Proteinase-activated receptor-2-induced colonic inflammation in mice: possible involvement of afferent neurons, nitric oxide, and paracellular permeability.

Abstract	Activation of colonic proteinase-activated receptor-2 (PAR-2) provokes colonic inflammation and increases mucosal permeability in mice. The mechanism of inflammation is under debate and could be neurogenic and/or the consequence of tight-junction opening with passage of exogenous pathogens into the lamina propria. The present study aimed to further characterize the inflammatory effect of PAR-2 activation by investigating: 1) the role of NO, 2) the role of afferent neurons, and 3) a possible cause and effect relationship between colonic paracellular permeability changes and mucosal inflammation. Thus, intracolonic infusion to mice of the PAR-2-activating peptide, SLIGRL, increased both myeloperoxidase (MPO) activity and damage scores indicating colonic inflammation, and enhanced colonic permeability to (51)Cr-EDTA from 2 to 4 h after its infusion. NO synthase inhibitors, L-NAME and aminoguanidine, as well as the neurotoxin capsaicin and NK1, calcitonin gene-related peptide (CGRP) receptor antagonists, SR140333 and CGRP(8-37), prevented SLIGRL-induced MPO and damage score increases and permeability. In contrast, although the tight-junction blocker, 2,4,6-triaminopyrimidine, and the myosin L chain kinase inhibitor, ML-7, prevented SLIGRL-induced increase in permeability, they did not prevent MPO and damage score increases. Taken together our data show that both NO and capsaicin-sensitive afferent neurons are involved in PAR-2-mediated colonic inflammation and paracellular permeability increase. Nevertheless, the inflammation process is not a consequence of increased permeability which results at least in part from the activation of myosin L chain kinase.
Authors	Nicolas Cenac, Rafael Garcia-Villar, Laurent Ferrier, Muriel Larauche, Nathalie Vergnolle, Nigel W Bunnett, Anne-Marie Coelho, Jean Fioramonti, Lionel Bueno
Journal	Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 170 Issue 8 Pg. 4296-300 (Apr 15 2003) ISSN: 0022-1767 [Print] United States
PMID	12682265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antigens Antigens, Surface Azepines Calcitonin Gene-Related Peptide Receptor Antagonists Enzyme Inhibitors Lectins, C-Type NK Cell Lectin-Like Receptor Subfamily B Naphthalenes Oligopeptides Peptide Fragments Piperidines Proteins Pyrimidines Quinuclidines Receptor, PAR-2 Receptors, Thrombin seryl-leucyl-isoleucyl-glycyl-arginyl-leucine 2,4,6-triaminopyrimidine ML 7 calcitonin gene-related peptide (8-37) SR 140333 Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Nos2 protein, mouse Nos3 protein, mouse Myosin-Light-Chain Kinase Calcitonin Gene-Related Peptide
Topics	Administration, Rectal Animals Antigens Antigens, Surface Azepines (administration & dosage, pharmacology) Calcitonin Gene-Related Peptide (pharmacology) Calcitonin Gene-Related Peptide Receptor Antagonists Cell Membrane Permeability (drug effects) Colon (drug effects, enzymology, metabolism, pathology) Denervation Enzyme Inhibitors (administration & dosage, pharmacology) Inflammation (enzymology, metabolism, physiopathology) Injections, Intraperitoneal Intercellular Junctions (drug effects, metabolism) Intestinal Mucosa (drug effects, enzymology, metabolism, pathology) Lectins, C-Type Male Mice Myosin-Light-Chain Kinase (antagonists & inhibitors) NK Cell Lectin-Like Receptor Subfamily B Naphthalenes (administration & dosage, pharmacology) Neurons, Afferent (pathology, physiology) Nitric Oxide (physiology) Nitric Oxide Synthase (antagonists & inhibitors, biosynthesis, metabolism) Nitric Oxide Synthase Type II Nitric Oxide Synthase Type III Oligopeptides (administration & dosage, antagonists & inhibitors, pharmacology) Peptide Fragments (pharmacology) Piperidines (administration & dosage, pharmacology) Proteins (antagonists & inhibitors) Pyrimidines (administration & dosage, pharmacology) Quinuclidines (administration & dosage, pharmacology) Receptor, PAR-2 Receptors, Thrombin (administration & dosage, physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!