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082 smoking and plaque inflammation

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082 smoking and plaque inflammation

  1. 1. Editorial Slides VP Watch, February 19, 2003, Volume 3, Issue 6 What Is The Link Between Smoking And Plaque Inflammation?
  2. 2. –Furie et al Habitual use of smokeless tobacco leads to accumulation of inflammatory leukocytes at the site of placement, which may contribute to tissue damage. 2 –Their observations suggested that smokeless tobacco may induce inflammatory changes in vivo by activating endothelium in a manner that promotes recruitment of leukocytes.2
  3. 3. –Tottie et al showed that nicotine is chemotactic for neutrophil and enhances neutrophil responsiveness to chemotactic peptides. 3 –Klapproth et al showed nicotine and ligands of nicotine receptors release GM-CSF from epithelial cells.4
  4. 4. – Bobryshev and Lord have reported “Vascular Dendritic Cells” in areas prone to atherosclerotic plaque formation. 5 - These dendritic cells may play a key role in the initiation of atherosclerosis. 6
  5. 5. –As featured in VP Watch of the Week, Aicher et al1 investigated the effect of nicotine on the dendritic cell- mediated adaptive immunity. –In the following slides, the investigators showed various effectd of nicotine on expression of nicotinic acetylcholine receptor in human dendritic cells.
  6. 6. αα7-nicotinic acetylcholine receptor (nAChR)7-nicotinic acetylcholine receptor (nAChR) expression on DCs is up-regulated afterexpression on DCs is up-regulated after nicotine stimulationnicotine stimulation Control αα7-nAChR expression7-nAChR expression NAChR expression in DC cells was increased by nicotine in aNAChR expression in DC cells was increased by nicotine in a dose-dependent manner.dose-dependent manner. Nicotine: 10-8 M Nicotine: 10-7 M Provided by Dr. Stefanie Dimmeler
  7. 7. Nicotine induces a dose-dependent increase in the expression of the co-stimulatory molecule CD86 PBS 10-8 10-7 10-6 10-5 10-4 10-7 10-4 M ChangeinCD86expression(%) Mecamylamine (MEC; 10-7 M) * * * * * * P<0.01 versus PBS Nicotine 250 200 150 100 50 CD86 PBS nicotine isotype MECMEC Ca++Na+ K+ AChACh NicotineNicotine -- nAChRnAChR++ Provided by Dr. Stefanie Dimmeler
  8. 8. Dose-dependent cytotoxicity of nicotine PercentageofdeadDCs * P<0.01 versus PBS * * * 0 20 40 60 80 100 120 PBS 10-7 10-6 10-5 10-4 10-3 10-2 Nicotine M Provided by Dr. Stefanie Dimmeler
  9. 9. Nicotine enhances expression of surface molecules involved in inflammation Changeinexpression(%ofcontrol) isotype PBS nicotine PBS nicotineisotype PBS nicotineisotype PBS nicotine isotype 50 100 150 200 250 CD11aCD11a CD18CD18 CD54CD54 CD40CD40 CD83CD83 CD86CD86 HLA-DRHLA-DR CD86 CD54 MHC class II CD40 Provided by Dr. Stefanie Dimmeler
  10. 10. Nicotine-induced IL-12 p40 production in DCs is mediated through nACh receptors * P<0.01 versus PBS PBS IL-12(pg/ml) 200 100 0 Nicotine Nicotine + BTX Nicotine + MEC * BTX: α-Bungarotoxin (α7-nAChR antagonist) MEC: Mecamylamine (unselective nAChR antagonist) MECMEC Ca++Na+ K+ AChACh NicotineNicotine -- nAChRnAChR ++BTX Both nicotine antagonists prevented nicotine-induced IL-12 P40 production Provided by Dr. Stefanie Dimmeler
