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Clinical Environmental Medicine

new science and praxis in Complex Multisystem Illnesses (CMI)

Pathomechanisms, immunology (NEIS),

therapy of illnesses associated to the environment

Kurt E. Müller

Brussels 19th of May, 2015

Dr. Kurt E. Müller

Dermatology – Occupational DermatologyEnvironmental Medicine - Preventive Medicine – Stress Medicine

EUROPAEM, dbu, DDG, DBG, D-A-C-HDresden International University (DIU)

Mozartstraße 16D-87435 Kempten – Germany

Fon: +49 (0)831 5126729 – Fax: +49 (0)831 5409294

Incidence of diseases in 6 coutries of EU

caused by 9 environmental stressors

© KEM

* Environmental burden: benzene, formaldehyde, dioxins/furans/PCB, lead,

ozone, transportation noise, second-hand smoke, particulate matter, radon

Hänninen O et al.: European Perspectives

on Environmental Burden of Disease.

National Institute for Health and Welfare

Helsinki, Finland 2011

other causes

93%

9 environmental stressors

cause 7% of all diseases7 %

Belgium

Germany

Finland

France

Italy

Netherlands

Different effect of low dose/long time and

high dose/short time exposure

© KEM

Human

being

Pollutant

dose

Time

High

dose ,

short time:

toxic effect

depending

from

toxicity of

pollutants Low dose – long time: effect

depending from reagibility of

NEIS* and genetic and epigenetic

conditions

*NEIS: neuro-endocrine-immune-system

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Different effect of low dose/long time and

high dose/short time exposure

© KEM

Human

being

Pollutant

Dose

Time

High

dose ,

short time:

toxic effect

depending

from

toxicity of

pollutants Low dose – long time: effect

depending from reagibility of

NEIS* and genetic and epigenetic

conditions

Diseases caused by toxic effects

Diseases depending from genetic

and epigenetic conditions and

reaction of NEIS

Interaction of neuroendocrine-immune system (NEIS)

NEIS: actor – not only reactor

neurogenic

system

endocrine

system

immune

system

NEIS

© KEMDörner 1973; Müller 2008, 2009

natural anthropogenic

social environment

Protection without antigen specific B and T cells – old enemiesRoitt et al. 2006

• C-reactive

protein

• mannose-

binding lectin

polyanions

lipoproteins

lipoteichoic

acid

lipopoly-

saccharide

formylpeptide

muramyl-

peptide

peptidoglycan

BACTERIA

complement C3a,C5a

phagocytes, tissue cells

NK

vascular

permeability

chemotaxis

activation of

phagocytes

adhesion of

Phagocytes

adhesion on

Endothelium

histamine

IFN-y

IL-12, TNF

IL-8

LTB4

CHEMOKINES

CYTOKINES

© KEM

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Protection without antigen specific B and T cells – new enemiesRoitt et al. 2006

• C-reactive

protein

• mannose-

binding lectin

polyanions

lipoproteins

lipoteichoic

acid

lipopoly-

saccharide

formylpeptide

muramyl-

peptide

peptidoglycan

BACTERIA

complement C3a,C5a

phagocytes, tissue cells

NK

vascular

permeability

chemotaxis

activation of

phagocytes

adhesion of

Phagocytes

adhesion on

Endothelium

histamine

IFN-y

IL-12, TNF

IL-8

LTB4

CHEMOKINES

CYTOKINES

metals

solvents

softener

pesticides

herbicides

radiation

electric

and

electro-

magnetic

fields

© KEM

LPS induced cascade of cytokinesDependance of clinical manifestation from quantity of cytokines

(Abbas, Lichtman, Pober (1994): Cellular and Molecular Immunology. Saunders)

LPS TNF-α IL-1ß IL-6 IL-8lipopolysaccharides tumornecrosisfactor-α interleukin-1ß interleukin-6, - 8

low quantities moderate quantities high quantities

locale inflammation

leukocytes

endothelial cells

systemic effects

heart

liver

intestines

central nervous system

damage of organs and

functional systems

heart

liver

kidney

sepsis

septic shock

© KEM

LPS induced cascade of cytokinesDependance of clinical manifestation from quantity of cytokines

