Effects of Spa therapy on anti-oxidative status, inflammation, immune system Prof. Dr. M. Zeki Karagülle Symposium on Research in Spa Medicine Aix-les-Bains - November 17th 2006
Bourget lake Practical information Microclimate Ports Exceptional surroundings Famous residents Department of Medical Ecology & Hydroclimatology Istanbul Medical Faculty, Istanbul University
Spa therapy and Balneotherapy • Do they have biologic effectson Immunesystem and Inflammation • and Oxidation ? • Which mechanisms and mediators are involved?
Terminology • Spa therapy; a complex intervention at a spa resort, (balneotherapy + others) • Balneotherapy ; Mineral/thermal water therapy (Bathing + Drinking + Inhalation)
Inflammation • the first response of the immune system to infection or irritationcharacterised by the following quintet: • redness (rubor), • heat (calor), • swelling (tumor), • pain (dolor) • dysfunction of the organs involved (functio laesa) • The first four characteristics have been known since ancient times and are attributed to Celsus; functio laesa was added to the definition of inflammation by Rudolf Virchow in 1858.
Immune System A scanning electron microscope (SEM) image of a T-lymphocyte (right), a platelet (center), and a red blood cell (left). Image: The National Cancer Institute at Frederick
Inflammation Chrousos G. N Engl J Med 1995;332:1351-1363
Cytokine Signaling Pathways Involved in Inflammatory Arthritis Choy E and Panayi G. N Engl J Med 2001;344:907-916
Cytokines and Other Mediators of Inflammation That Influence the Hypothalamic-Pituitary-Adrenal Axis Chrousos G. N Engl J Med 1995;332:1351-1363
Spa-and Balneotherapy Studies on Anti-oxidative status • Anti-oxidant status in patients with Rheumatoid Arthritis after Spa Therapy M KARAGÜLLE, MZ KARAGÜLLE , O KARAGÜLLE, A AVCI , İ DURAK35th Congress of ISMH, June 6-10, 2006, Istanbul • The Effect of Balneotherapy on Oxidant-Antioxidant Systems in Primary OsteoarthritisHN AKSOY, N ERDOĞAN, Ö AKSOY, GÖ ERATA, AH KAYAR, MZ KARAGÜLLE 35th Congress of ISMH, June 6-10, 2006, Istanbul
Malondialdehyde (MDA) nmol/mL After 2-week spa therapy; • increased in SPA group, decreased in control group • No statistically significant change intergroup (p=0.5) and between group (p=0.2) comparisons
Nonenzymatic Superoxide Radical Scavenger Activity (NSSA) U/mL After 2-week spa therapy; • increased in both groups • Statisticaly significant increase in SPA group (p<0,05)
Antioxidant Defense Potential (AOP) U/mL After 2-week spa therapy; • increased in both groups İn spa group agreater extend but , not statistically significant
Discussions Increased levels of MDA (although not statistically significant) suggests that; • Per-oxidation reactions are accelerated during or after spa therapy • spa therapy may cause an extra oxidative stress
Discussions Increased levels of NSSA (statistically significant) and AOP suggests that; • antioxidant potential and activity are improved
The Effect of Balneotherapy on Oxidant-Antioxidant Systems in Primary OsteoarthritisHN AKSOY, N ERDOĞAN, Ö AKSOY, GÖ ERATA, AH KAYAR, MZ KARAGÜLLE 35th Congress of ISMH, June 6-10, 2006, Istanbul • Decreasein MDA levels in patients with high MDA levels • Increasein MDA levels in patients with low MDA levels • Increase in TAA levels in male patients • Decrease in TAA levels in females (menopause-estrogens deficiency?)
