Systemic Effects of Smoking

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Systemic Effects of Smoking

Systemic Effects of SmokingBill MacNeeE.L.E.G.I. / Colt LaboratoriesUniversity of Edinburgh Medical Schooland the Royal Infirmary of Edinburgh,Scotland, UK


Systemic Effects of SmokingSystemic inflammation• Systemic oxidative stress• Effects on vasomotor and endothelial function


Systemic Effects of SmokingSystemic inflammation• Systemic oxidative stress• Effects on vasomotor and endothelial function


THE PULMONARY MICROCIRCULATIONCAPILLARY BEDMacNee et al NEJM 1989


NEUTROPHIL DEFORMABILITY (STIFFNESS):THE EFFECTS OF CIGARETTE SMOKINGDrost et al AJRCCM 1993;148:1277


THE RESPONSE OF THE HUMAN BONE MARROW TOCHRONIC CIGARETTE SMOKINGPMN L- selectin MFI4321 1*Control Smoker p-valuePMNx10 9 /l 3.2 ±0.19 4.2±0.18 0.003Band cellsx10 9 /l 0.03±0.006 0.18±0.04 0.01Myeloperoxidase MFI432*0Control Smoker ControlSmokerVan Eeden and Hogg ERJ 2000;15:915


Circulating cytokines in healthy smokers31IL-6 (pg/ml)2IL-6* p


Interleukin – 6 causes neutrophil release from the bone marrowchanges in deformability and increases sequestration in the lungsNeutrophil release frombone marrow and lungsequestrationDecreased circulatingneutrophil deformabilityBrdU-Labelled PMN (10 7 /ml tissue)2.52.52.52.5* **12h 24h 48hTime after treatmentIL-6ControlSUWA ET AL AJRCCM 2001;163:970


Leukocyte count, smoking, and lung functionChan Yeung et al. Am J Med 1984;76:31Chan-Yeung et al Thorax 1998:43;462


Relation of FEV 1 and peripheral blood leukocyte count tototal mortality: The normative aging study• 1,956 men (aged 21-81)in Boston Mass 1961-69Cox proportional hazards model of factors predicting mortalityVariable Hazard 95% CIratioAge 1.84 1.51-2.23FEV 1 0.60 0.45-0.80WBC 1.12 1.02-1.20Smoking status 1.40 0.99-1.97Total cholesterol 1.03 1.00-1.06Systolic BP 1.09 0.99-1.21Weiss et al Am J Epidemiol 1995;142:493


Modification of surface antigens in blood CD8+T-lymphocytes in COPD: effects of smokingKoch et al. ERJ 2007;29:42


The interactions between cigarette smoking andreduced lung function on systemic inflammationOdds ratio of having an elevated CRP5.04.03.02.01.00.0Q4 & Cot10SmokerGood FEV1Q4 & Cot10SmokerPoor FEV1Gan et al. Chest 2005;127:558


Systemic Effects of SmokingSystemic inflammation• Systemic oxidative stress• Effects on vasomotor and endothelial function


CIGARETTE SMOKE6000 Different molecules100,000,000,000,000,000 oxidant molecules per puff


The effect of smoking on plasmaanti-oxidant capacity (TEAC)TEAC (mM)1.41.21.00.80.60.40.20Nonsmoker(n=14)***Chronicsmoker(n=11)***Acutesmoker(n=9)Lipid peroxides TBARS(µm)43210Nonsmoker(n=14)**Chronicsmoker(n=11)***Acutesmoker(n=9)***p


Levels of Free and Esterified F2-Isoprostanes in Plasma fromSmokers and Nonsmokers.Morrow et al. NEJM 1995;332 : 1198


Plasma concentrations mean{+/-}standard deviation) of nitrate and nitrite, ascorbic acid, cysteine,methionine, and uric acid in smokers 5 minutes after smoking a single cigarette compared with thosewho smoked a sham cigaretteTsuchiya, M. et al. Circulation 2002;105:1155-1157


Proposed mechanisms of lung inflammation-inducedvascular disease.oxidantsVan Eeden et al PATS 2005 ;2:61


