082 smoking and plaque inflammation

Editorial Slides VP Watch, February 19, 2003, Volume 3, Issue 6

What Is The Link Between Smoking And Plaque Inflammation?

– 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

–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

– 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

–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.

7-nicotinic acetylcholine receptor (nAChR) 7-nicotinic acetylcholine receptor (nAChR) expression on DCs is up-regulated after expression on DCs is up-regulated after

nicotine stimulationnicotine stimulation

Control

7-nAChR expression 7-nAChR expression NAChR expression in DC cells was increased by nicotine in a NAChR 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

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

Cha

nge

in C

D86

exp

ress

ion

(%)

Mecamylamine(MEC; 10-7 M)

*

*

*

* *

* P<0.01 versus PBS

Nicotine

250

200

150

100

50

CD86PBS

nicotine

isotype

MECMEC

Ca++Na+

K+

AChAChNicotineNicotine

--nAChR nAChR ++


Dose-dependent cytotoxicity of nicotine

Perc

enta

ge o

f dea

d D

Cs

* 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


Nicotine enhances expression of surface molecules involved in inflammation

Cha

nge

in e

xpre

ssio

n (%

of c

ontr

ol)

isotypePBS nicotine

PBS

nicotineisotype

PBS nicotineisotype

PBS nicotine

isotype

50

100

150

200

250

CD

11a

CD

11a

CD

18C

D18

CD

54C

D54

CD

40C

D40

CD

83C

D83

CD

86C

D86

HLA

-DR

HLA

-DR

CD86 CD54

MHC class II CD40


Nicotine-induced IL-12 p40 production in DCs is mediated through nACh receptors

* P<0.01 versus PBS

PBS

IL-1

2 (p

g/m

l)

200

100

0Nicotine Nicotine

+ BTX

Nicotine +

MEC

*

BTX: -Bungarotoxin (7-nAChR antagonist)

MEC: Mecamylamine (unselective nAChR

antagonist)

MECMEC

Ca++Na+

K+

AChAChNicotineNicotine

--nAChR nAChR ++BTX

Both nicotine antagonists prevented nicotine-induced IL-12 P40 production Provided by Dr. Stefanie Dimmeler

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)

nicotineLPS

PBS nicotine

LPS

PBS nicotine

LPS

PBS


CSF

E

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

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


Nicotine-preactivated DCs increase expression of CD40 ligand (CD40L) on T cells

0

10

20

30

40

PBS nicotine

CD

40 L

+ T c

ells

(%)

*

* P<0.01 versus PBS


Nicotine activates MAPK and Akt pathways

phospho p38

β-tubulinA

phospho Erk1/2

β-tubulinB

0 5 15 30 60 120 min

phospho Akt

β-tubulinC

These studies demonstrate that the effects of nicotine are mediated, at least in part, by phosphorylation of Akt and MAPK


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


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

Summary Nicotine enhances adaptive immunity andmay contribute to plaque destabilization

NicotineNicotine

Adaptive Adaptive immunity immunity

Plaque Plaque destabilizationdestabilization


Conclusion:Nicotine has a direct proinflammatory effect through enhancement of cell-mediated adaptive immunity.

Conclusion: Nicotine enhances the

recruitment of dendritic cells to atherosclerotic plaques which can result in increasing recruitment of monocytes / macrophages to plaque.

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 plaquescontinue next page

Questions:

4- to increased thrombogenesity of blood

5- to increased arrhythmogenesity of myocardium

6- to increased respiratory infections and total infectious burden

082 smoking and plaque inflammation

Health & Medicine

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