Proteinase-Activated Receptor-4 is implicated in the pathogenesis of Dextran Sodium Sulfate colitis

Ferazzini, Mara; Santi, Stacey A.; MacNaughton, Wallace K.; Hollenberg, Morley D.; Wallace, John L.; Vergnolle, Nathalie

doi:10.1016/s0016-5085(03)82463-0

Cited by 6 publications

(3 citation statements)

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“…Recently, we have shown that luminal administration of selective peptidic agonists for PAR 1 (TFFLR), PAR 2 (SLIGRL) and PAR 4 (AYPGKF) provoked a colonic inflammation within a few hours (from 4 to 24 h). This inflammation was characterized by an increased wall thickness, the presence of erythema and significant infiltration of granulocytes ( Cenac et al , 2002 ; Ferazzini et al , 2004 ; Vergnolle et al , 2004 ). PAR 2 ‐induced colitis was dependent on sensory neuron activation, substance P and CGRP release ( Cenac et al , 2003 ; Nguyen et al , 2003 ).…”

Section: Proteases and Pars: Role In Inflammation Of The Gi Tractmentioning

confidence: 99%

“…However, the overexpression of PAR 2 observed in biopsies from ulcerative colitis patients strongly suggests a role for PAR 2 in IBD ( Kim et al , 2003 ). We have reported that treatment of mice with the PAR 4 antagonist palmitoyl‐SGRRYGHALR reduced inflammation induced by dextran sodium sulfate ( Ferazzini et al , 2003 ). However, the specificity of such antagonist could still be questioned and only experiments performed with PAR 4 ‐deficient mice would completely clarify the role of PAR 4 in IBD models.…”

Section: Proteases and Pars: Role In Inflammation Of The Gi Tractmentioning

confidence: 99%

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Modulation of visceral pain and inflammation by protease‐activated receptors

Vergnolle

2004

British J Pharmacology

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The gastrointestinal (GI) tract is exposed to a large array of proteases, under both physiological and pathophysiological conditions. The discovery of G protein-coupled receptors activated by proteases, the protease-activated receptors (PARs), has highlighted new signaling functions for proteases in the GI tract, particularly in the domains of inflammation and pain mechanisms. Activation of PARs by selective peptidic agonists in the intestine or the pancreas leads to inflammatory events and changes in visceral nociception, suggesting that PARs could be involved in the modulation of visceral pain and inflammation. PARs are present in most of the cells that are potentially actors in the generation of irritable bowel syndrome (IBS) symptoms. Activation of PARs interferes with several pathophysiological factors that are involved in the generation of IBS symptoms, such as altered motility patterns, inflammatory mediator release, altered epithelial functions (immune, permeability and secretory) and altered visceral nociceptive functions. Although definitive studies using genetically modified animals, and, when available, pharmacological tools, in different IBS and inflammatory models have not yet confirmed a role for PARs in those pathologies, PARs appear as promising targets for therapeutic intervention in visceral pain and inflammation processes.

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Section: Proteases and Pars: Role In Inflammation Of The Gi Tractmentioning

confidence: 99%

Section: Proteases and Pars: Role In Inflammation Of The Gi Tractmentioning

confidence: 99%

Modulation of visceral pain and inflammation by protease‐activated receptors

Vergnolle

2004

British J Pharmacology

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“…PAR 3 has been detected in the stomach and small intestine [Ishihara et al, 1997] and PAR 4 is expressed in high levels in the small intestine and to a more moderate extent in the colon [Xu et al, 1998], including on the epithelium [Ferazzini et al, 2003]. A potential role for these PARs in the regulation of intestinal ion transport has yet to be examined, however.…”

Section: Other Parsmentioning

confidence: 99%

Intestinal epithelial secretory function: Role of proteinase‐activated receptors

Buresi

MacNaughton

2003

Drug Development Research

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The ability of enterocytes to secrete electrolytes and water into the intestinal lumen represents a critical feature of mucosal defense. During disease, this function may be altered and may initiate or exacerbate pathological conditions. Although many of the intracellular mechanisms linking stimulation to secretion have been elucidated, novel pathways continue to be revealed. These pathways provide potential for therapeutic manipulation of cellular function. In addition, the importance of the microenvironment surrounding enterocytes is increasingly being acknowledged, and the interactions between epithelial cells and their milieu are proving to be essential to the regulation of secretory function, both in health and disease. In this way, epithelial ion transport functions can be modulated by mediators released from neighboring nerves, inflammatory cells, and pathogens, or by endocrine factors. Much interest has recently been elicited by the discovery that proteinases can regulate cellular functions through the activation of proteinase-activated receptors (PARs). Because of the abundance of proteases within the gastrointestinal tract, particularly in the setting of development, inflammation, and healing, it is likely that PARs have an important role to play in these processes. PARs have been localized to a variety of cell types in the gastrointestinal tract, and have been shown to influence epithelial secretory function on several levels. In this review, we discuss the mechanisms by which proteases and PARs regulate intestinal secretory function, and the manner in which these modulations might contribute to inflammatory processes. Drug Dev. Res. 59:386-394, 2003.

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Serine Protease Inhibition Reduces Post-Ischemic Granulocyte Recruitment in Mouse Intestine

Gobbetti

Cenac

Motta

et al. 2012

The American Journal of Pathology

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Proteases and proteinase-activated receptor (PAR) activation are involved in several intestinal inflammatory conditions. We hypothesized that serine proteases and PAR activation could also modulate the intestinal injury induced by ischemia-reperfusion (I-R). C57Bl/6 mice were subjected to 90 minutes of intestinal ischemia followed or not by reperfusion. Sham-operated animals served as controls. After ischemia, plasma and tissue serine protease activity levels were increased compared to the activity measured in plasma and tissues from sham-operated mice. This increase was maintained or further enhanced after 2 and 5 hours of reperfusion, respectively. Trypsin (25 kDa) was detected in tissues both after ischemia and 2 hours of reperfusion. Treatment with FUT-175 (10 mg/kg), a potent serine protease inhibitor, increased survival after I-R, inhibited tissue protease activity, and significantly decreased intestinal myeloperoxidase (MPO) activity and chemokine and adhesion molecule expression. We investigated whether serine proteases modulate granulocyte recruitment by a PAR-dependent mechanism. MPO levels and adhesion molecule expression were significantly reduced in I-R groups pre-treated with the PAR(1) antagonist SCH-79797 (5 mg/kg) and in Par(2)(-/-)mice, compared, respectively, to vehicle-treated group and wild-type littermates. Thus, increased proteolytic activity and PAR activation play a pathogenic role in intestinal I-R injury. Inhibition of PAR-activating serine proteases could be beneficial to reduce post-ischemic intestinal inflammation.

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Proteinase-Activated Receptor-4 is implicated in the pathogenesis of Dextran Sodium Sulfate colitis

Cited by 6 publications

References 0 publications

Modulation of visceral pain and inflammation by protease‐activated receptors

Modulation of visceral pain and inflammation by protease‐activated receptors

Intestinal epithelial secretory function: Role of proteinase‐activated receptors

Serine Protease Inhibition Reduces Post-Ischemic Granulocyte Recruitment in Mouse Intestine

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