(Abbas, Lichtman, Pober (1994): Cellular and Molecular Immunology. Saunders)

LPS TNF-α IL-1ß IL-6 IL-8lipopolysaccharides tumornecrosisfactor-α interleukin-1ß interleukin-6, - 8

low quantities moderate quantities high quantities

systemic inflammation

leukocytes

endothelial cells

systemic effects

heart

liver

Intestines

central nervous system

damage of organs and

functional systems

heart

liver

kidney

sepsis

septic shock

common cinical diseasesalmost unknown

© KEM

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Expression of cytokines by LPS und TNF (Roitt 2006)

„Immunologic engrams“ and induktion of „montonous“ and chronic reactionsLPS = Lipopolysaccharide; TNF = Tumornekrosefaktor

1 2 3 4 5 1 2 3 4 5

Hours after having started the reaction

LPS

TNF-α

IL-1

IL-6

TNF-α

IL-1

IL-6

LPS Challenge TNF-α Challange

© KEM

Expression of cytokines by LPS und TNF (Roitt 2006)

„Immunologic engrams“ and induktion of „montonous“ and chronic reactionsLPS = Lipopolysaccharide; TNF = Tumornekrosefaktor

1 2 3 4 5 1 2 3 4 5

Hours after having started the reaction

LPS

TNF-α

IL-1

IL-6

TNF-α

IL-1

IL-6

LPS Challenge TNF-α Challange

infections

pollutants

© KEM

The new „enemies“ – causing new diseases:

Chronic Multisystem Illnesses (CMI)

Susceptibility

Functional

Modulation

Epigenetic

influence

Genetic

condition

INFECTIONS

© KEM

METALS

GENETIC

ENGENEERING

CHEMICALS

PARTICLES

RADIATION

EMF

Silent

epidemics

caused by

silent(smouldering)

inflammation

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Chron. Multisystem

Illnesses (CMI):

CFS, MCS, FMS, PTSD,

SBS, GWS

Depression ? EHS?

Chronic Pain Disease ?

radiation,

electromagnetic

fields

nutrition,

additivesoccupational

conditions

drugs,

cosmetics

particles, metals,

alloplastic materials

hobbies,

leishure time

activities

living conditions

CMI and environmental influences

© KEM

Pollutants

The new „enemies“ – causing new diseases:

with unspecific symptoms

Susceptibility

Functional

Modulation

Epigenetic

influence

Genetic

condition

INFECTIONS

© KEM

METALS

GENETIC

ENGENEERING

CHEMICALS

PARTICLES

RADIATION

EMF

Symptoms of CMI:

fatigue

myalgia

tendopathia

arthropathia

disturbance

of coordination

cognitive impairment

low stress tolerance

dizziness

vertigo

chemical sensitivity

depression

Therapeutic targets in clinical environmental medicine

© KEM

Control of NEIS (neuroendocrine immune system)

Stop of exposure to pollutants

Optimization of gut function, diet and micronutrients

Regeneration of mitochondrial function

Stress management

Inhibition of NO/ONOOˉ -cycle

Restitution of receptor function

Detoxification

Chronic

Multisystem

Illness

(CMI)

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infections,

pollutants

MHCIITCR

T cell

NF-ĸB APC

proteins or

protein-bound molecules (haptenes)

infections

pollutants

ROS

monoclonal

T cell proliferation:

specificity: IL2

inflammation: IFNy

no proliferation or

specificity → polyclonal

T-cells producing:

IFNy, TNFα, IL1ß; IL6, IL8

MHC II restrictednot MHC restricted

Unspecific immune reaction

© KEM

Cytokine profile in MCS patientens (F. Bartram)

Interferon-y (IFN-y) and susceptibility

Roitt I., Brostoff J., Male D.:Immunology. Sixth Edition, 2001. Mosby; Edinburgh, London, New York, Toronto.

..... IFN y makes cells abnormally

susceptible to intracellular

pathogenes .....

