title: Regulation of intestinal permeability: The role of proteases.
abstract: The gastrointestinal barrier is - with approximately 400 m2- the human body's largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteinsviaactivation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases.
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Hanne
authors.initials: H
authors.lastname: Van Spaendonk
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: Ceuleers
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Leonie
authors.initials: L
authors.lastname: Witters
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Eveline
authors.initials: E
authors.lastname: Patteet
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Joris G
authors.initials: JG
authors.lastname: De Man
authors.affiliation: Hanne Van Spaendonk, Hannah Ceuleers, Leonie Witters, Eveline Patteet, Joris G De Man, Benedicte Y De Winter, Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Benedicte Y
authors.initials: BY
authors.lastname: De Winter
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D004573:Electrolytes; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D015212:Inflammatory Bowel Diseases / Q000503:physiopathology; D007422:Intestines / Q000473:pathology*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry; D051379:Mice; D010447:Peptide Hydrolases / Q000378:metabolism*; D010539:Permeability; D011480:Protease Inhibitors / Q000737:chemistry; D015842:Serine Proteinase Inhibitors / Q000737:chemistry; D019108:Tight Junctions; D016896:Treatment Outcome
chemical_list: D004573:Electrolytes; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D010447:Peptide Hydrolases
keywords: Antiproteases; Intestinal barrier; Intestinal permeability; Paracellular permeability; Protease inhibitor; Proteases; Proteinase-activated receptor; Tight junction