percent for group 1 (balneotherapy and electrotherapy) and
group 2 (electrother.apy).
lt is observed that mean serum
naptoglobin
concentrations of group I patients inereased at the end of the
cure (316:t 12.2mg/di) compared to the serum haptoglobin
concentratians at the beginning of the cure (217.3 :t 10.5 mg/di)
Cp< 0.00 I). In group 2 there was not a significant change in
haptoglobinserum concentration. When changesin mean hap-
70
"60
50
c
40
ci)
e
ci)
30
a.
.5
20
ci)
ci
c
10
LO
.s:
(J
O
-10
-20
-30
_ Group1
kys RehabKurMed6(1996)
toglobin serum levelsof the 2 groups were eompared it was
found to be highlysignifieant(p< 0.001).Changes in the mean
haptoglobin serum levels in percentage for both groups are
summarized in fig.2.
DIscusslon
it is known. that during balneotherapeutie full
bath applieations, organism is under the influenee of repeated
stimuli due to the physieoehemieal properties of tliermomineral
water. Serial bath applieations end with some changes in immu-
nologieal funetionsof theorganism(Heroldand Güniher 1989,
Herold and Günther 1990, Gilsdorf et ai. 1990, Mielile and
Bunge 1986,Roberts 1991,Peter 1990, Herold and Güniher
1994).
Although there is not much known about the
ehemieal and general etfeets of aeratothermal bath applieations,
aeratothermal waters are plaeed among the stimulative thermal
waters. In a double blind study aeratothermal and tap water bath
applications were applied to 2 different groups of patients under
the same eonditions. Thermal crisis was not observed in the tap
water group in comparison to the acratothermal group (Fritz
1925). In another study thermal crisis appeared after aemtother-
mal bath cure applieation in patients who are used to having
daily hot-shower baths (Bur! i934). The reaetive changes in the
organism may not only be due to the thermal and ehemieal
effeets of aeratothermal waters. General effeet should be via
natural and humoral stimuH (011 1962).
In a study performed in Badgastein aemtother-
mal water was gained after removing radon. This thermal water
defayed the splitting of frog eggs but sped up the frog growth
(Sehmidi 1989). There was an inerease in TNFCLand interferon
CL(IFNa.) serum levels ofpatients with inflammatory rheumatic
disease at the end of a eure in another study performed in
Badgastein (Heroldand Güniher 1990). .
in the present study,TNFCLand ARPs serum
levelsrise signifieantlywithinnormalranges in the balneother-
apy group in comparisonto the eleetrotherapygroup. Our data
revealed that with balneotherapicbath applications eutaneous
immune system is activatedand one of the mediators of im-
mune system-TNFarise.The outer layerof the skin, epidermis
is composed .of 3 eeUtypes: keratinocytes, melanoeytes and
Langerhans cells. Keratinocytesform 80% of the epidermis
eells. Keratinoeytesweresaidto releasegranuloeyte-monocyte
eolony stimulatorfaetor,IFN, IL-I and TNFCLapart from pro-
ducing keratin (Schmidaset ai. 1988). IL-6 and TNFCLhave
been found in the intercellularregion and .membrane layers
(Ox/iolm et ai. 199I). Moreover,increasedkeratinocyte ongi-
natedTNFCLlevelshavebeenobtainedwithendotoxin and ultra-
violet light stimulation (Kock et ai. (990). During aeratothermal
full bath applieations the reaetivity of the eutaneous immune
system may be triggered with the cytokines that are released
from keratinoeytes (Selimidt 1990).
In suminary this study hiis shown that by eom-
bining aeratothermal full bath applieations and eleetrotherapy
the organism's proteetive and response meehanisms are stimu-
lated although we eould not find a speeifie reason conceming
the meehanisms that aetivate eutaneous immune system.
Z. N. Tütüncil et al.
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Doz. Dr. Zühre Nur Tütüncü
i. O. Istanbul Tip Fakültesi
Tibbi Ekoloji ve Hidroklimatoloji Anabilim Dali
34399 Çapa, Istanbul
wrkei
... Secondly, we did not look for any biomarkers of osteoarthritis that spa therapy may influence, suggesting a disease modifying effect. In the literature, there is limited and conflicting evidence on the biologic effects of spa therapy and balneotherapy in patients with osteoarthritis [57][58][59][60][61]. A study reported a decrease of TNF-α levels [57], while the other an increase [58]. ...
... In the literature, there is limited and conflicting evidence on the biologic effects of spa therapy and balneotherapy in patients with osteoarthritis [57][58][59][60][61]. A study reported a decrease of TNF-α levels [57], while the other an increase [58]. Again, here, these results are not comparable, as these studies evaluated different types of spa therapy modalities and spa waters such as balneotherapy plus mud pack therapy [57,59,60], low mineralised thermal water [58] and radon water [61]. ...
