This paper reviews cellular and molecular mechanisms of gastrointestinal
ulcer healing.
Ulcer healing, a genetically programmed repair process, includes
inflammation, cell proliferation, re-epithelialization, formation of granulation tissue, angiogenesis, interactions between various cells and the matrix and tissue remodeling, all resulting in
scar formation. All these events are controlled by the
cytokines and
growth factors (
EGF, PDGF, KGF, HGF,
TGFbeta,
VEGF,
angiopoietins) and
transcription factors activated by tissue injury in spatially and temporally coordinated manner. These
growth factors trigger mitogenic, motogenic and survival pathways utilizing Ras, MAPK, PI-3K/Akt,
PLC-gamma and Rho/Rac/actin signaling.
Hypoxia activates pro-angiogenic genes (e.g.,
VEGF,
angiopoietins) via HIF, while
serum response factor (SRF) is critical for
VEGF-induced angiogenesis, re-epithelialization and muscle restoration.
EGF, its
receptor, HGF and Cox2 are important for epithelial cell proliferation, migration re-epithelializaton and reconstruction of gastric glands.
VEGF,
angiopoietins,
nitric oxide,
endothelin and
metalloproteinases are important for angiogenesis,
vascular remodeling and mucosal regeneration within
ulcer scar. Circulating progenitor cells are also important for
ulcer healing. Local gene therapy with
VEGF + Ang1 and/or SRF cDNAs dramatically accelerates esophageal and
gastric ulcer healing and improves quality of mucosal restoration within
ulcer scar. Future directions to accelerate and improve healing include the use of stem cells and tissue engineering.