Molekulare Physiologie und Pathobiochemie ausgewählter Magen ...
Molekulare Physiologie und Pathobiochemie ausgewählter Magen ...
Molekulare Physiologie und Pathobiochemie ausgewählter Magen ...
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ZIEL<br />
<strong>Magen</strong>-Darmtrakt<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
<strong>Molekulare</strong> <strong>Physiologie</strong> <strong>und</strong> <strong>Pathobiochemie</strong><br />
<strong>ausgewählter</strong> g <strong>Magen</strong>-Darmfunktionen<br />
g<br />
Gr<strong>und</strong>lagen der Verdauungs Verdauungs- <strong>und</strong> Resorptionsprozesse<br />
Maldigestionsphänomene<br />
Malabsorptionsphänomene<br />
Di Diarrhoen h <strong>und</strong> d ihre ih Gr<strong>und</strong>lagen<br />
G dl<br />
Wirkungsmechanismen von E. coli STa-Toxin & Choleratoxin<br />
Orale Rehydrierung bei Diarrhoen <strong>und</strong> Basis der Wirksamkeit<br />
Malfunktionen von SGLT1
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Gastrointestinaltrakt: Anatomie <strong>und</strong> Passagezeiten
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Intestinaltrakt: Morphologie <strong>und</strong> Ultrastruktur
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Intestinaltrakt: Morphologie <strong>und</strong> Ultrastruktur
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
White-light endoscopy, in vivo imaging and histology of normal villi architecture of the terminal ileum<br />
Kiesslich R et al (2007) Technology Insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer<br />
Kiesslich R et al. (2007) Technology Insight: confocal laser endoscopy for in vivo diagnosis of colorectal cancer<br />
Nat Clin Pract Oncol 4: 480–490 doi:10.1038/ncponc0881
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Übersicht zur Verdauung <strong>und</strong> Resorption von Nährstoffen
ZIEL<br />
Gallenblase<br />
Pankreas<br />
<strong>Magen</strong><br />
Duodenum<br />
ca. 30 cm<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Jejunum<br />
ca. 120 cm<br />
α<br />
α<br />
Ileum<br />
ca. 180 cm<br />
Dickdarm<br />
Rektum<br />
membrangeb<strong>und</strong>ene<br />
Phase
ZIEL<br />
-AMYLASE<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Mechanismen der Resorption der Monosaccharide<br />
Amylose<br />
Amylopectin<br />
Gl Glycogen<br />
MMembrangeb<strong>und</strong>ene b b d Di-<strong>und</strong> Di d Oligosaccharid-Hydrolasen<br />
Oli h id H d l<br />
-Dextrine<br />
Malto-oligosaccharide<br />
Maltose<br />
Glucose<br />
Saccharose<br />
Lactose<br />
Glucose<br />
Galactose<br />
Fructose<br />
Glucose<br />
Galactose<br />
Fructose<br />
SGLT1<br />
Glut5<br />
Energiemetabolismus<br />
Na +<br />
Glucose<br />
Glut2<br />
Fructose<br />
Glut2<br />
Glut2<br />
Glut2<br />
Glucose<br />
K +<br />
Na +<br />
Glucose<br />
Galactose<br />
FFructose t<br />
Portalvenen-Blut
ZIEL<br />
Pankreasproteasen<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Mechanismen der Resorption der Aminosäuren<br />
Proteine<br />
Oligopeptide<br />
Di-/Tripeptide<br />
freie Aminosäuren<br />
Di-/Tripeptide<br />
H +<br />
PEPT-1 PEPT 1<br />
Imino<br />
Membran-geb<strong>und</strong>ene Peptidhydrolasen<br />
Aminosäuren<br />
ß<br />
B<br />
Aminosäuren-Pool<br />