  11. 11. Nicotine-prestimulated dendritic cells (DCs) and monocytes (MCs) induce allogeneic T cell activation IL-2(pg/ml) nicotine DC / T cell ratio (1:10) LPS DC / T cell ratio (1:50) 200 100 0 300 PBS * * * * * P<0.01 versus PBS 0 200 100 300 * * * * MC / T cell ratio (1:10) MC / T cell ratio (1:50) * P<0.01 versus PBS IL-2(pg/ml) nicotine LPS PBS nicotine LPS PBS nicotine LPS PBS Provided by Dr. Stefanie Dimmeler
  12. 12. CSFE CD4 MCs control nicotine DCs Proliferation of allogeneic CSFE-labeled CD4+ T cells in mixed lymphocyte reactions with nicotine-stimulated DCs or MCs as stimulator cells CD4-allophycocyanin 7.2% 24.1% 5.2% 10.7% Loss of incorporated CSFE labeling was increased by nicotine, indicating its enhancing effect on proliferation of T-lymphocytes. Provided by Dr. Stefanie Dimmeler
  13. 13. IL-2(pg/ml) 0 20 40 60 80 100 120 140 PBS 0.1 1.0 PBS Nicotine * * * OVA (µg/ml) * P<0.01 versus PBS Nicotine-preactivated DCs stimulate OVA-TCR-transgenic T cells in OVA-antigen specific assays OVA: ovalbumine peptide 323-339 OVA-TCR transgenic mice OVA OVA- TCR Provided by Dr. Stefanie Dimmeler
  14. 14. Nicotine-preactivated DCs increase expression of CD40 ligand (CD40L) on T cells 0 10 20 30 40 PBS nicotine CD40L+ Tcells(%) * * P<0.01 versus PBS Provided by Dr. Stefanie Dimmeler
  15. 15. Nicotine activates MAPK and Akt pathways phospho p38 β-tubulin A phospho Erk1/2 β-tubulin B 0 5 15 30 60 120 min phospho Akt β-tubulin C These studies demonstrate that the effects of nicotine are mediated, at least in part, by phosphorylation of Akt and MAPK Provided by Dr. Stefanie Dimmeler
  16. 16. isotype PBS nicotine + PD98059 nicotine nicotine + SB203580 nicotine + LY294002 CD86 LY294002: PI3-K inhibitor PD98059: MEK 1/2 inhibitor (ERK-pathway) SB203580: p38 MAPK inhibitor Nicotine-induced up-regulation of CD86 is strongly dependent on MAPK and phosphatidylinositoI-3 (PI3) kinase These studies demonstrate that the effects of nicotine are mediated, at least in part, by phosphorylation of Akt and MAPK Provided by Dr. Stefanie Dimmeler
  17. 17. control nicotine B Homing of CSFE-labeled DCs to atherosclerotic plaques in nicotine-treated hypercholesterolemic mice Nicotine induced recruitment of dendritic cells into the atherosclerotic plaque in vivo Provided by Dr. Stefanie Dimmeler
  18. 18. Summary Nicotine enhances adaptive immunity and may contribute to plaque destabilization NicotineNicotine AdaptiveAdaptive immunityimmunity PlaquePlaque destabilizationdestabilization Provided by Dr. Stefanie Dimmeler
  19. 19. Conclusion: Nicotine has a direct proinflammatory effect through enhancement of cell-mediated adaptive immunity.
  20. 20. Conclusion: Nicotine enhances the recruitment of dendritic cells to atherosclerotic plaques which can result in increasing recruitment of monocytes / macrophages to plaque.
  21. 21. Questions: The role of smoking in cardiovascular disease is more related to the contribution of nicotine: 1- to endothelial injury and initiation of atherosclerotic plaque 2- to progression of plaques that already exist 3- to thrombotic complications of plaques continue next page
  22. 22. Questions: 4- to increased thrombogenesity of blood 5- to increased arrhythmogenesity of myocardium 6- to increased respiratory infections and total infectious burden

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