Systemic Effects of SmokingSystemic inflammation• Systemic oxidative stress• Effects on vasomotor and endothelial function


Endothelial dysfunction and atherothrombosisClassical risk factorsSmokingDiabetes mellitusDyslipidaemiaHypertensionNovel risk factorsInfection/inflammationPhysical inactivityHomocysteineAir pollution? ?COPDVascularendotheliumImpairedvasodilatationImpairedfibrinolysisPlateletactivationMonocyteadhesionAtherosclerotic lesion formation and progressionPlaque ruptureThrombosis and vasospasm


Changes in Coronary Blood FlowFollowing 30 minute Exposure to ETSOtsuka et al, JAMA 2001;286:436


Fibrinolytic balance and propagation of microthrombiStable plaqueUnstable plaqueRuptured/denuded plaqueMicrothrombus formationFIBRINOLYTICBALANCEFibrinolytic excessDissolution ofthrombusFibrinolytic deficitPropagation ofthrombusArterial occlusion andischaemia


The fibrinogenesis/fibrinolysisbalanceTissue factorFibrinogenesissystemfibrinogenPA inhibitor(PAI)t-PAFibrinolysissystemCross-linkedfibrin clotPlasminogenPlasminFibrindegradationproducts


Evidence of a shift in the balance offibrinolysis in smokersBlood flow and plasma fibrinolytic factors were measured in both forearms of12 smokers and 12 age- and sex-matched nonsmokers who received unilateralbrachial artery infusions of substance P (2 to 8 pmol/min).t-PAactivity4030201000 20 30 40Substance p(pmol/min)non-smokerssmokersNewby et al Circulation 1999; 99:1411-1415.


Upregulation of the CD40/CD40 ligand and plateletmonocyteaggregation in cigarette smokersHarding et al. Circulation 2004;109:1926


Cigarette smoking is associated with an acuteimpairment of microvascular function in humansAcetylcholine-mediatedvasodilatation(%)800600400200*SmokingSham smokingSodium nitroprusside-mediatedvasodilatation(%)05004003002001000Before AfterBefore AfterIjzerman et al. Clin Sci 2003;104:247


Vascular abnormalities in asymptomatic, healthy young adultsmokers without other major cardiovascular risk factors: TheBogalusa Heart StudyLi et al Am J Hypertens 2005;18:319


Dysfunctional endothelial nitric oxide biosynthesis and fibrinolytic activity inhealthy smokers with impaired endothelium-dependent vasodilatation8NO Conc n (nmol/l)50004000300020001000*Basal tPA (ng/ml)642*0Non-smoker Smoker0Non-smoker SmokerBarua et al. Circulation 2001;104:1905Barua et al. Circulation 2002;106:905


Reactive oxygen species are involved in smoking-induced dysfunction of nitricoxide biosynthesis and upregulation of endothelial nitric oxide synthaseBarua et al. Circulation 2003;107:2342


A Counterblaste to Tobacco“ A custome lothsome to theeye, hateful to the nose,…..dangerous to the lungs, and theblacke stinging fume thereof,neerest resembling the horribleStigian smoke of the pit that isbottomless”. James VI&I 1604


Implications of increased arterialstiffnessPressure (mm Hg)1401201008060P1systoleP2diastoleP1P2systoleAPdiastolePP↑ central systolicpressure↑ LV load↓ coronary arteryperfusion in diastolecompliant arteriesstiff arteriesAugmented pressure (AP) = P2 - P1Augmentation index (AIx) = AP as a percentage of PPAIx is associated with cardiovascular risk 1AIx and AP are independent risk markers for premature CHD 21 Nurnberger J et al. J Hypertens 2002, 2 Weber T et al. Circulation 2004


Augmentation index @75,%Increased cardiovascular risk factors inCOPDBlood pressure analysis for Arterial wall stiffness3530252015105*** ***Time to Reflection,msecs175150145140135130125Mean±SE****p


Sir Walter Raleigh’s servant throws a bucket of water over his master thinkinghe is on fire. By kind permission of the Wellcome Institute.

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