Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

Abstract

Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors (PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.

Keywords: Inflammatory bowel diseases; Irritable bowel syndrome; Protease inhibitors; Proteases; Proteinase-activated receptors; Visceral hypersensitivity; Visceral pain.

Figure 1

Simplified representation of the concept of endo- and exopeptidases. Endopeptidases cleave internal peptide bonds. Exopeptidases cleave terminal peptide bonds; they can be subdivided into amino- and carboxypeptidases according to the position of the cleavage of the peptide bond. Aminopeptidases cleave at amino (NH₂) terminal bonds, while carboxypeptidases cleave at carboxy (COOH) terminal bonds. Image constructed using the Servier Image Bank.

Figure 2

Classification of proteases based on the chemical structure of their active site. For each class, the chemical structure of the core residue in their active site is shown on top and a few examples with medical relevance of proteases belonging to that family are displayed below. MMP: Matrix metalloprotease.

Figure 3

Schematic representation of the activation of a protease-activated receptor. A protease cleaves the N-terminal domain (1), releasing a new N-terminus (2). The new N-terminus binds to the receptor as a tethered ligand, providing an intracellular signal (3). Image constructed using the Servier Image Bank. N-terminus: Amino-terminus; PAR: Protease-activated receptor.