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

Infectious Pathogens Implicated in Crohn’s Disease
Escherichia coli Listeria monocytogenes Yersinia enterocolitica Mycobacterium avium subspecies paratuberculosis Measles virus

Immune Component

• Altered immune response:
  • An abnormal antibody response to an unspecified bacterial antigen is mainly responsible for inflammation in Crohn's disease.
  • The inflammatory response is believed to be triggered when elimination of specified microbial antigen was unsuccessful leading to altered immune response
  • Dysregulation of normal mucosal immune response results in failure of phagocytosis leading to antigen persistence.
  • Antigen persistance leads to antibodies production against all the normal gut flora.
  • Activation resulted in secretion of tumor necrosis factor-alpha (TNF-alpha) and subsequent epithelial changes.
• Cytokine response:
  • A T-cell mediated immune response has been identified in the mucosa of CD, in contrast to UC, and is postulated to be the primary precipitating event.
  • The ensuing production of inflammatory cytokines can cause ulceration and increased intestinal permeability.
  • Animal models confirm the generally held consideration that CD is primarily a T-helper 1-(Th1) dominant condition.
  • In murine models, disease induced by a Th1 over-expression results in lesions histologically compatible with CD (including granulomas), while a T-helper 2- (Th2) mediated response results in lesions more closely resembling ulcerative colitis (including a lack of granulomas).
  • As mentioned, the characteristic granulomatous lesion seen in Crohn’s disease is evidence of a cell-mediated immune response.
  • In human studies, while chronic CD appears to involve primarily an overactive Th1 response characteristic of a cell-mediated phenomenon, some researchers have determined divergent cytokine patterns at different stages of the disease.
  • Chronic lesions are associated with high levels of interleukin-2 (IL-2), interferon gamma (IFN-gamma),87 TNF-alpha, and interleukin-12 and -18 (IL-12 and IL-18).
  • Desreumaux et al, however, found a distinctly different cytokine pattern in the early CD.
  • By examining ileal biopsy specimens of 17 patients compared to 11 controls, the researchers determined that early lesions were characterized by elevations in interleukin-4 (IL-4) and decrease in IFN-gamma, a pattern more consistent with an overactive Th2 immune response.
  • Other researchers have found, at least in animal models, the opposite may be true. In a mouse model of ileitis (a CD-like enteritis), researchers found elevated Th2 cytokines, including IL-4, during the chronic phase of the disease.
  • IL-18 is up-regulated in Crohn’s disease. Although typically considered to be an activator of Th1 responses, IL-18 has actually been shown to be a pleiotropic cytokine capable of mediating both Th1 and Th2 responses, providing more potential evidence for divergent cytokine patterns in the pathogenesis of CD.
  • Another study examined human colonic tissue samples and found IL-16 protein levels elevated in CD patients but not UC patients.
  • The same study found an anti-human IL-16 antibody could suppress colonic injury in a murine model of Crohn’s-like experimental colitis.
  • Pro-inflammatory cytokines are normally kept in check by immunosuppressive cytokines such as transforming growth factor beta (TGFbeta).
  • It is believed the transcription factor T-bet is integral to controlling the balance between pro and anti-inflammatory cytokines.
  • T-bet is elaborated by Th1 cells, but not Th2 cells. IFN-gamma is enhanced by T-bet. Neurath et al examined Tbet activity in lamina propria T-cells of patients with CD as well as in animal models.
  • The researchers discovered T-bet over-expression in the lamina propria T-cell nucleus in patients with CD, but not UC or controls.
  • In the animal models, T-bet overexpression was consistent with Th1-mediated colitis (animal model of CD), while a T-bet deficiency was protective.
  • Tumor necrosis factor appears to play a significant role in the pathogenesis of CD. Mucosal biopsies of children with IBD compared to controls found a significantly greater number of TNF-alpha-secreting cells in patients with CD compared to those with UC or non-specific bowel inflammation.91 A significant difference between mild-to-moderate and severe disease was also noted for the CD subgroup, with severe disease demonstrating a significantly greater percentage of TNF-secreting cells. In animal models of Crohn’s ileitis, neutralization of TNF resulted in significant decrease in inflammation.
  • Indeed, suppression of TNF-alpha is the primary mechanism of action of the monoclonal antibody category of CD medications (see Conventional Treatments below).
  • TNF-alpha contributes to gut inflammation in several ways. It induces expression of adhesion factors that allow for inflammatory cells to infiltrate and activates macrophages to promote release of other pro-inflammatory mediators such as IFN-gamma.
  • TNF-alpha concentrations in the stool can be used to monitor disease activity in both CD and UC.
  • Braegger et al compared 13 children with