Abstract
In this article we review the cellular and molecular mechanisms of gastric ulcer healing. A gastric ulcer (GU) is a deep defect in the gastric wall penetrating through the entire mucosa and the muscularis mucosae. GU healing is a regeneration process that encompasses cell dedifferentiation, proliferation, migration, re-epithelialization, formation of granulation tissue, angiogenesis, vasculogenesis, interactions between various cells and the matrix, and tissue remodeling, all resulting in scar formation. All these events are controlled by cytokines and growth factors (e.g., EGF, TGFα, IGF-1, HGF, bFGF, TGFβ, NGF, VEGF, angiopoietins) and transcription factors activated by tissue injury. These growth factors bind to their receptors and trigger cell proliferation, migration, and survival pathways through Ras, MAPK, PI3K/Akt, PLC-γ, and Rho/Rac/actin signaling. The triggers for the activation of these growth factors are tissue injury and hypoxia. EGF, its receptor, IGF-1, HGF, and COX-2 are important for epithelial cell proliferation, migration, re-epithelialization, and gastric gland reconstruction. VEGF, angiopoietins, bFGF, and NGF are crucial for blood vessel regeneration in GU scars. The serum response factor (SRF) is essential for VEGF-induced angiogenesis, re-epithelialization, and blood vessel and muscle restoration. Local therapy with cDNA of human recombinant VEGF165 in combination with angiopoietin1, or with the NGF protein, dramatically accelerates GU healing and improves the quality of mucosal restoration within ulcer scars. The future directions for accelerating and improving healing include local gene and protein therapies with growth factors, their combinations, and the use of stem cells and tissue engineering.
Highlights
Medical Research Service, VA Long Beach Healthcare System Long Beach, 5901 East Seventh Street, Long Beach, CA 90822, USA
A gastric ulcer is a deep defect in the gastric wall penetrating through the entire mucosa and the muscularis mucosae (Figure 1—modified and reprinted with permission from [1])
It has been demonstrated that serum itself induces a number of genes that are usually activated during tissue injury and wound healing, including pro-inflammatory regulators, immediate early genes (e.g., c-fos, egr-1, and jun B), and angiogenic factor genes [85]
Summary
In addition to the initial pool of growth factors (e.g., EGF, TGFα, bFGF, HGF, and trefoil peptides) and COX-2 in a well synchronized from the platelets, macrophages, and injured tissue, gastric ulceration triggers in cells linspatial and temporal manner [7,13,17] These growth factors, which are produced locally, ing the mucosa of the ulcer margin, activation of genes encoding for growth factors In the study of human ulcer specimens, Wright and coworkers showed that ulceration in the human gastrointestinal tract induces the development of a novel cell lineage, the “ulcer-associated cell lineage” (UACL), which likely originates from gastrointestinal stem cells [16] This cell lineage secreting EGF buds from the ulcer margin, grows locally forming new glands, and serves to regenerate mucosal structures during ulcer healing. Expression occupy the entire mucosal thickness (reprinted with permission from [15])
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