... A study reported a decrease of TNF-α levels [57], while the other an increase [58]. Again, here, these results are not comparable, as these studies evaluated different types of spa therapy modalities and spa waters such as balneotherapy plus mud pack therapy [57,59,60], low mineralised thermal water [58] and radon water [61]. On the other hand, the observed beneficial effects of spa therapy on pain and functional status may be seen without any effects on disease progression of knee osteoarthritis [62,63]. ...
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Our earlier investigations dealing with DNA-repair and natural killer cells indicated that immunological reactions are activated by spa treatment in Badgastein. In patients with rheumatic diseases urinary neopterin excretion increased and indicated an activation of monocytes and macrophages. Determinations of blood cell counts with modern Coulter-counters at the beginning and at the end of spa treatment confirmed a decrease of leucocyte number and an increase of hemoglobin concentration. Measurement of cytokine concentrations like TNF-alpha and IFN-gamma in serum of patients with ankylosing spondylitis and patients with rheumatoid arthritis revealed a slight increase of serum concentrations caused by spa treatment.
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The presence of human cytokines was examined in parallel skin biopsies and epidermal single cell preparations obtained from normal individuals. Using biotin-avidin-peroxidase and immunofluorescence techniques and antibodies against recombinant cytokines, a granular intercellular/membrane-associated staining for interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF alpha), but not IL-1 alpha or beta, was observed. An epidermal cytoplasmic staining pattern was also detected, which was most pronounced using the anti-rIL-6 antiserum. In the epidermal single cell preparations, membrane-associated staining was detected for both IL-6 and TNF alpha. Double staining revealed that CD1-positive Langerhans cells (LC) failed to express any of the examined cytokines. In vitro binding of rIL-6 or rTNF alpha to skin sections and epidermal single cell preparations indicated that the cell surface-associated IL-6 and TNF alpha originally demonstrated on keratinocytes were truly membrane-bound. Finally, co-cultivation of epidermal cells with an IL-6 responsive cell line, B9, and testing of epidermal cell supernatants in this assay, indicated that the in vivo membrane-bound IL-6 had biological activity.
Article
Fever is a common response to infection and to other challenges to host defense. Temperature elevation has been associated with effects on the recognition, recruitment, and effector phases of the immune response. Specific immunologic responses are generally enhanced in the setting of temperature elevation within the physiologic range but not the supraphysiologic range. In contrast, natural immune responses may be unchanged or adversely affected. Temperature elevation appears to affect primarily the phase of recognition and sensitization or activation of mononuclear leukocytes. T lymphocyte responses (and/or the interactions of T lymphocytes with monocytes-macrophages) are enhanced for generation of effector cells. The activities of the effector cells, once generated, are usually not enhanced — or may even be depressed — by temperature elevation, but decreases are more than offset by increased T helper function. Overall, the data suggest that temperature elevations of the febrile response constitute a beneficial component of effective host defense.
Article
The epidermis is a heterogeneous tissue comprised of cells that may play a role in various types of immunologic responses. This review focuses on the importance of epidermal Langerhans' cells in antigen presenting and accessory cell functions, on the role of la-positive keratinocytes in generating certain types of immune responses, on the role of normal keratinocytes in the liberation of cytokines, on the identification of murine Thy-1-bearing dendritic epidermal cells, and on the modulation of epidermal immune functions by various physical and chemical agents.
Schultlieiss: Kurliiiigsschnittuntersuchungen humoraler und zel1ul~rer Immunparametcr
  • H Lyi
H. lYI. Schultlieiss: Kurliiiigsschnittuntersuchungen humoraler und zel1ul~rer Immunparametcr. ' Z. Phys. Med. Baln. Med. Klim. 19 (1990) 306-~13
Güiit1ier:Neoptemin im Morgenham von P~tienten mit Arthrose, rhewnatoider Artliriris und Spondylitis ankylosans wa1,-rend eines Kuraufenthaltes in Badgastein
  • M . R Herold
Herold, M.. R. Güiit1ier:Neoptemin im Morgenham von P~tienten mit Arthrose, rhewnatoider Artliriris und Spondylitis ankylosans wa1,-rend eines Kuraufenthaltes in Badgastein. 17 (1989) 326-327
Gün/lier: Immunologische und hamatologisehe Veriimlcrungen \vahrend einer Badekur in Badgastein
  • M R Herold
Herold. M.. R. Gün/lier: Immunologische und hamatologisehe Veriimlcrungen \vahrend einer Badekur in Badgastein. Z. Phys. Med. B~lri. Med. Klim. 19 (1990) 300-305