X- X AG<br />
b 0,+<br />
cytosolische<br />
Hydrolasen ? Di-/Tripeptide<br />
Aminosäuren Aminosäuren<br />
B<br />
ASC<br />
L<br />
y +<br />
Aminosäuren<br />
Portalvene
ZIEL<br />
α<br />
β<br />
γ<br />
FS<br />
FS<br />
FS<br />
Triglyzeride mit<br />
llangkettigen k tti FS<br />
Lipase<br />
Lipase<br />
Lipase p<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Mechanismen der Resorption der Lipide<br />
FS<br />
α<br />
β<br />
γ<br />
α<br />
β<br />
γ<br />
FS<br />
FS<br />
FS<br />
OH<br />
OH<br />
FS<br />
OH<br />
ca. ca 10% 0%<br />
ca. 70%<br />
BP<br />
FS-BP<br />
ATP CoA-SH<br />
Thiokinase<br />
AMP + PP i<br />
FS-CoA<br />
OH<br />
FS<br />
OH<br />
Acyltransferasen<br />
CoA-SH<br />
FS FS, FFettsäure; ä BP BP, Bi Bindungsprotein<br />
d i<br />
FS Blutgefäße<br />
FS<br />
FS<br />
α OH<br />
FS<br />
FS<br />
β OH ca. 20% Lymphgefäße<br />
γ OH Apolipoproteine<br />
α FS<br />
β FS<br />
γ FS<br />
Triglyzeride mit kurz<strong>und</strong><br />
mittelkettigen FS<br />
Lipase<br />
Glyzerin<br />
FS<br />
Lymphgefäße<br />
y p g<br />
Blutgefäße
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Maldigestion (Ursachen von Verdauungsstörungen)<br />
Reduzierung oder Ausfall der Verdauungsfunktion des <strong>Magen</strong>s:<br />
Ursachen: Resektion, chronische atrophische Gastritis<br />
Folgen: Pepsin ↓: leicht durch Pankreasenzyme kompensierbar;<br />
Achlorhydrie: Bildung schwer lösl. Eisenkomplexe im neutralen Milieu = Eisenmangel<br />
Reduzierung oder Ausfall der exokrinen Pankreasfunktion:<br />
Ursachen: chronische Pankreatitis Pankreatitis, Karzinom Karzinom, Resektion Resektion, Fehlen von CCK <strong>und</strong> Sekretin<br />
nach <strong>Magen</strong>resektion.<br />
Folgen: Lipase (am störanfälligsten) ↓ mit Steatorrhoe, deren Ausmaß eine Klassifizierung<br />
der Pankreasinsuffizienz ermöglicht: leicht – nur nach Erhöhung des Fettanteils in<br />
der Nahrung; mäßig – bei Normalkost; schwer – bei fettreduzierter Kost.<br />
Gewichtsreduktion, Mangel an fettlöslichen Vitaminen, Durchfallneigung.<br />
Reduzierung oder Ausfall der Gallensäurenwirkung:<br />
Ursachen: Cholestase, Gallensäuren-Verlustsyndrom durch Ileumentzündung,<br />
stark beschleunigte Passage, Bestrahlungsschäden, bakterielle Fehlbesiedelung.<br />
FFolgen: l Fettverdauung F tt d <strong>und</strong> d –resorption ti ↓ (GS (GS-Verlust V l t mit it <strong>und</strong> d ohne h KKompensation), ti )<br />
chologene Diarrhoe durch sek. GS im Kolon, Gallensteinbildung, enterale Hyperoxalurie<br />
mit Nierensteinbildung durch Detergenzwirkung der GS im Kolon.
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
MMalabsorption l b ti (Ursachen (U h von Dünndarmepithelstörungen)<br />
Dü d ith l tö )<br />
Erkrankungen g des Dünndarms mit den Leitsymptomen y Diarrhoe <strong>und</strong> Gewichtsverlust<br />
primär: Mucosa morphologisch unverändert;<br />
sek<strong>und</strong>är: Schädigung (Atrophie) der Mucosa oder Behinderung des Abtransportes<br />
resorbierter Stoffe durch Blut oder Lymphe.<br />
Beispiel: Zöliakie<br />
Hematoxylin-eosin stained cross-sections of intestinal villi: normal epithelium<br />
(left) and celiac epithelium (right), characterized by infiltration of intraepithelial lymphocytes and flattened villi.
