Cellular and molecular mechanisms of gastrointestinal ulcer healing.
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.
Tarnawski
Andrzej S
AS
Department of Medicine, VA Long Beach Healthcare System Long Beach, Long Beach, California 90822, USA. atarnawski@yahoo.com
D049109:Cell Proliferation; D002470:Cell Survival; D002921:Cicatrix; D016207:Cytokines / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D005753:Gastric Mucosa / Q000166:cytology* / Q000473:pathology*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D018919:Neovascularization, Physiologic; D015398:Signal Transduction; D013276:Stomach Ulcer / Q000276:immunology / Q000473:pathology*; D014945:Wound Healing / Q000502:physiology*
D016207:Cytokines; D006133:Growth Substances