Einfluss des PAR-2 auf die epitheliale Permeabilität und Ionensekretion im Gastrointestinaltrakt

The aim of the study was to characterize the very complex and diverse effects mediated by PAR-2 (Protease activated receptor-2) in the gastrointestinal tract. Especially the regulatory influence of PAR-2 on intestinal ion-secretion and -permeability in the lower gastrointestinal tract has been studied. The formation of the inner intestinal barrier depends to a large degree on proteases. According to Bacher a prolonged intraluminal (apical) effect of proteases plays a crucial role for the maturation and development of well functioning cell-cell connections (Bacher A, et al, 1992). Considering that the inhibition of proteases leads to a reduced formation of transepithelial resistance (Bacher et al, 1992), we have investigated the influence of trypsin and PAR-2-activating peptide on short-term changes in transepithelial resistance (TER) and the short circuit current. Evidence of a possible protective role in terms of increase in transepithelial resistance by proteases was obtained by the work of Lynch (Lynch RD, et al, 1995). He showed that basolateral stimulation with trypsin has resulted in reformation of the tight-junction complexes (especially ZO-1 proteins), but he did not investigate which receptors were involved in this process. Critical was that the basolateral stimulation led to an increase in TER (transepithelial resistance) lasting about 1 hour at a level of 190% of baseline. The aim of the present study was to characterise the mechanism of tight junction regulation by Trypsin/PAR-2-activating peptide (AP) in the intestine in more detail. A potential candidate for the receptor involved in the regulation of the very complex organization of intercellular junctions is PAR-2. The change of the transepithelial resistance demonstrated in our study could not only be explained by unspecific effects of trypsin via various other receptors in bowel epithelia, but also by PAR-2. This is supported by the fact that the same effects were achieved using the activating peptide with the specific amino acid sequence. Though the effect of PAR-2-AP was weaker compared to trypsin, this phenomenon is well explained by the specific receptor activation mechanism of the PARs (one molecule trypsin is able to activate several PARs sequentially, whereas one PAR-2-AP can only activate a single receptor and is removed from the surface by internalization). The finding that endogenous proteases can affect the permeability of the gastrointestinal tract and that the transepithelial resistance is a dynamic rather than a static property of the intestine provides not only a more detailed view and better understanding of epithelial barrier but also a potential pharmacological approach in medicine. In this context disease entities showing an increased permeability of the enteric barrier either as cause or as immediate result of the illness contributing to further deterioration of the organism could be of great interest. In this regard inflammatory bowel disease which is associated with an increased permeability is of great relevance. In future a possible therapeutic option could be the development of PAR-2 agonists to increase the transepithelial resistance to prevent bacterial invasion in acute intestinal infections as supportive medication.