Increased susceptibility of aging gastric mucosa to injury and delayed healing: Clinical implications

Table 1 Action of Aspirin on platelets and gastrointestinal mucosa and its unique features compared with other nonsteroidal anti-inflammatory drugs

Aspirin is a non-selective inhibitor of cyclooxygenase (COX), an enzyme involved in the synthesis of prostaglandins and thromboxanes (TXA) from arachidonic acid

Aspirin inhibits both COX-1 and COX-2 isoforms with a greater inhibition of COX-1 than COX-2 (approximately 100-fold) in low doses COX-1 isoform is expressed constitutively in most tissues: Gastrointestinal mucosa and kidneys and by generating prostaglandin E2 (PGE2) and prostacyclin (PGI2) and plays a critical role in maintaining tissue integrity at basal level COX-1-induced thromboxane A2 (TXA2) generation causes platelet aggregation and thrombi formation and is the basis for cardiovascular events

COX-2 isoform is constitutively expressed in some tissues (the brain, kidneys, intestine, and endothelial cells). In other tissues COX2 is induced in response to local irritants, proinflammatory cytokines and growth factors.

COX2 generated prostaglandins PGE2 and PGI2 play a critical role in gastric mucosal defense in response to injury and promote angiogenesis, ulcer healing, and (cancer growth)

Aspirin–has potent antithrombotic and cardioprotective properties: Irreversibly inactivates platelet COX-1 (vs only temporary inhibition by other nonselective NSAIDs)

↓ TXA2 synthesis, platelet aggregation, and thrombi formation which are all basis for cardiovascular events

↓ Cardiocerebrovascular events

In addition, aspirin may prevent and/or reduce cancer. A recent meta-analysis of 8 trials[38,39] showed that LDA reduces cancer incidence and mortality

Aspirin advantage - single daily dose, low cost, good safety profile

Table 2 Structural, functional and biochemical abnormalities of aging gastric mucosa

Partial atrophy of gastric glands and their replacement with connective tissue

Degenerative changes in parietal and chief cells

↓ Sensory innervation and abolished hyperemic response to mild and moderate irritants

↓ Bicarbonate and prostaglandin generation and secretion

↓ Mucosal blood flow (by > 60%) and profound hypoxia of all mucosal cells

↑ Expression and transcriptional activity of early growth response-1→ ↑ PTEN and ↓ survivin (anti-apoptosis protein) → ↑ apoptosis

Other abnormalities include:

↓ Telomerase activity, cellular senescence, increased lipid peroxidation, impaired hypoxia sensor in endothelial (and epithelial?) cells

↑ Reactive oxygen species

Downregulated or mutated Klotho protein and dysregulated mitochondrial-nuclear communication

↓ Importin-α expression in endothelial cells of gastric mucosa → ↓activation and ↓expression of vascular endothelial growth factor (VEGF), which is a pro-angiogenic factor and protects gastric endothelial cells; imbalance between VEGF and endostatin

↓ Expression of nerve growth factor in gastric mucosal endothelial cells → reduced endothelial cell viability, impaired angiogenesis and gastric ulcer healing

Revised from World J Gastroenterol 2014[29] and updated based on our previous publications[24-29].