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Celiac Disease (Zöliakie=glutensensitive Enteropathie<br />
Prävalenz auf 1:500 in Deutschland <strong>und</strong> Dänemark <strong>und</strong> etwa 1:110 in den USA <strong>und</strong> Großbritannien,<br />
im weltweiten Durchschnitt ungefähr 1:270<br />
Symptoms of celiac disease are caused by a glutamine and proline rich peptides fo<strong>und</strong> in gluten that<br />
initiates the inflammatory response when bo<strong>und</strong> to these HLA haplotypes (Shan, (Shan Lu et al, al 2002). 2002) The<br />
primary HLA association in most patients with celiac disease is with DQ2 (DQA*05/DQB1*02) and in a<br />
minority of patients with DQ8 (DQA1*03/DQB1*0302). Approximately 97% of individuals with celiac disease<br />
have the HLA-D2Q or HLA-DQ8, compared to 40% of the general population (NIH, 2006). The x-ray crystal<br />
structure of the soluble domain of HLA HLA-DQ2 DQ2 was observed bo<strong>und</strong> to the deaminated gluten epitope alpha- alpha<br />
I-gliadin. The HLA association in celiac disease can be explained by a superior ability of DQ2 to bind the<br />
repertoire of proline-rich gluten pepties that have survived gastrointestinal digestion and that have been<br />
deaminated by tissue transglutaminase (Kim et al., 2004).<br />
Celiac disease is diagnosed in about 10% of first degree relatives of an individual with celiac disease<br />
(Logan, 1992). Although hereditary factors play a significant role, genetic factors alone do not explain the<br />
development of the disease because the disease is concordant in only 60% to 70% of identical twins. All<br />
people with HLA DQ2 and DQ8 do not develop into disease, and others without those alleles can develop<br />
celiac disease, so more genes may be involved. Additional factors such as hormones and infectious<br />
agents may also be involved in linking the ingestion of gluten with a chronic inflammatory reaction in the<br />
intestine in genetically predisposed individuals (Fasano,1996).
<strong>Magen</strong>-Darmtrakt<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Gliadins are compact and in the globular shape and the glutenins are linear and have<br />
relatively higher molecular weight 50,000-millions compare with the molecular weight of gliadins 20,000-50,000.
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Digestion breaks down gluten (A) into peptides (B) that are absorbed by the small intestine.<br />
There, the enzyme tissue transglutaminase (C) modifies certain peptides, which are picked up<br />
by dendritic cells and, in people with celiac disease, stimulate immune cells (D) to attack the intestine.<br />
Nearly all people with the disease have one of two immune-molecule types: About 90 percent<br />
ea y a peop e t t e d sease a e o e o t o u e o ecu e types bout 90 pe ce t<br />
carry so-called DQ2 molecules, and most of the rest carry DQ8 molecules.<br />
Genetics determines whether a person has either or both of these disease-associated molecules
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Depiction of the intestinal mucosa with emphasis on the factors that take part in the development and control of coeliac disease. a | The parts of gluten that are<br />
resistant to processing p gby y luminal and brush-border enzymes y will survive digestion, g , and can be transported p across the mucosal epithelium p as polypeptides.<br />
p yp p<br />
Gluten peptides are deamidated by tissue transglutaminase (TG2), which, in the intestinal mucosa, is located mainly extracellularly in the subepithelial region,<br />
but is also fo<strong>und</strong> in the brush border. CD4+ T cells in the lamina propria recognize deamidated gluten peptides predominantly, presented by HLA-DQ2 or -DQ8<br />
molecules on the cell surface of antigen-presenting cells (APCs). b | Immunofluorescence staining of TG2 (pink), HLA-DQ (green) and T cells (CD3; purple) in<br />
the small-intestine mucosa of an untreated coeliac-disease patient. Note that there is a close spatial relationship between TG2, APCs that express HLA-DQ and<br />
T cells just beneath the epithelium.
