Sandbox cerebral palsy

Pathophysiology

Mucosal barrier

• The gastric mucosa is protected from the acidic environment by mucus, bicarbonate, prostaglandins, and blood flow.
• This mucosal barrier consists of three protective components which include:
  • Layer of epithelial cells lining.
  • Layer of mucus, secreted by surface epithelial cells and Foveolar cells.
  • Bicarbonate ions, secreted by the surface epithelial cells.

Mechanism of Action

• The insoluble mucus forms a protective gel-like coating over the entire surface of the gastric mucosa.
• The mucus protects the gastric mucosa from autodigestion by e.g. pepsin and from erosion by acids and other caustic materials that are ingested.
• The bicarbonate ions act to neutralize harsh acids.
• If the balance of gastric acid secretion and mucosal defenses is disrupted, acid interacts with the epithelium to cause damage

Pathogenesis

• Regardless of etiology, if the balance of gastric acid secretion and mucosal defenses is disrupted, acid interacts with the epithelium to cause damage.
  • Helicobacter pylori disrupts the mucosal barrier and causes inflammation of the mucosa of the stomach and duodenum.
  • As the ulcer progresses beyond the mucosa to the submucosa the inflammation causes weakening and necrosis of arterial walls, leading to pseudoaneurysm formation followed by rupture and hemorrhage.
  • NSAIDs inhibit cyclooxygenase, leading to impaired mucosal defenses by decreasing mucosal prostaglandin synthesis.
  • During stress, there is acid hypersecretion; therefore, the breakdown of mucosal defenses leads to injury of the mucosa and subsequent bleeding.
  • Mucosal defects along with dilated and tortuous vessels in dieulafoy lesion put them at risk for rupture because of necrosis of the arterial wall from exposure to gastric acid.

NSAIDS

Inhibits cycloxygenase pathway

COX-1

COX-2

Reduced mucosal blood flow

Reduced mucosal and bicarbonate secreation

Impaired platelet aggregation

Reduced angiogenesis

Increased leucocyte adherence

Impaired defence Impaired healing

Mucosal Injury

A01

A02

A02

B01

B02

C01

C02

D01

E01

B01

B02

B03

C01

C02

C03

Pathogenesis of Crohn's disease

• Genetic component
• Stress and environmental component
• Microbial component
• Inflammatory component

Genetic Component

Genes involved

• NOD2/CARD15 gene
• OCTN1 gene
• DLG5 gene
• TLR4 gene

Genes	Chromosome		Function	Mutation
NOD2/CARD15	16	16q12.1	Encodes a scaffolding protein important for maintaining epithelial integrity	Disrupts normal epithelial integrity
OCTN1	05	5q31	Ecodes an ion channel	Alters the function of cation transporters and cell-to-cell signaling
DLG5	10	10q22.3	Interact additively with the NOD2/CARD15 gene	Iincrease susceptibility to CD along with CARD15
TLR4	09	9q33.1	Lipopolysaccharide signaling, bacterial recognition, and subsequent immune response	Altered immune response to pathogens and a subsequent increase in inflammation.

Stress and Environmental Component

• Stress signals are perceived by the central nervous system (CNS), triggering the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis.
• Neuroendocrine mediators released in response to stress not only modulate secretory, absorptive, and barrier functions in the gut but also increase the gut permeability.
• Factors involved in the effects of stress on gut permeability include
  • Corticotropin-releasing factor
  • Autonomic nervous system
  • Enteric nervous system

Microbial Component

The possible mechanisms for a bacterial etiology in the development of CD include:

• Initial immune response to a specific pathogen resulting in intestinal infection
• Alterations in normal bacterial flora of the intestinal tract
• Defective mucosal barrier and overwhelming exposure to resident bacteria and their antigens and endotoxins
• Alterations to the intestinal immune response

Common bacteria responsible for Crohn's disease
Escherichia coli Listeria monocytogenes Yersinia enterocolitica Mycobacterium avium subspecies paratuberculosis Measles virus