Intestinal Epithelial Wound Healing: NSAIDs and Calpain
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications worldwide despite their well-documented gastrointestinal (GI) toxicity. The GI epithelium has several functions, the most important of which are nutrient absorption and barrier function, separating the internal milieu from the external environment. Mucosal restitution represents a primary repair modality in the GI tract, and allows resealing of the epithelial barrier in minutes to hours via reformation of tight junctions between cells. Restitution requires cell migration, but not cell proliferation nor differentiation and it is a well coordinated event relying on numerous cellular pathways. Recent evidence suggests that calpains (cysteine proteases) are vital to several key pathways of cell migration. Recently we have shown that: a) irrespective of COX selectivity, ulcerogenic NSAIDs inhibit cell migration after wounding; b) individual NSAIDs differ significantly in their effects on the cellular signals that modulate cell migration; and c) ulcerogenic NSAIDs either down-regulate calpain gene expression or up-regulate the constituent inhibitor, calpastatin. Project experiments are specifically designed to link NSAID inhibition of cell migration with NSAID effects on events vital to calpain function within differentiated intestinal epithelial cells (IECs).