ArticleGastroenterology2007
Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis.
Article in Gastroenterology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 54 citations in OpenAlex.
- Protease-serpin-microbiome interactions in inflammatory bowel disease: toward integrated biomarkers of gut health.Gut microbes · 2026Review
- Par2-mediated responses in inflammation and regeneration: choosing between repair and damage.Inflammation and regeneration · 2024Review
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Resolving the conflicts around Par2 opposing roles in regeneration by comparing immune-mediated and toxic-induced injuries.Inflammation and regeneration · 2022Article
- Protease-activated receptor 2 enhances innate and inflammatory mechanisms induced by lipopolysaccharide in macrophages from C57BL/6 mice.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Article
- Mice expressing fluorescent PARProceedings of the National Academy of Sciences of the United States of America · 2022Article
- SP-1, a Serine Protease from the Gut Microbiota, Influences Colitis and Drives Intestinal Dysbiosis in Mice.Cells · 2021Article
- Blockage of protease-activated receptor 2 exacerbates inflammation in high-fat environment partly through autophagy inhibition.American journal of physiology. Gastrointestinal and liver physiology · 2021Article
- Rotavirus infection induces glycan availability to promote ileum-specific changes in the microbiome aiding rotavirus virulence.Gut microbes · 2020Article
- Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer.Frontiers in endocrinology · 2019Review
- Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2.British journal of pharmacology · 2016Article
- Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane.The Journal of biological chemistry · 2016Article
- Local injection of dsRNA targeting calcitonin receptor-like receptor (CLR) ameliorates Clostridium difficile toxin A-induced ileitis.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Autocrine extra-pancreatic trypsin 3 secretion promotes cell proliferation and survival in esophageal adenocarcinoma.PloS one · 2013Article
- Enteric bacterial proteases in inflammatory bowel disease- pathophysiology and clinical implications.World journal of gastroenterology · 2013Review
- Chemotherapy patients with C. difficile colitis have outcomes similar to immunocompetent C. difficile patients.Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract · 2012Article
- Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110).British journal of pharmacology · 2012Article
- Targeting proteinase-activated receptors: therapeutic potential and challenges.Nature reviews. Drug discovery · 2012Review
- Cathepsin S is activated during colitis and causes visceral hyperalgesia by a PAR2-dependent mechanism in mice.Gastroenterology · 2011Article
- Mast cell proteases as protective and inflammatory mediators.Advances in experimental medicine and biology · 2011Review
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsWe studied the role of protease-activated receptor 2 (PAR(2)) and its activating enzymes, trypsins and tryptase, in Clostridium difficile toxin A (TxA)-induced enteritis.
methodsWe injected TxA into ileal loops in PAR(2) or dipeptidyl peptidase I (DPPI) knockout mice or in wild-type mice pretreated with tryptase inhibitors (FUT-175 or MPI-0442352) or soybean trypsin inhibitor. We examined the effect of TxA on expression and activity of PAR(2) and trypsin IV messenger RNA in the ileum and cultured colonocytes. We injected activating peptide (AP), trypsins, tryptase, and p23 in wild-type mice, some pretreated with the neurokinin 1 receptor antagonist SR140333.
resultsTxA increased fluid secretion, myeloperoxidase activity in fluid and tissue, and histologic damage. PAR(2) deletion decreased TxA-induced ileitis, reduced luminal fluid secretion by 20%, decreased tissue and fluid myeloperoxidase by 50%, and diminished epithelial damage, edema, and neutrophil infiltration. DPPI deletion reduced secretion by 20% and fluid myeloperoxidase by 55%. In wild-type mice, FUT-175 or MPI-0442352 inhibited secretion by 24%-28% and tissue and fluid myeloperoxidase by 31%-71%. Soybean trypsin inhibitor reduced secretion to background levels and tissue myeloperoxidase by up to 50%. TxA increased expression of PAR(2) and trypsin IV in enterocytes and colonocytes and caused a 2-fold increase in Ca(2+) responses to PAR(2) AP. AP, tryptase, and trypsin isozymes (trypsin I/II, trypsin IV, p23) caused ileitis. SR140333 prevented AP-induced ileitis.
conclusionsPAR(2) and its activators are proinflammatory in TxA-induced enteritis. TxA stimulates existing PAR(2) and up-regulates PAR(2) and activating proteases, and PAR(2) causes inflammation by neurogenic mechanisms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.