© KEM

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0

100

200

300

400

500

600

IFN-gamma 155 584

IL 2 213 1,13

IL 10 2,85 34,66

Quotient IFN-g/IL2/IL10 0,26 14,91

Influenza Antigen Phthalate

Control: no expression of IFN-y

0

0,2

0,4

0,6

0,8

1

1,2

1,4

IFN-gamma 1 1

IL 2 1,31 1

IL 10 1,04 1

Quotient IFN-g/IL2/IL10 0,73 1

Influenza Antigen Phthalate

TI

TI

Expression of IFN-y caused by phthalates

Silent (smouldering)

inflammation caused

by phthalates

© KEM

Inflammation caused by various pollutants

© KEM

infections

pollutants

MHCIITCR

T cell

NF-ĸBAPC

Proteins or

protein bound molecules (haptens)

infections

pollutants

ROS

Monoclonal

T cell proliferation:

specificity: IL2

inflammation: IFNy

no proliferation or

specificity → polyclonal T

cells producing:

IFNy, TNFα, IL1ß; IL6, IL8

MHC II restrictednot MHC restricted

Specific immune reaction

© KEM

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Path. LTT nach E.

Path. LTT vor E.0

5

10

15

20

25

30

NickelTitan

org. Hganorg. Hg

CadmiumGold

BleiPalladium

Path. LTT nach E. Path. LTT vor E.

Stimulation index (SI) of lymphocyte transformation test (LTT)

before and after removal of metals

n = 124

© KEM © KEM

T cell sensitization caused by various pollutants and moulds

© KEM

© KEM 2014

T cell sensitization to methyl methacrylate

© KEM

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© KEM 2014

T cell proliferation caused by Borrelia burgdorferi

Leaky gut

(GALT = gut associated lymphoid tissue)

Endothelium

tight junctions

leaky gut

physiological and pathological flora

invasive flora

immune reaction

© KEM

T cell mediated food allergy → Colon irritabile?Stimulation index (SI) before and one year after elimination diet

© KEM

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Nitric

oxide(NO˙)

Peroxynitrite(ONOOˉ)

Oxidative

Stress

NF-kB

iNOS

Ca 2+

Superoxide(OO˙ˉ)

Inflammatory

cytokines:

IL-1ß, IL-6, IL-8,

TNF-α, IFN-y

nNOS

eNOS

Circulus vitiosus – NO/ONOOˉ cycle„Vicious cycle“ n. M. Pall 2007

iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS

© KEM

Nitric

oxide(NO˙)

Peroxynitrite(ONOOˉ)

Oxidative

Stress

NF-kB

iNOS

Ca 2+

Superoxide(OO˙ˉ)

Inflammatory

cytokines:

IL-1ß, IL-6, IL-8,

TNF-α, IFN-y

nNOS

eNOS

Circulus vitiosus - Inflammation„Vicious cycle“ n. M. Pall 2007

iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS

1. Stop of exposure

2. Control of Inflammation:

Curcumin

S-Adenosylmethionine (SAMe)

Omega 3 fatty acids

Bromelaine

Cats Claw

Boswellia serrata (indian incense)

Boswellia carterii (afrikan incense)

Coriolus

Reishi

Diclofenac

Ibuprofen

3. Detoxification

© KEM

Nitric

oxide(NO˙)

Peroxynitrite(ONOOˉ)

Oxidative

Stress

NF-kB

iNOS

Ca 2+

Superoxide(OO˙ˉ)

Inflammatory

cytokines:

IL-1ß, IL-6, IL-8,

TNF-α, IFN-y

nNOS

eNOS

Circulus vitiosus – Control of effects„Vicious cycle“ n. M. Pall 2007

iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS

1. Stop of exposure

2. Control of Inflammation:Curcumin

S-Adenosylmethionine (SAMe)

Omega 3 Fettsäuren

Bromelain

Teufelskralle

Cats Claw

Boswellia serrata (indian incense)

Boswellia carterii (afrikan incense)

Coriolus

Reishi

Diclofenac

Ibuprofen

3. Detoxification

Before use control the effect

by TNF-α inhibition test !

