PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat

Abstract

Fernández-Blanco JA, Hollenberg MD, Martínez V, Vergara P. PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat. Am J Physiol Gastrointest Liver Physiol 304: G390 -G400, 2013. First published December 13, 2012; doi:10.1152/ajpgi.00387.2012.-Proteinase-activated receptor-2 (PAR-2) and mast cell (MC) mediators contribute to inflammatory and functional gastrointestinal disorders. We aimed to characterize jejunal PAR-2-mediated responses and the potential MC involvement in the early and late phases of a rat model of postinfectious gut dysfunction. Jejunal tissues of control and Trichinella spiralis-infected (14 and 30 days postinfection) rats, treated or not with the MC stabilizer, ketotifen, were used. Histopathology and immunostaining were used to characterize inflammation, PAR-2 expression, and mucosal and connective tissue MCs. Epithelial barrier function (hydroelectrolytic transport and permeability) and motility were assessed in vitro in basal conditions and after PAR-2 activation. Intestinal inflammation on day 14 postinfection (early phase) was significantly resolved by day 30 (late phase) although MC counts and epithelial permeability remained increased. PAR-2-mediated ion transport (Ussing chambers, in vitro) and epithelial surface PAR-2 expression were reduced in the early phase, with a trend toward normalization during the late phase. In control conditions, PAR-2 activation (organ bath) induced biphasic motor responses (relaxation followed by excitation). At 14 days postinfection, spontaneous contractility and PAR-2-mediated relaxations were enhanced; motor responses were normalized on day 30. Postinfectious changes in PAR-2 functions were not affected by ketotifen treatment. We concluded that, in the rat model of Trichinella spiralis infection, alterations of intestinal PAR-2 function and expression depend on the inflammatory phase considered. A lack of a ketotifen effect suggests no interplay between MCs and PAR-2-mediated motility and ion transport alterations. These observations question the role of MC mediators in PAR-2-modulating postinfectious gut dysfunction.

Plasticity of dorsal root ganglion neurons in a rat model of post-infectious gut dysfunction: potential implication of nerve growth factor

“…After the infection, animals were regularly monitored for clinical signs and body weight changes. Normal course of the infection was confirmed by a significant decrease of body weight in infected animals compared with controls, with a peak reduction on days 8-10 PI and a subsequent linear increase over time, as previously described by us [9,10].…”

“…Muscle-stage larvae of T. spiralis were obtained from infected CD1 mice as previously described [9,10]. Rats were infected at 7-8 weeks of age by administration of 7500 T. spiralis larvae, suspended in 1 ml of saline by oral gavage.…”

“…In the model of experimental infection with Trichinella spiralis in rats, an accepted and well-validated model of post-infectious-IBS (PI-IBS), we have demonstrated the presence of a long-lasting jejunal epithelial barrier dysfunction associated with a persistent state of local immune activation and mucosal mast cell (MMC) infiltration [9,10]. In the present study, we used the same model with the aim of characterizing changes in DRG neurons and the potential implication of NGF.…”

Lipopolysaccharides Facilitate Colonic Motor Alterations Associated to the Sensitization to a Luminal Antigen in Rats

“…For instance, we have described a similar increase in CTMCs in the jejunum of Trichinella spiralis-infected rats, an accepted model of post-infectious IBS that also courses with dysmotility. 33 Moreover, CTMC counts are increased in mice with food allergy 34,35 and the degranulation of CTMCs excites the intestinal smooth muscle in vitro. 36 Although further in deep studies are required, these observations suggest that submucosal CTMC could be taking part in the altered contractile responses observed in OVA-LPS-treated rats.…”

Mast Cell-dependent Mesenteric Afferent Activation by Mucosal Supernatant From Different Bowel Segments of Guinea Pigs With Post-infectious Irritable Bowel Syndrome

“…Mast cells have been widely studied in IBS patients and several animal models; for example, mast cell tryptase increased epithelial permeability and intestinal barrier dysfunction in a PAR2-mediated manner. 38 Lee et al 39 found that rectal mucosal mast cell count was significantly correlated with intestinal permeability in IBS-D patients, which indicated mucosal mast cells to play an important role for increased permeability in patients with IBS-D. As an important component of the innate immune system, mast cells also play a significant role in immune disorders in the gut and especially in the neuro-immune interaction that may be involved in the development of visceral hyperalgesia. Previous study by Yu et al 40 demonstrated that mast cell activation induced long-lasting mechanical hypersensitivity of nodose C-fibers in the guinea pig esophagus and mast cell trypase played an important role in this sensitization process.…”