The Effect of Balneotherapy on Oxidant-Antioxidant Systems in Primary OsteoarthritisHN AKSOY, N ERDOĞAN, Ö AKSOY, GÖ ERATA, AH KAYAR, MZ KARAGÜLLE 35th Congress of ISMH, June 6-10, 2006, Istanbul • Spa therapy decreases oxidant stress ?! • Decrease in oxidant stress is more prominent • Increase of antioxidant defence is less manifest
Free radicals and thermal water-controlled pilot study T BENDER,G NAGY,J BARISKA,R VÁGHY,R GOMEZ,I KOVÁCS4.Turkish-Hungarian Balneological Meeting, 25-26 January, Izmir, 2006 • Patients: Spondylosis lumbalis N:30(10 in each group) • They got no NSAID and steroids, no other disease • Duration of the bath 30 minutes, at 34°C • Blood samples were taken before the first bath, after the first bath and at end of 10 baths
Free radicals and thermal water-controlled pilot study T BENDER,G NAGY,J BARISKA,R VÁGHY,R GOMEZ,I KOVÁCS4.Turkish-Hungarian Balneological Meeting, 25-26 January, Izmir, 2006 • There is difference between tap water and mineral water therapy concerning the effects on the free radicals • The changes during tap water therapy may be due to the thermal effect
Effect of sulfur baths on antioxidative defense systems, peroxide concentrations and lipid levels in patients with degenerative osteoarthritis. Forsch Komplementarmed Klass Naturheilkd. 2002 Aug;9(4):216-20. Ekmekcioglu C, Strauss-Blasche G, Holzer F, Marktl W. Effect of 3-week spa therapy, two groups of patients with and without sulfur baths Sulfur bath therapy could cause a reduction in oxidative stress, alterations of SOD activities
[Effect of sulfur administration on lipid levels, antioxidant status and peroxide concentration in health resort patients] [Article in German] Forsch Komplementarmed Klass Naturheilkd. 2000 Apr;7(2):75-8. Scheidleder B, Holzer F, Marktl W. Effect of a 3-week spa therapy, two groups of patients with and without drinking sulphurous In both groups similar alterations of the activities of antioxidative enzymes as well as peroxide concentrations could be detected.
Spa-and Balneotherapy Studies on Inflammation, Immune System • Physiological effects studies in healthy subjects • In-vitro studies in cell cultures • Experimental (animal) models of arthritis studies • Therapeutic affects studies in patients groups; ie in patients with rheumatic or dermatological diseases
The decrease in paw volume in adjuvant injected paws at the end of the experiment was the greatest in the sulfur group followed by tap water group. There was not any significant difference between the two experiment and the control groups.
The chronic arthritis which developed in the non-injected left hind paws reached maximum severity on the 9th day after CFA injection in tap water and control groups and not before the 19th day in the sulfur group. Later on, edema in the sulfur group decreased statistically more rapidly (p <0.001) compared to the other two groups.
Mud-bath applications reduced inflammation at day 20, at theend of the treatment, the paw volume was significantly reduced in comparison to the controls (p<0.01) Indomethacin therapy caused a more rapid reduction of paw volume, significant both at day 15 and at day 20 (p<0.05)
Studies in patient groups • Rheumatic diseases • Osteoarthritis • Ankylosing Spondylitis • Fibromyalgia • Dermatological diseases • Psoriasis • Atopic dermatitis
Is immune systeminfluenced in OA by spa therapy (mud pack + balneotherapy) ?
Is immune systeminfluenced in healthy subjects by spa therapy (mud pack + balneotherapy) ?
Why does a 3-week spa therapy, in addition to drug treatment andweekly group physical therapy alone, provide beneficial effects that may last for at least 40 weeks, in patients with AS?
Why spa therapy in addition to medical therapy has both short- and long-term beneficial effects in female patients with Fibromyalgia ?
Conclusions The results of the published clinical, experimental, in-vitro and in-vivo studies suggeststhat; • Spa therapy and balneotherapy provide • Anti-inflammatory • Immunosuppressive • Immunomodulatory • Anti-oxidative effects
Cytokines influenced by spa-and balneotherapy • TNF-α • IL-1α • IL-1β • IL-6 • IFN-γ • IL-2 • IL-4 • EGF • TGF- β1
Prostaglandines influenced by spa-and balneotherapy • PGE2 • Leukotriene; LTB4 • PGF2 α
Matrix Metalloproteinases influenced by spa-and balneotherapy • MMP-1 • MMP-2 • MMP-3 • MMP-8 • MMP-9
Cell Populations influenced by balneotherapy • Langerhans cells • T- and B-cells • CD4+, CD4- cells • CD8+, CD8- cells
Others • CRP • Haptoglobuline • Substance P
Conclusions • There is high level (1A and 1B) clinical evidence that spa therapy and balneotherapy are effective interventions in the management of rheumatoid arthritis, osteoarthritis, fibromyalgia and ankylosing spondylitis, • The mechanisms involved in this efficacy are probably via cytokines and other inflammatory mediators • The anti-oxidative mechanisms may be also involved !
Perspectives • The favorable effects of spa and balneotherapy on the cytokines and other mediators of inflammation may create an interesting future for these interventions in the anti-cytokine / ‘‘biologic’’ therapy era.
Perspectives • The favorable effects of spa and balneotherapy on oxidative stress and anti-oxidative status suggest that they may have an important role to play in the rheumatic diseases, as they lower the oxidative stress and the resultant inflammatory damage.
Conclusions • These effects of balneo- and spa therapy seems to differ among different patient groups, but may be also different among spa resorts, thermal/mineral waters used and type of spa treatments provided