Jerrold Turner, M.D., Ph.D. Professor of Pathology and Medicine Brigham and Women's Health Harvard Medical School
Mucosal barrier dysfunction as a cause of and therapeutic target in chronic disease
Compromised intestinal barrier function is characteristic of intestinal and systemic diseases including inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD). The degree of barrier loss often correlates with disease severity, but it is not clear however whether this contributes to disease progression, is a consequence of disease-induced intestinal damage, or both. Intestinal barrier loss occurs by two primary processes. In the first, direct damage disrupts continuity of the epithelium that normally establishes the mucosal barrier and allows unrestricted, i.e., size-nonselective, mixing of luminal materials with the underlying lamina propria. Increasing the permeability of paracellular tight junctions, which seal the space between adjacent epithelial cells, is a second mechanism of intestinal barrier loss. This can occur by either of two well-defined trans-tight junction flux routes, the pore and leak pathways. Data implicating the unrestricted pathway (tight junction-independent) and both tight junction-dependent (pore and leak) pathways in disease progression will be considered in the context of understanding pathogenesis and identifying opportunities for therapy. Recent work identifying means of reversing leak pathway barrier defects for therapeutic benefit will also be presented.