© KEM

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Nitric

oxide(NO˙)

Peroxynitrite(ONOOˉ)

Oxidative

Stress

NF-kB

iNOS

Ca 2+

Superoxide(OO˙ˉ)

Inflammatory

cytokines:

IL-1ß, IL-6, IL-8,

TNF-α, IFN-y

nNOS

eNOS

Circulus vitiosus – Inconstant effects„Vicious cycle“ n. M. Pall 2007

iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS

1. Stop of exposure

2. Control of Inflammation:Curcumin

S-Adenosylmethionine (SAMe)

Omega 3 Fettsäuren

Bromelain

Teufelskralle

Cats Claw

Boswellia serrata (indian incense)

Boswellia carterii (afrikan incense)

Coriolus

Reishi

Diclofenac

Ibuprofen

3. Detoxification

TNF-α Inhibition Test (pg/ml):

LPS stimulated basic level: 885

Boswellia carterii: 301

SAMe: 11

Omega 3: 1450

Bromelain: 1986

Curcuma: 491

© KEM

Nitric

oxide(NO˙)

Peroxynitrite(ONOOˉ)

Oxidative

Stress

NF-kB

iNOS

Ca 2+

Superoxide(OO˙ˉ)

ProInflammator.

cytokines:

IL-1ß, IL-6, IL-8,

TNF-α, IFN-y

nNOS

eNOS

Circulus vitiosus – Nitric stress „Vicious cycle“ n. M. Pall 2007

iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS

Actions of nitric oxide:

Binding to aromatic

amines:

Dopamine, Norepinephrine,

Epinephrine, L-Thyroxin

Formation of peroxinitrite

with superoxide.

NO-Scavenger:

Vitamin B12

Melatonine

© KEM

Nitric

oxide(NO˙)

Peroxynitrite(ONOOˉ)

Oxidative

Stress

NF-kB

iNOS

Ca 2+

Superoxide(OO˙ˉ)

Inflammatory

cytokines:

IL-1ß, IL-6, IL-8,

TNF-α, IFN-y

nNOS

eNOS

Circulus vitiosus - Antioxidants

iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS

Antioxidants:

Melatonin Ubiquinol

Lycopin Vitamin C

Vitamin E Karotinoide

NAC α-Lipoic acid

Flavonoides Selenium© KEM

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Inflammation and …….

Tryptophan

5-HTP

Serotonin

TDO

IDO

Kynurenine

99% 1%

IDO

3-OH-Kynurenine

Quinolate

NMDA-ANTAGONIST

3-HK 3-Hydroxy-Kynurenine KAT Kynurenine-Aminotransferas NMDA N-Methyl-D-Aspartat-Receptor

IDO Indolamin-Dioxigenase KMO Kynurenin-Monooxygenase TDO Tryptophan-Dioxygenase

KMO

Inflammation

IFN-y

TNF-α

IL-1ß

LEGENDE:

Melatonin

NEURODESTRUCTION

DESTRUCTION OF

ASTROCYTES

© KEM

Inflammation and Depression

Tryptophan

5-HTP

Serotonin

TDO

IDO

Kynurenine

99% 1%

IDO

3-OH-Kynurenine

Quinolate

NMDA-ANTAGONIST

3-HK 3-Hydroxy-Kynurenine KAT Kynurenine-Aminotransferas NMDA N-Methyl-D-Aspartat-Receptor

IDO Indolamin-Dioxigenase KMO Kynurenin-Monooxygenase TDO Tryptophan-Dioxygenase

KMO

Inflammation

IFN-y

TNF-α

IL-1ß

LEGENDE:

Melatonin

NEURODESTRUCTION

DESTRUCTION OF

ASTROCYTES

DEPRESSION

© KEM

L- Tryptophan

Tryptophanhydroxylase (TPH1, TPH2)Tetrahydrobiopterin

Folate

Dihydrobiopterin

5-Hydroxytryptophan

DOPA-Decarboxylase

Vit. B6

CO2

5-Hydroxytryptamine (Serotonin)

Modulation of function of serotonergic system

Food, Infections

Environment:

chemicals, metals,

EMF, radiation

InflammationINF-y, IL-1ß, TNF-α

Kynurenine

Depression

Serotonintransporter (SERT)