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Factors that might contribute to this clustering are indicated. | Proline protects peptides from proteolytic degradation during digestion. | Proline has a<br />
dominant role in the specificity of tissue transglutaminase (TG2) and guides which glutamine residues can be deamidated. c | Oligomerized epitopes<br />
can be particularly efficient as T-cell antigens and TG2 substrates. A 33-mer fragment of α-gliadin, which results from physiological processing, is<br />
shown. This fragment contains three unique T-cell epitopes, which are present three, two and one times, respectively. d | Proline can facilitate binding<br />
to HLA-DQ2 by acting as an anchor residue or by inducing a type-II polyproline helical conformation.
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Gliadin peptide fragment derived from gluten protein is presented by antigen-presenting<br />
cells with specific class II HLA-DQ alleles.<br />
Model of the gliadin peptide.<br />
Surface of HLA-DQ with bo<strong>und</strong> gliadin peptide to red region.<br />
Hydrogen-bonding network in the HLA-DQ-gliadin complex
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Gliadin is absorbed into the lamina propia and presented in conjunction with HLA-DQ2 or DQ8 cell-surface antigens by antigen-presenting cells,<br />
probably dendritic cells, to sensitized T cells expressing the α/β TT-cell cell receptor. Tissue transglutaminase deaminates gliadin peptides, generating<br />
acidic, negatively charged residues of glutamic acid from neutral glutamines (inset). Since negatively charged residues are preferred in positions 4,6,<br />
and 7 of the antigen-binding groove of HLA-DQ2, deaminated gliadin elicits a stronger T-cell response. These lymphocytes then activate other<br />
lymphocytes to generate cytokines, such as interferon-γ, interleukin-4, and tumor necrosis factor α (TNF- α), which damage the villi, resulting in<br />
enteritis. Induction of aberrant HLA class II cell-surface antigens on the enterocytes may permit these cells to present additional antigens to the<br />
sensitized lymphocytes (Westerberg et al.,2006).
ZIEL<br />
Diät bei Zöliakie<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Momentan ist die einzige gesicherte Möglichkeit Möglichkeit, die Krankheit zu behandeln, behandeln eine lebenslange glutenfreie Diät Diät, wodurch der Darm wieder heilt <strong>und</strong><br />
auch die Risiken der Langzeitfolgen sinken. Strikt zu vermeiden sind alle Getreidesorten mit hohem Glutengehalt (Weizen, Gerste, Roggen, wie auch<br />
deren botanisch verwandten Ursorten Dinkel, Grünkern, Einkorn, Emmer sowie die Roggen-Weizen-Kreuzung Triticale).<br />
Ausdrücklich erlaubt sind Hirse, Mais, Reis, Amarant, Buchweizen, Quinoa, Sojabohnen, Teff, Kastanie, Kochbanane.<br />
Ein Teil dieser Sorten wird beispielsweise auch zur Herstellung von glutenfreiem Bier verwendet verwendet. Ohnehin erlaubt sind Gemüse einschließlich<br />
Kartoffeln, Salate, Früchte, Fleisch <strong>und</strong> Fisch, Eier, Milch <strong>und</strong> Milchprodukte.<br />
Subtotal villous atrophy<br />
Same patient after 4 weeks<br />
on gluten free diet
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Störungen der Elektrolyt- Elektrolyt <strong>und</strong> Wasserresorption
ZIEL<br />
<strong>Magen</strong><br />
ca. 1000 ml<br />
Getränke/Nahrung<br />
ca. 1500 ml<br />
ca. 2000 ml<br />
Pankreas <strong>und</strong> Galle<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Intestinale Flüssigkeitsbilanz beim Ges<strong>und</strong>en<br />
