Proteinase-activated receptor-2-induced colonic inflammation in mice: possible involvement of afferent neurons, nitric oxide, and paracellular permeability.
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.
Cenac
Nicolas
N
Neuro-Gastroenterology and Nutrition Unit, Institut National de la Recherche Agronomique, Toulouse, France.
Garcia-Villar
Rafael
R
Ferrier
Laurent
L
Larauche
Muriel
M
Vergnolle
Nathalie
N
Bunnett
Nigel W
NW
Coelho
Anne-Marie
AM
Fioramonti
Jean
J
Bueno
Lionel
L
D000285:Administration, Rectal; D000818:Animals; D000941:Antigens; D000954:Antigens, Surface; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002463:Cell Membrane Permeability / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D003714:Denervation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D037181:Lectins, C-Type; D008297:Male; D051379:Mice; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology; D009475:Neurons, Afferent / Q000473:pathology / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009842:Oligopeptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011506:Proteins / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000008:administration & dosage* / Q000502:physiology*
D000941:Antigens; D000954:Antigens, Surface; D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004791:Enzyme Inhibitors; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009281:Naphthalenes; D009842:Oligopeptides; D010446:Peptide Fragments; D010880:Piperidines; D011506:Proteins; D011743:Pyrimidines; D011812:Quinuclidines; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; C012070:2,4,6-triaminopyrimidine; C070571:ML 7; C058636:calcitonin gene-related peptide (8-37); C085215:SR 140333; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D009219:Myosin-Light-Chain Kinase; D015740:Calcitonin Gene-Related Peptide