Serrotoninreceptors (15 Typs)

pre- and postsynaptische

NO/ONOO

Genetic - Mikronutrients - Catabolic products

© KEM

26/05/2015

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L- Tryptophan

Tryptophanhydroxylase (TPH1, TPH2)Tetrahydrobiopterin

Folate

Dihydrobiopterin

5-Hydroxytryptophan

DOPA-Decarboxylase

Vit. B6

CO2

5-Hydroxytryptamine (Serotonin)

Modulation of function of serotonergic system

Food, Infections

Environment:

Chemicals, Metals,

EMF, Radiation

InflammationINF-y, IL-1ß, TNF-α

Kynurenine

Depression

Serotonintransporter (SERT)

Serotoninreceptors (15 Typs)

pre- and postsynaptic

NO/ONOO

Genetic - Mikronutrients - Catabolic products

SSRI

&

TAD

© KEM

Inflammation and therapy

Tryptophan

5-HTP

Serotonin

TDO

IDO

Kynurenine

99% 1%

IDO

3-OH-Kynurenine

Quinolate

NMDA-ANTAGONIST

3-HK 3-Hydroxy-Kynurenine KAT Kynurenine-Aminotransferas NMDA N-Methyl-D-Aspartat-Receptor

IDO Indolamin-Dioxigenase KMO Kynurenin-Monooxygenase TDO Tryptophan-Dioxygenase

KMO

Inflammation

IFN-y

TNF-α

IL-1ß

Melatonin

NEURODESTRUCTION

DESTRUCTION OF

ASTROCYTES

1. Identification of causes

2. Inhibition of inflammationCurcumin

SAMe

Omega 3 fatty acid

Cats claw

Boswellia.

Bromelain

Diclofenac u.a.m.

3. Detoxification

© KEM

Depression and substitution

Tryptophan

5-HTP

Serotonin

TDO

IDO

Kynurenine

99% 1%

IDO

3-OH-Kynurenine

Quinolate

NMDA-ANTAGONIST

3-HK 3-Hydroxy-Kynurenine KAT Kynurenine-Aminotransferas NMDA N-Methyl-D-Aspartat-Receptor

IDO Indolamin-Dioxigenase KMO Kynurenin-Monooxygenase TDO Tryptophan-Dioxygenase

KMO

Inflammation

IFN-y

TNF-α

IL-1ß

Melatonin

NEURODESTRUCTION

DESTRUCTION OF

ASTROCYTES

Substitution:

L-Tryptophan

5-Hydroxytryptophan (5-HTP)

Tetrahydrobiopterin

Vit. B6

Folate

© KEM

26/05/2015

14

Nitric

oxide(NO˙)

Peroxynitrite(ONOOˉ)

Oxidative

Stress

NF-kB

iNOS

Ca 2+

Superoxide(OO˙ˉ)

Proinflammator.

cytokines:

IL-1ß, IL-6, IL-8,

TNF-α, IFN-y

nNOS

eNOS

Circulus vitiosus – Inhibition of COMT „Vicious cycle“ n. M. Pall 2007

iNOS=inducible Nitric Oxide Synthase ; nNOS=neural NOS; eNOS=endothelial NOS

COMT Catechol-O-

methyltransferase

-

© KEM

What has changed?

The Speed

The Speed© KEM

Catecholamines

CORTISOL

PARASYMPATHICUS ??

ATP

© KEM

26/05/2015

15

Stress and dysfunction of

dopamine -, norepinephrine - and epinephrin - axis

Dopamin Noradrenalin Adrenalin

praise, satisfaction,

luck, reward,

motoric and intellectual

harmony, peace

restlessness, hurry,

agitation, aggression,

fear, phobia, panic,

© KEM

Catabolism of norepinephrine

NOREPINEPHRINE EPINEPHRINE

COMT

MAO-A

Methionine

S-Adenosylmethionine

(SAMe, AdoMet)

Homocysteine

Methyltetrahydrofolate

ReductaseGlutathion

ATPProtection: SOD2

NO˙/ONOOˉ

DNA-Methylation, Detoxification, Cholin

Vanillinmandelic

acid

© KEM

Catabolism of norepinephrine

NOREPINEPHRINE EPINEPHRINE

COMT

MAO-A

Methionine

S-Adenosylmethionine

(SAMe, AdoMet)

