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HEALING (spontaneous
ULCER Acid or therapeutic)
EROSIONS
Risk Factors for NSAIDs Induced
Gastroduodenal Ulceration
Established Possible
Advanced age Concomitant infection with
History of ulcer H. pylori
Concomitant use of glucocorticoids Cigarette smoking
High-dose NSAIDs Alcohol consumption
Multiple NSAIDs
Concomitant use of anticoagulants
Serious or multisystem disease
Disorders Associated with Peptic
Ulcer Disease
Inflammatory
H. pylori cell
TNF-
D –
IL-1
––
– P +–
– – SMS
acid
+ + + ECL
D G +
– + – +
TNF-
Inflammatory IFN-
IL-8+ cell IL-8
Bacterial factors Host factors
Structure Duration
Adhesins Location
Ponns Inflammatory response
Enzymes Genetics??
(urease, vac A, cag A, etc)
Chronic gastritis
Peptic ulcer disease
Gastric MALToma
Gastric cancer
Reported Pathophysiologic Abnormalities
in Patients with Duodenal Ulcers
Acetylcholine
Cannaliculus
Histamine
H, K ATPase ECL cell
Tubulovesicles
Histamine –
– –
ECL cell
Somatostatin Somatostatin
Gastrin D cell
Phospholipase A2
Arachidonic acid
Stomach Macrophages
Kidney COX-1 COX-2 Leukocytes
Platelets housekeeping inflammation Fibroblasts
Endhothelium Endothelium
Preepithelial
H+ Pepsin Lumen
• Mucus pH 1-2
• Bicarbonate
• Surface active Mucus gel
phospholipids HCO3- pH 7 HCO3-
Epithelium
Epithelial
• Cellular resistance Prostaglandin
• Restitution
• Growth factors, Microcirculation
protaglandins
•Cell proliferation
Subepithelial
• Blood flow
•Leukocyte
ADHESION MOLECULES, CYTOKINE AND CHEMICAL
MEDIATOR IN LEUKOCYTE-ENDOTHELIAL INTERACTIONS
Rolling Sticking Transmigration
PAF
L-selection C5a
SLeX LTB4
SLea IL-8 H2 O 2 IL-8
PAF
CD11/CD18 Endothelial cells
P-selectin E-selectin ICAM-1 PAF PECAM-1
Endothelial injury
Thrombin
Collagenase
IL-1 Elastase
Histamine Activated
H2O2 TNF PMN
LTC4 LPS
LTD4 Oxygen radicals, Protease
Tissue injury
POSSIBLE MECHANISM OF ULCER
RECURRENCE
ULCER RECURRENCE
IL-1, TNF-
(NSAID, H. pylori, stress) Neurophil Infiltration
Gastric acid
Cytokines
(IL-1, TNF-)
Chemokines Neutrophil activation
(MCP-1, TGF- 1)
Cytokines
Macrophage activation Chemokines
Monocyte infiltration
ULCER SCAR
Endothelial cell-leukocyte interaction
(ICAM-1/LFA-1, ICAM-1/Mac-1)
Role of neutrophil-endothelial
interactions in the pathogenesis
NSAIDs
LT/PG
Monocyte
activation
LTC4, LTD4 LTB4
TNF-
Vasospasm
Neutrophil activation Endothelial cell activation
(CD11b/CD18) (ICAM-1)
H. pylori H. pylori
infection infection
Duodenal Gastric
Virulence Factors of Helicobacter pylori that
Promote Colonization and induce Tissue Injury
Promote Colonization
Flagella (for motility)
Urease*
Adherence factors
Induce Tissue Injury
Lipopolysaccharide
Leukocyte recruitment and activating factors
Vacuolating cytotoxin (VacA)
Cytotoxin-associated antigen (CagA)
Other membrane inflammatory protein (OipA)
Heat shock proteins (HspA, HspB)
* Not essential for colonization
Proposed natural history of Helicobacter
pylori infection in humans
Environmental
Factors
Gastric Cancer
Multifocal
Atrophic Gastric Ulcer
Gastritis
Lymphoma
ECL EC EC
G
35% 25% 29%
49%
D D
Other 26% 19%
14% Other
3%
Oxyntic Mucosa Pyloric Mucosa
ECL, enterochromaffin-like (histamine); EC, enterochromaffin (serotonin);
D (somatostatin); G (gastrin)
Exocrine Cells within Gastric Glands and
Their Secretory Products*,†
GLAND EXOCRINE
AREA CELLS
% OF ANATOMIC WITHIN SECRETORY
TOTAL COUNTERPART GLANDS PRODUCTS
Cardiac Proximal stomach Mucus neck Mucin, PGII
(<5%) just below esoph-
agogastric junc-
tion
Oxyntic Fundus and body Mucus neck Mucin, PGI and
(75%) PGII‡
Chief PGI and PGII, ‡
leptin
Parietal HCI, intrinsic
factor§
Pyloric Antrum and pylorus Mucus neck Mucin, PGII
*Pepsinogen I (PGI), includes Pg 1-5; PGII includes Pg6 and Pg7.
†Endocrine cells are also present within glands
‡PGI and PGII are colocalized in zymogen granules and are secreted concurectly
§Some intrinsic factor may also be produced in chief cells and endocrine cells
Factors That May Modulate the Rate of
Gastric Emptying
Meal Factors
Volume Emptying rate proportional to volume
Acidity Slowing of emptying
Osmolarity Slower emptying of hypertonic meals
Nutrient density Emptying rate inversely proportional to
nutrient density
Fat Slowing of emptying
Certain amino acids Slowing of emptying
(e.g., L-tryptophan)
Other Factors
Ileal fat Slowing of emptying (ileal “brake”)
Rectal/colonic distention Slowing of emptying
Pregnancy Slowing of emptying