title: Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury.
abstract: Nitric oxide (NO) generated by vascular NO synthases can exert anti-inflammatory effects, partly through its ability to decrease leukocyte recruitment. Inorganic nitrate and nitrite, from endogenous or dietary sources, have emerged as alternative substrates for NO formation in mammals. Bioactivation of nitrate is believed to require initial reduction to nitrite by oral commensal bacteria. Here we investigated the effects of inorganic nitrate and nitrite on leukocyte recruitment in microvascular inflammation and in NSAID-induced small-intestinal injury. We show that leukocyte emigration in response to the proinflammatory chemokine MIP-2 is reduced by 70% after 7 days of dietary nitrate supplementation as well as by acute intravenous nitrite administration. Nitrite also reduced leukocyte adhesion to a similar extent and this effect was inhibited by the soluble guanylyl cyclase inhibitor ODQ, whereas the effect on emigrated leukocytes was not altered by this treatment. Further studies in TNF-α-stimulated endothelial cells revealed that nitrite dose-dependently reduced the expression of ICAM-1. In rats and mice subjected to a challenge with diclofenac, dietary nitrate prevented the increase in myeloperoxidase and P-selectin levels in small-intestinal tissue. Antiseptic mouthwash, which eliminates oral nitrate reduction, markedly blunted the protective effect of dietary nitrate on P-selectin levels. Despite attenuation of the acute immune response, the overall ability to clear an infection with Staphylococcus aureus was not suppressed by dietary nitrate as revealed by noninvasive IVIS imaging. We conclude that dietary nitrate markedly reduces leukocyte recruitment to inflammation in a process involving attenuation of P-selectin and ICAM-1 upregulation. Bioactivation of dietary nitrate requires intermediate formation of nitrite by oral nitrate-reducing bacteria and then probably further reduction to NO and other bioactive nitrogen oxides in the tissues.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Jädert
authors.affiliation: Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden.
authors.forename: Joel
authors.initials: J
authors.lastname: Petersson
authors.affiliation: Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Massena
authors.affiliation: Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Ahl
authors.affiliation: Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden.
authors.forename: Liza
authors.initials: L
authors.lastname: Grapensparr
authors.affiliation: Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Holm
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden. Electronic address: jon.lundberg@ki.se.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Lundberg
authors.affiliation: Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden. Electronic address: mia.phillipson@mcb.uu.se.
authors.forename: Mia
authors.initials: M
authors.lastname: Phillipson
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D006152:Cyclic GMP / Q000378:metabolism; D004008:Diclofenac / Q000009:adverse effects; D019587:Dietary Supplements; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007421:Intestine, Small / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000473:pathology*; D009067:Mouthwashes / Q000494:pharmacology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009566:Nitrates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009573:Nitrites / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054426:Chemokine CXCL2; D009067:Mouthwashes; D009566:Nitrates; D009573:Nitrites; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; D004008:Diclofenac; D009195:Peroxidase; D006152:Cyclic GMP