Dünndarm<br />
ca. 2000 ml<br />
Dünndarm Dickdarm Rektum ca. 100 ml im Stuhl<br />
ca. 4500 ml ca. 2000 ml<br />
Resorbiert: ca. 6500 ml
ZIEL<br />
Ileocaecaler<br />
Fluss<br />
Stuhlwasser<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Wasserbewegungen im Darm <strong>und</strong> ihre Störungen<br />
Ges<strong>und</strong> Dünndarmerkrankung Dickdarmerkrankung<br />
2000 ml 4500 ml 5900 ml 2500 ml 2500 ml<br />
100 ml<br />
1900 ml 4400 ml 4400 ml 1000 ml<br />
100 ml<br />
1500 ml<br />
1500 ml 3000 ml<br />
Diarrhoe nein nein ja ja ja<br />
500 ml
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Funktionelle Gr<strong>und</strong>lagen der Elektrolytresorption im Darm (Colon)<br />
Na<br />
K<br />
Cl -<br />
Na<br />
NHE-3<br />
H<br />
K<br />
Na<br />
K K<br />
NaCl NaCl<br />
HCO -<br />
HCO 3<br />
Cl -<br />
CA<br />
HCO -<br />
3<br />
H2O+ CO2 Cl -<br />
Na<br />
0 mV V -40 40 mV V<br />
-20 20 mV V<br />
osmotischer Wasser-Gradient<br />
Cl -
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Von der <strong>Physiologie</strong> y g zur Pathophysiologie p y g <strong>und</strong> ihrer molekularen Gr<strong>und</strong>lagen g
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Diarrhoen als weltweites Ges<strong>und</strong>heitsproblem<br />
In 2002, 142,311 cases of cholera including 4564 deaths<br />
were officially reported to the World Health Organization,<br />
although this is almost certainly an <strong>und</strong>erestimate
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Diarrhoen als weltweites Ges<strong>und</strong>heitsproblem
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Wirkungen von Cholera-Toxin auf die Sekretionsprozesse
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Invasionsweg des Choleratoxins
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Choleratoxin führt zur ADP-Ribosylierung des G-α-Protein der Adenylatcyclase<br />
constitutiv erhöhte<br />
c-AMP-Spiegel
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Vom Cholera-Toxin zu E. coli STa-Toxin (Reisediarrhoe)<br />
( )
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Struktur des Guanylacyclase C-Gens <strong>und</strong> seiner funktionellen Dömänen<br />
Sequenzhomologien/ Sequenzhomologien/-identitäten identitäten in Guanylin <strong>und</strong> EE. coli STa-Toxin<br />
STa Toxin
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Mechanismus der Aktivierung der Guanylatcyclase C<br />
durch Guanylin/E Guanylin/E. coli STa-Toxin
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Signalkette von Guanylin/E. coli STa-Toxin bei der Initiation<br />
der intestinalen Elektrolytsekretion
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Behandlung intestinaler Sekretionsstörungen (Diarrhoen)<br />
Orale Rehydrierungslösung (WHO)
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Die zentrale Rolle von SGLT1 in der oralen Rehydrierung<br />
Immunhistochemischer Nachweis<br />
von SGLT1 im Dünndarmepithel
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
Die Membrantopologie von SGLT1<br />
Die SGLT-Proteinfamilie in Prokaryoten <strong>und</strong> Eukaryoten
ZIEL<br />
<strong>Molekulare</strong> <strong>Physiologie</strong> - <strong>Pathobiochemie</strong><br />
HHereditäre ditä Gl Glucose/Galactose /G l t Malabsorption<br />
M l b ti<br />
durch Mutationen (autosomal recessiv) im SGLT1-Gen
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