Pathophysiology of the Peritoneal Membrane during Peritoneal Dialysis: The Role of Hyaluronan

Figure 1

Changes to hyaluronan synthesis during PD alter mesothelial cell functions. The mesothelium contributes to peritoneal homeostasis. Under physiologic conditions, mesothelial cells secrete HMW hyaluronan which is the main constituent of the glycocalyx. The glycocalyx surrounds the apical surface of mesothelial cells and provides a protective barrier against abrasion, and a slippery, nonadhesion surface for intracoelomic movement (1). Mesothelial cells participate in tissue repair and in the induction and resolution of peritoneal inflammation through their ability to synthesize cytokines and growth factors that are secreted into the peritoneal cavity (2). Mesothelial cells also synthesize matrix proteins which provide a substratum onto which mesothelial cells adhere (2). Mesothelial cells facilitate the transport of fluids and solutes across the peritoneal membrane (3), are the first line of defense against bacterial peritonitis (4), and can maintain a chemotactic gradient to assist in leukocyte infiltration (5) during bacterial, chemical, or surgical insult. Changes to the peritoneum following the initiation of PD. Constant exposure of the peritoneal membrane to bioincompatible PD solution results in either a reduction of the glycocalyx volume (6) or its complete depletion from the surface of mesothelial cells. Changes in the content of hyaluronan in the peritoneum can induce morphologic and phenotypic changes to mesothelial cells that include reduced length and density of microvilli on the surface of mesothelial cells (7), generation of senescent cells (8), and frequent denudation of the mesothelium (9), thereby allowing PD solutions to leak into the submesothelium causing peritoneal injury (10). Activation of both immune cells and mesothelial cells further increases synthesis of cytokines and growth factors (11), which exacerbates peritoneal inflammation, fibrogenesis, and increases submesothelial expression of HMW hyaluronan (12). Activation of mesothelial cells induces EMT (13), breakdown of the basement membrane, and their migration into the submesothelium. Communication of activated mesothelial cells with peritoneal fibroblasts and endothelial cells may provoke further inflammatory and fibrotic processes in the submesothelium resulting ultimately in peritoneal fibrosis.