Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open‐label pilot study

Tremaine, WJ; Brzezinski, Aaron; Katz, Jeffrey A.; Wolf, D.; Fleming, Thomas; Mordenti, Joyce; Strenkoski-Nix, Laura C.; Kurth, Matthias

doi:10.1046/j.1365-2036.2002.01194.x

Cited by 79 publications

(47 citation statements)

References 14 publications

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“…S1 and Movies S4 and S5). In support of our data, others have reported that 27 of the 56 UC patients that received the tryptase inhibitor APC-2059 improved clinically (28) and that the tryptase/kallikrein inhibitor nafamostat mesilate decreased mucosal inflammation in TNBStreated rats (29).…”

Section: Discussionsupporting

confidence: 79%

Essential role for mast cell tryptase in acute experimental colitis

Hamilton

Sinnamon

Lyng³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

102

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Patients with inflammatory bowel disease (IBD) have increased numbers of human tryptase-β (hTryptase-β)-positive mast cells (MCs) in the gastrointestinal tract. The amino acid sequence of mouse mast cell protease (mMCP)-6 is most similar to that of hTryptase-β. We therefore hypothesized that this mMCP, or the related tryptase mMCP-7, might have a prominent proinflammatory role in experimental colitis. The dextran sodium sulfate (DSS) and trinitrobenzene sulfonic acid (TNBS) colitis models were used to evaluate the differences between C57BL/6 (B6) mouse lines that differ in their expression of mMCP-6 and mMCP-7 with regard to weight loss, colon histopathology, and endoscopy scores. Microarray analyses were performed, and confirmatory real-time PCR, ELISA, and/or immunohistochemical analyses were carried out on a number of differentially expressed cytokines, chemokines, and matrix metalloproteinases (MMPs). The mMCP-6-null mice that had been exposed to DSS had significantly less weight loss as well as significantly lower pathology and endoscopy scores than similarly treated mMCP-6-expressing mice. This difference in colitis severity was confirmed endoscopically in the TNBS-treated mice. Evaluation of the distal colon segments revealed that numerous proinflammatory cytokines, chemokines that preferentially attract neutrophils, and MMPs that participate in the remodeling of the ECM were all markedly increased in the colons of DSS-treated WT mice relative to untreated WT mice and DSS-treated mMCP-6-null mice. Collectively, our data show that mMCP-6 (but not mMCP-7) is an essential MC-restricted mediator in chemically induced colitis and that this tryptase acts upstream of many of the factors implicated in IBD.

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Section: Discussionsupporting

confidence: 79%

Essential role for mast cell tryptase in acute experimental colitis

Hamilton

Sinnamon

Lyng³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

102

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“…Because MCs from humans and other species release a variety of proteinases upon activation and degranulation, a link between MCs and PAR-2 activation has been suggested. Indeed, some data indicate that MC-derived proteinases can act as local activators of PAR-2, leading to PAR-2-mediated functional responses (22,29,33,46). In contrast, other work suggests that, because of NH 2 -terminal PAR-2 receptor glycosylation, MC-derived proteinases, like tryptase, are restricted in their ability to activate PAR-2 (6).…”

mentioning

confidence: 97%

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

Fernandez-Blanco¹,

Hollenberg

Martínez

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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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.

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“…The result of a pilot study has revealed that systemic administration of APC2059, a specific tryptase inhibitor, is safe and there is evidence of activity in the treatment of UC (41).…”

Section: Anti-proteinase / Par 2 Therapy In Colonic Mucosal Inflammationmentioning

confidence: 99%

Basic and Translational Research on Proteinase-Activated Receptors: Implication of Proteinase/Proteinase-Activated Receptor in Gastrointestinal Inflammation

Yoshida

Yoshikawa

2008

J Pharmacol Sci

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Abstract. Recently, the role of serine proteinases in the pathogenesis of inflammation and autoimmune diseases via interaction with the proteinase-activated receptor (PAR) has attracted attention. Activation of PAR has a pro-inflammatory effect through the overproduction of inflammatory cytokines such as interleukin (IL)-6 and IL-8. PAR 2 activation in human esophageal epithelial cells by trypsin induces NFκB-and AP-1-dependent IL-8 production in association with activation of p38 MAPK and ERK1 / 2, suggesting that esophageal inflammation may be induced by PAR 2 activation via reflux of trypsin. It has been also proposed that Helicobacter pylori (H. pylori) induces PAR expression in the gastric epithelial cells and H. pylori-derived serine proteinase promotes IL-8 production via PAR in the epithelial cells. In addition, an increase of PAR-dependent IL-8 production has been observed in H. pylori-infected human gastric mucosa, suggesting an important role for PAR 2 in the modulation of gastric inflammation associated with H. pylori. Recent studies have strongly indicated that tryptase and PAR are implicated in the pathogenesis of inflammatory bowel disease and experimental colitis. We demonstrated that anti-tryptase therapy may become a new therapeutic strategy in human ulcerative colitis. Thus, the role of PAR in the gastrointestinal tract has been gradually clarified, but further investigations are needed because the receptor has a variety of functions.

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Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open‐label pilot study

Cited by 79 publications

References 14 publications

Essential role for mast cell tryptase in acute experimental colitis

Essential role for mast cell tryptase in acute experimental colitis

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

Basic and Translational Research on Proteinase-Activated Receptors: Implication of Proteinase/Proteinase-Activated Receptor in Gastrointestinal Inflammation

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