Homocysteine

Folate, Vit. B6,

Vit. B12, BiotinGlutathion

L-Carnitin, NADH,

Q10, Methyl-B12

NO˙/ONOOˉ

DNA-Methylation, Detoxification, Cholin

Vanillinmandelic

acid

© KEM

26/05/2015

16

Secretion of catecholamines and receptor expression on immune cells -

interaction with sympathetic nerve system

NK cells,

B-lymphocytes

dentritic cells

macrophages

sympath.

nerve

dopamin

norepinephrine

epinephrine

dopamin-receptor

α-receptor

ß-receptor© KEM

Stress reaction: COMT- polymorphism, ATP synthesis

and immune function

Aggression

Phobia, Panic

COMT V/V, ATP ↑

COMT V/V, ATP ↓

COMT M/M, ATP ↑

COMT M/M, ATP ↓

IL-10

beforeafter

© KEM

Stress reaction: COMT- polymorphism,

ATP and immune function

Aggression

Phobia, Panik

COMT V/V, ATP ↑

COMT V/V, ATP ↓

COMT M/M, ATP ↑

COMT M/M, ATP ↓

IL-10

beforeafter

Expression of catecholamines

• inhibits TH1 cells

• activates TH2 cells

• elevates use of ATP

• needs Tyrosine

• lowers synthesis of ubiquinon

• elevates use of methylcobalamin

© KEM

26/05/2015

17

Function and structure of mitochondria

citric

cycle

NADH

eˉ

O2

H+ H+ H+

2 H2O

NAD+

ADP

ATP

Q10

H+

ATP

acetyl-CoA

pyruvate fatty acids

pyruvate fatty acids

CARNITIN

ATP synthase

CO2

ADP

outer membrane

inner membrane

INSULIN

DNA

© KEM

Damage of function and structure of mitochondria

citric

cycle

NADH

eˉ

O2

H+ H+ H+

2 H2O

NAD+

ADP

ATP

Q10

H+

ATP

acetyl-coA

pyruvate fatty acids

pyruvate fatty acids

L-carnitin

ATP synthase

CO2

ADP

outer membrane

inner membrane

INSULIN

DNA

demage

by

pollutants

demage

by

pollutants

© KEM

pollutant

Adenosine triphosphate (ATP) as energy pool

ADENOSIN -

TRI PHOSPHATE

ADENOSIN –

DI PHOSPHATE

ADENOSIN -

MONO PHOSPHATE

ATPPP

ADPP

AMP

P

P

32.3 kJ/mol

32.3 kJ/mol

ADENOSINE

© KEM

P 32.3 kJ/mol

© KEM

26/05/2015

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Adenosine triphosphate (ATP) as energy pool

ADENOSIN -

TRI PHOSPHATE

ADENOSIN –

DI PHOSPHATE

ADENOSIN -

MONO PHOSPHATE

ATPPP

ADPP

AMP

P

P

32.3 kJ/mol

32.3 kJ/mol

ADENOSINE

© KEM

P 32.3 kJ/mol

Sports:

Marathon, Triathlon

excessive work

© KEM

Adenosine triphosphate (ATP) as energy pool

ADENOSIN -

TRI PHOSPHATE

ADENOSIN –

DI PHOSPHATE

ADENOSIN -

MONO PHOSPHATE

ATPPP

ADPP

AMP

P

P

32.3 kJ/mol

32.3 kJ/mol

ADENOSINE

© KEM

P 32.3 kJ/molWhat else?

© KEM

Adenosine triphosphate (ATP) as energy pool

ADENOSIN -

TRI PHOSPHATE

ADENOSIN –

DI PHOSPHATE

ADENOSIN -

MONO PHOSPHATE

ATPPP

ADPP

AMP

P

P

32.3 kJ/mol

32.3 kJ/mol

TOTAL 96.9 kJ/mol

STRESS !! P

ADENOSINE

© KEM

P

P

Rassow 2008

© KEM

26/05/2015

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Adenosine triphosphate (ATP) as energy pool

ADENOSIN -

TRI PHOSPHAT(E)

ADENOSIN –

DI PHOSPHAT(E)

ADENOSIN -

MONO PHOSPHAT(E)

ATPP

ADP

AMP

P

P

32.3 kJ/mol

32.3 kJ/mol

TOTAL ENERGY 96.9 kJ/mol

STRESS !! P

ADENOSINE

© KEM

P

P

Rassow 2008

How much social stress

is caused by the strategies

of health systems?

