Pathways of gastrointestinal protection and repair: mechanisms of action of sucralfate.

Protection, i.e., prevention of major lesions and the mechanisms of repair/healing of major tissue loss in the gastrointestinal mucosa, are multifactorial processes. Conceptually, it is useful to categorize the components and mechanisms of gastroprotection and distinguish between: (1) Preservation of existing cells either by enhanced resistance of cells or by decreased exposure to damaging agents that can be achieved by maintenance of proper blood flow, vascular permeability, motility, mucus and bicarbonate secretion. If these mechanisms fail and tissue necrosis ensues, (2) replacement of lost tissue is achievable by either the original cells (e.g., epithelia), by cell migration (restitution) and proliferation (regeneration), and/or by connective tissue repair (e.g., fibroblasts, collagen) through cell proliferation and production of extracellular matrix. For acute gastroprotection ("cytoprotection"), maintenance of blood flow in the upper mucosa and epithelial restitution are listed as key mechanisms. For the long-term safeguarding of the mucosa, proper mucus and bicarbonate secretion, as well as ability to respond by cell proliferation, are the proposed key mechanisms of mucosal defense. The mechanisms of action of sucralfate are also multifactorial. The acute gastroprotection by sucralfate is a prostaglandin- and sulfhydryl-sensitive process: after early protection of microvasculature and maintenance of blood flow, along with direct or indirect preservation of the proliferative zone, rapid restitution repairs the initial epithelial defect. The mechanisms of accelerated healing by sucralfate of chronic ulcers include enhanced mucus and bicarbonate secretion, increased ability of mucus to maintain pH gradient, stimulated binding of epidermal growth factor and other growth factors, and maintained or enhanced blood flow resulting in increased cell proliferation leading to granulation tissue formation and re-epithelialization. The slight direct antipeptic and bile-acid binding property of sucralfate might also contribute to its ability to accelerate ulcer healing.