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Human neutrophil-pulmonary microvascular endothelial cell interactions in vitro: differential effects of nitric oxide vs. peroxynitrite. 2008

Jennifer L Shelton, and Lefeng Wang, and Gediminas Cepinskas, and Richard Inculet, and Sanjay Mehta
Department of Medicine, Division of Respirology, London Health Sciences Center, Centre for Critical Illness Research, Lawson Health Research Institute University of Western Ontario, London, Ontario Canada.

Sepsis-induced acute lung injury is characterized by activation and injury of pulmonary microvascular endothelial cells (PMVEC), increased neutrophil-PMVEC adhesion and migration, and trans-PMVEC high-protein edema. Inducible NO synthase (iNOS) inhibits septic murine neutrophil migration in vivo and in vitro. The effects of NO in human neutrophil-PMVEC interactions are not known. We isolated human PMVEC using magnetic bead-bound anti-PECAM antibody. Confluent PMVEC at passage 3-4 were co-cultured with human neutrophils for assessment of neutrophil-PMVEC adhesion, and trans-PMVEC neutrophil migration and Evans-Blue dye-labeled albumin leak. Two NO donors (spermine-NONOate, S-nitroso-N-acetylpenicillamine) attenuated both cytomix-enhanced neutrophil-PMVEC adhesion by 64+/-14% (p<0.01) and 32+/-3% (p<0.05), respectively, and cytomix-induced trans-PMVEC neutrophil migration by 85+/-16% (p<0.01) and 43+/-5% (p<0.01), respectively. Correspondingly, iNOS inhibition with 1400W enhanced cytomix-stimulated neutrophil migration by 52+/-3% (p<0.01), but had no effect on neutrophil-PMVEC adhesion. Conversely, a peroxynitrite donor (SIN-1) increased both neutrophil-PMVEC adhesion (38+/-2% vs. 14+/-1% control, p<0.01) and trans-PMVEC neutrophil migration; with both effects were completely inhibited by scavenging of NO, superoxide, or peroxynitrite (p<0.05 for each). Scavenging of peroxynitrite also eliminated cytomix-induced neutrophil adhesion and migration. Blocking CD18-dependent neutrophil adhesion prevented cytomix-stimulated trans-PMVEC EB-albumin leak (p<0.05), while inhibiting neutrophil migration paradoxically enhanced cytomix-stimulated EB-albumin leak (11+/-1% vs. 7+/-0.5%, p<0.01). FMLP-induced neutrophil migration had no effect on trans-PMVEC EB-albumin leak. In summary, we report differential effects, including the inhibitory action of NO and stimulatory effect of ONOO(-) on human neutrophil-PMVEC adhesion and trans-PMVEC migration under cytomix stimulation. Moreover, neutrophil-PMVEC adhesion, but not trans-PMVEC migration, contributes to human PMVEC barrier dysfunction.

UI MeSH Term Description Entries
D007097 Imines Organic compounds containing a carbon-nitrogen double bond where a NITROGEN atom can be attached to HYDROGEN or an alkyl or aryl group. Imine
D008665 Metalloporphyrins Porphyrins which are combined with a metal ion. The metal is bound equally to all four nitrogen atoms of the pyrrole rings. They possess characteristic absorption spectra which can be utilized for identification or quantitative estimation of porphyrins and porphyrin-bound compounds. Metalloporphyrin
D008981 Molsidomine A morpholinyl sydnone imine ethyl ester, having a nitrogen in place of the keto oxygen. It acts as NITRIC OXIDE DONORS and is a vasodilator that has been used in ANGINA PECTORIS. Morsydomine,Corpea,Corvaton,Duracoron,Fali-Cor,Korvatone,MTW-Molsidomin,Molsi 1A Pharma,Molsi-AZU,Molsi-Puren,Molsibeta,Molsicor,Molsidain,Molsidomin,Molsidomin Heumann,Molsidomin Stada,Molsidomin Von Ct,Molsidomin-Ratiopharm,Molsihexal,Molsiket,SIN-10,Sydnopharm,Fali Cor,Heumann, Molsidomin,MTW Molsidomin,Molsi AZU,Molsi Puren,Molsidomin Ratiopharm,SIN 10,SIN10,Von Ct, Molsidomin
D009240 N-Formylmethionine Leucyl-Phenylalanine A formylated tripeptide originally isolated from bacterial filtrates that is positively chemotactic to polymorphonuclear leucocytes, and causes them to release lysosomal enzymes and become metabolically activated. F-Met-Leu-Phe,N-Formyl-Methionyl-Leucyl-Phenylalanine,Formylmet-Leu-Phe,Formylmethionyl Peptide,Formylmethionyl-Leucyl-Phenylalanine,Formylmethionylleucylphenylalanine,N-Formylated Peptide,N-formylmethionyl-leucyl-phenylalanine,fMet-Leu-Phe,F Met Leu Phe,Formylmet Leu Phe,Formylmethionyl Leucyl Phenylalanine,Leucyl-Phenylalanine, N-Formylmethionine,N Formyl Methionyl Leucyl Phenylalanine,N Formylated Peptide,N Formylmethionine Leucyl Phenylalanine,N formylmethionyl leucyl phenylalanine,Peptide, Formylmethionyl,Peptide, N-Formylated,fMet Leu Phe
D009504 Neutrophils Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. LE Cells,Leukocytes, Polymorphonuclear,Polymorphonuclear Leukocytes,Polymorphonuclear Neutrophils,Neutrophil Band Cells,Band Cell, Neutrophil,Cell, LE,LE Cell,Leukocyte, Polymorphonuclear,Neutrophil,Neutrophil Band Cell,Neutrophil, Polymorphonuclear,Polymorphonuclear Leukocyte,Polymorphonuclear Neutrophil
D009569 Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP. Endogenous Nitrate Vasodilator,Mononitrogen Monoxide,Nitric Oxide, Endothelium-Derived,Nitrogen Monoxide,Endothelium-Derived Nitric Oxide,Monoxide, Mononitrogen,Monoxide, Nitrogen,Nitrate Vasodilator, Endogenous,Nitric Oxide, Endothelium Derived,Oxide, Nitric,Vasodilator, Endogenous Nitrate
D002448 Cell Adhesion Adherence of cells to surfaces or to other cells. Adhesion, Cell,Adhesions, Cell,Cell Adhesions
D002450 Cell Communication Any of several ways in which living cells of an organism communicate with one another, whether by direct contact between cells or by means of chemical signals carried by neurotransmitter substances, hormones, and cyclic AMP. Cell Interaction,Cell-to-Cell Interaction,Cell Communications,Cell Interactions,Cell to Cell Interaction,Cell-to-Cell Interactions,Communication, Cell,Communications, Cell,Interaction, Cell,Interaction, Cell-to-Cell,Interactions, Cell,Interactions, Cell-to-Cell
D002465 Cell Movement The movement of cells from one location to another. Distinguish from CYTOKINESIS which is the process of dividing the CYTOPLASM of a cell. Cell Migration,Locomotion, Cell,Migration, Cell,Motility, Cell,Movement, Cell,Cell Locomotion,Cell Motility,Cell Movements,Movements, Cell
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell

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