The role of adhesion molecules in gastric ulcer healing

Abstract

Key Words: stomach ulcer, adhesion molecules, vascular cell surface adhesion molecul-1, platelet endothelial cell addesion molecule

TEXT

Gastric ulcer is a deep necrotic lesion involving the entire mucosal depth and the muscularis mucosae. Ulcer healing is an active and complicated process of filling the mucosal defect with proliferating and migrating epithelial cells and connective tissue components, so as to reconstruct the mucosal architecture. In this process, the concerted interaction of a variety of tissues and cellular systems are reguired, including those of soluble mediators, formed blood elements, extracellular matrix (ECM), and parenchymal cells. In fact, healing of an ulcer follows a specific time sequence and can be temporally categorized into three processes which occur in a sequential order: (I) inflammation; (II) tissue formation; and (III) tissue remolding. This editorial will mainly discuss the involvement of adhesion molecules in the phase of tissue formation, a fundamentally important process in ulcer healing

The critical steps of tissue formation during the repair of the gut mucosal injuries include the reconstitution of the epithelial mucosal barrier and the development of new microvasculature by angiogenesis. The healing of the gut is initiated by restitution. Enterocytes at the edge of the wound lose their differentiated characteristics and migrate across the region of denuded basement membrane in mucosa, while stimulation of angiogenesis during initial wound healing facilitates the reconstruction of original appearing mucosa and submucosa. These processes could be initiated by a variety of soluble chemotactic cytokines and growth factors secreted from damaged cells.

Epithelial restitution is a fundamental protective mechanism that allows the gastrointestinal mucosa to reestablish functional and structural integrity following superficial injury. The initial step and progression of epithelial cell migration depends on the adherence between epithelial cells and establishment of stable cell-substratum adhesion to generate friction and forward movement. The transformation from an attached to a motile cell requires disruption of cell junctional proteins such as E-cadherin/catenin complex and the modulation of expression, affinity and binding specificity of ECM adhesion receptors (e.g., integrins). Integrins have been implicated in the regulation of cell migration in a variety of systems[1]. Knock-out of β1 integrin gene in embryonic stem cells has been shown to inhibit cell migration and adhesion[2]. The up-regulation of the functional activity of integrins α2β1 and α3β1, which are receptors for laminin and collagen, is required for cell attachment and migration. Epithelial cadherin is the prime mediator of cell-cell adhesion in epithelial cells. Perturbation of E-cadherin/catenin mediated adhesion is as sociated with epithelial migration and restitution following ulceration of the gastrointestinal tract[3]. Epidermal growth factor has been shown to induce rapid tyrosine phosphorylation of β-catenin and γ-catenin. This is associated with scattering and dispersion of epithelial cells and disruption of E-cadherin from the cell-cell junctions[4].

Angiogenesis is another crucial factor for ulcer healing and tissue regeneration[5], which is a process of new blood vessel formation from pre-existed vessels. The importance of angiogenesis in gastroduodenal u lcer healing has been extensively studied. For instance, stimulation of angiogenesis in granulation tissues has been shown to dramatically accelerate the healing of experimental duodenal ulcer in rats[6]. Furthermore, chronic indomethacin administration inhibits angiogenesis in granulation tissues and delays healing of experimental gastric ulcers in animals[7]. Blood vessels are especially important during tissue injury. When there is inflammation, blood delivers nutrients, growth factors, and immunocytes to the site of injury, whereas waste products are removed from there. In addition, regulation of blood flow in the gastrointestinal mucosa is important for the maintenance of the integrity of gastric mucosa and protection against further mucosal injury. The formation of new vessels in ulcer healing is a dynamic process that is controlled by many diverse, sometimes complex factors acting together in a local environment. Again, a wide variety of growth factors are involved in the regulation of adhesion molecule expression in a concerted manner during the process of vessel assembly. The principal cell type involved in the process of angiogenesis is the microvascular endothelial cell.

Angiogenesis begins with proteolysis of the basement membrane. Proteolysis is necessary to induce microvascular endothelial cell invasion and tube formation. Activation of both endothelial cells and lymphocytes or monocytes is required for their secretion of proteases. Their activation, however, is dependent on adhesion molecules interaction. During the course of inflammation, local endothelial cells are exposed to various cytokines that induce a series of endothelial surface adhesion molecules. One of these inducible molecules, vascular cell surface adhesion molecule-1 (VCAM-1), a member of the immunoglobulin (Ig) supergene family, is the counter-receptor for very late antigen-4 (VLA-4), a surface protein present on lymphocytes and monocytes. VCAM-1/VLA-4 interaction induces the increased expression of a series of proteases required for proteolysis, and therefore endothelial cells could get a hold on the basement membrane, where they proliferate and extend.

Following proteolysis, tube formation occurs. A series of adhesion molecules come to play in tube formation. Early events of tube formation are mediated by platelet endothelial cell adhesion molecule (PECAM-1/PECAM-1) interactions. As a result of the cell to cell contact, a tube-like structure is formed. Antibodies directed against PECAM-1 can inhibit tube formation in vitro[8]. Integrin αvβ3 is another adhesion molecule found only on the tips of the endothelial cells in sprouting vessels. Its immunoreactivity is absent in mature and quiescent vessels. Both β1 and β3 integrins are involved in the attachment between cells and their substrates. But the presence of the latter adhesion molecule was also thought to induce gelatinase expression on the surface of the endothelial cells so as to enhance migration and proliferation[9]. When the tube-like structure is stabilized with β1 and β3 integrins, tight junction formation occurs, which correlates with the junction-associated molecules assembly and organization[10].

Epithelial restitution, as well as angiogenesis, two of the fundamental components of the ulcer healing process, are characterized by complex alterations in adhesion between cells and the ECM. Growth and motility factors involved in mucosal repair of the gastrointestinal tract seem to modulate these interactions in a coordinated fashion in order to reestablish functional and structural integrity of the mucosa. The mechanisms that regulate the production of these adhesion molecules await further exploration and clarification, as do the differences between the consequences of different types of mucosal injury. It is clear, however, that the modulation of the cell migration, and angiogenesis by adhesion molecules may be the fruitful targets for future pharmacological intervention in gastrointestinal wound healing.

ACKNOWLEDGEMENT

This review is supported in part by the RGC grant of the Hong Kong Research Grant Council, awarded to C.H. Cho.