© KEM

Immune activation

NF-kB,TNF-α,IFN-γ,IL-1ß,IL-6

VasodilationAktivatierung des

Glutamat-Rezeptors

ATP-

deficit

Nitric oxide+

Superoxide

= Peroxinitrite

Lack of energy

Immune activation -

nitric oxide - peroxinitrite - cascade

NO˙/ONOO¯

Loss of energy:

25 – 30 %/day

BH2* → BH4*

* BH2 = Dihydrobiopterin

* BH4 = Tetrahydrobiopterin(Pall 2009)

Straub et al. 2010

Pall 2007

Kuklinski 2007

Hill 2007+2010

Myhill 2010

ROS

L-Carnitine

NADH

Ubiquinol

Vit. B12 (Met-B12)

IHHT

© doc.müller.ke

Published papers about endocrine disruptors

between 1993 and november 2006 (Gies)

Colborn, vom Saal, Soto (1993): EHP

endocrine disruptors

26/05/2015

20

TNF-α activates cortisol axis and

blocks sex hormones

Adrenal Gland

Cholesterol

Progesteron

e

Pregnenolone

11-Desoxycorticosterone

Corticosterone

18-Hydroxy-Corticosterone

Aldosterone

17a-Hydropregnenolone

17a-Hydroprogesterone

11-Desoxycortisol

Cortisol

Cortison

Gonads

DHEADHEA(S)

7ß-Hydroxy-DHEA

Androstendione Estron

Testosteron 17ß-Estradiol

Straub R.H. Pathophysiologie komplexer chronischer Erkrankungen, Band 1

TNF-α activates cortisol axis and

blocks sex hormones

Adrenal Gland

Cholesterol

Progesterone

Pregnenolone

11-Desoxycorticosterone

Corticosterone

18-Hydroxy-Corticosterone

Aldosterone

17a-Hydropregnenolone

17a-Hydroprogesterone

11-Desoxykortisol

Kortisol

Kortison

TNF-a+

Gonads

DHEADHEA(S)

7ß-Hydroxy-DHEA

Androstendione

TNF-α

TNF-α TNF-α

Estrone

+

Testosterone 17ß-Estradiol

TNF-α

TNF-α

+

Straub R.H. Pathophysiologie komplexer chronischer Erkrankungen, Band 1

TNF-α aktiviert die Synthese von Kortisol und hemmt

die der Sexualhormone

Adrenal Gland

Cholesterol

Progesterone

Pregnenolone

11-Desoxycorticosterone

Corticosterone

18-Hydroxy-Corticosterone

Aldosterone

17a-Hydropregnenolone

17a-Hydroprogesterone

11-Desoxycortisol

Kortisol

Kortison

TNF-a+

Gonads

DHEADHEA(S)

7ß-Hydroxy-DHEA

Androstendione

TNF-α

TNF-α TNF-α

Estron

+

Testosterone 17ß-Estradiol

TNF-α

TNF-α

+

Straub R.H. Pathophysiologie komplexer chronischer Erkrankungen, Band 1

26/05/2015

21

NMDA*- ReceptorAgonists, Co-Agonists, Channel Blockers und Antagonists

NMDA*- Receptor (*N-Methyl-D-Aspartat)

Agonists, Co-Agonists, Channel Blockers and Antagonists

Mg

The German Solution

%

psychogenic diseases

225

100

© KEM

26/05/2015

22

END

Stick

oxid

Peroxinitrit

Oxidativer

Stress

NF-kB

iNOS

Ca 2+

Superoxid

Proinflammator.

Zytokine:

IL-1ß, IL-6, IL-8,

TNF-α, IFN-y

nNOS

eNOS

Circulus vitiosus – stress regulaion„Vicious cycle“ n. M. Pall 2007

iNOS=induzierbare; nNOS=neurogene; eNOS=endotheliale Stickoxidsynthase

Blocks

activity of

Catechol-O-

methyltransferase

© KEM