Pathophysiology of COPD Cigarette Smoking and COPD

Smokers฀ display฀ inter-individual฀ differences฀ in฀ terms฀ of฀ lung฀ changes฀ and฀ functional฀ lesions฀ [131] .฀Changes฀in฀the฀terminal฀regions฀of฀the฀bronchial฀tree,฀the฀loss฀of฀bronchiolar฀ consistency฀ due฀ to฀ inlammatory฀ processes฀ and฀ alveolar฀ destruction฀ lead฀ to฀ increasing฀ functional฀impairment฀ [128,฀129,฀131,฀132] .฀Inlammatory฀processes฀sustain฀the฀progres- sion฀ of฀ COPD฀ [133] .฀ Smoking-induced฀ pulmonary฀ emphysema฀ is฀ centrilobular฀ and฀ is฀ principally฀restricted฀to฀the฀upper฀lung฀segments,฀where฀the฀attachment฀of฀the฀alveoli฀to฀ the฀bronchioles฀becomes฀lost฀see฀Table฀ 5.4 ฀for฀an฀overview฀of฀these฀changes฀ [128] .฀It฀is฀ postulated฀that฀in฀COPD,฀a฀protease-antiprotease฀imbalance฀leads฀to฀accelerated฀destruc- tion฀of฀lung฀tissue,฀with฀proteolytic฀activity฀being฀enhanced฀by฀cigarette฀smoke฀ [134] .฀ Neutrophils฀are฀encountered฀in฀larger฀numbers฀in฀the฀lower฀respiratory฀tract฀of฀smokers,฀ especially฀in฀those฀with฀COPD.฀The฀concentration฀of฀inlammatory฀cells฀and฀their฀prod- ucts฀in฀the฀lower฀respiratory฀tract฀correlates฀negatively฀with฀FEV 1 ฀ [135] .฀Moreover,฀smok- ers฀have฀higher฀elastase฀levels฀in฀BAL฀luid฀than฀non-smokers฀ [136] ,฀as฀well฀as฀a฀50฀ reduction฀ in฀ a 1 -antiprotease฀ activity฀ [76] ,฀ probably฀ as฀ a฀ result฀ of฀ oxidation฀ processes฀ caused฀by฀cigarette฀smoke.฀Biopsy฀studies฀indicate฀that฀in฀smokers฀with฀existing฀COPD,฀ there฀ is฀ increased฀ expression฀ of฀ the฀ adhesion฀ molecules฀ E-selectin฀ on฀ vessels฀ and฀ ICAM-1฀on฀basal฀epithelial฀cells฀ [137] .฀The฀adhesion฀molecules฀are฀important฀in฀prepar- ing฀ cells฀ for฀ the฀ inlammatory฀ processes฀ and฀ hence,฀ for฀ the฀ pathogenesis฀ of฀ airways฀ obstruction฀in฀smokers. Until฀ a฀ few฀ years฀ ago,฀ emphysema฀ was฀ considered฀ to฀ be฀ the฀ decisive฀ criterion฀ for฀ COPD;฀now,฀however,฀greater฀importance฀is฀assigned฀to฀the฀inlammatory฀and฀structural฀ changes฀in฀the฀smaller฀airways฀ [131] .฀CT฀scans฀of฀the฀lungs฀of฀patients฀with฀advanced฀ COPD฀have฀revealed฀that฀detectable฀emphysema฀was฀also฀present฀in฀fewer฀than฀one฀third฀ of฀patients฀with฀respiratory฀limitation฀ [138] .฀Even฀in฀young฀smokers฀and฀the฀children฀of฀ women฀who฀smoke,฀respiratory฀bronchiolitis฀is฀the฀irst฀pathological฀sign฀of฀disturbed฀lung฀ function฀and฀this฀occurs฀without฀obstruction฀Fig.฀ 5.4 ฀ [139] .฀In฀older฀smokers,฀the฀inlam- matory฀changes฀are฀accompanied฀by฀connective฀tissue฀deposition฀ [132] .฀Following฀thora- cotomy,฀thickening฀of฀the฀bronchiolar฀membrane฀0.4฀mm฀internal฀diameter฀by฀50฀and฀ of฀the฀bronchioles฀by฀100฀was฀detected฀only฀in฀smokers.฀These฀indings฀also฀correlated฀ with฀the฀results฀of฀preoperative฀pulmonary฀function฀tests฀ [132] .฀A฀reduction฀in฀wall฀thick- ness฀bronchial฀atrophy฀and฀thinning฀of฀the฀bronchial฀wall฀has฀also฀been฀detected฀in฀smok- ers,฀ a฀ possible฀ indicator฀ of฀ airways฀ collapse฀ [51] .฀ Hypertrophy฀ of฀ the฀ bronchiolar฀ musculature฀has฀been฀observed฀in฀smokers,฀possibly฀contributing฀to฀bronchial฀obstruction฀ in฀COPD฀patients. Thickening฀of฀the฀pulmonary฀muscular฀artery฀wall,฀particularly฀of฀the฀intimal฀layer,฀is฀ seen฀in฀smokers฀with฀mild฀COPD฀ [140] .฀These฀vascular฀changes฀are฀associated฀with฀dis- turbances฀of฀ventilation฀and฀perfusion฀and฀with฀a฀reduced฀vascular฀reaction฀in฀terms฀of฀ pO 2 ฀changes฀ [140] .฀To฀date,฀it฀is฀unclear฀to฀what฀extent฀these฀indings฀contribute฀to฀the฀ development฀ of฀ COPD.฀ However,฀ pulmonary฀ vessel฀ resistance฀ at฀ least฀ is฀ increased฀ in฀ patients฀with฀emphysema.฀These฀haemodynamic฀functional฀disturbances฀correlate฀with฀ reduced฀diffusion฀capacity,฀but฀not฀with฀bronchial฀obstruction.฀The฀clinical฀correlate฀of฀ these฀changes฀is฀increased฀cough฀and฀mucus฀secretion,฀reduced฀elastic฀recoil,฀increased฀ expiratory฀obstruction,฀increased฀respiratory฀work,฀dyspnoea,฀wheezing฀and฀reduced฀gas฀ exchange.฀These฀respiratory฀problems฀have฀been฀investigated฀in฀long-term฀studies฀ [32] .฀ Wheezing฀was฀the฀most฀common฀inding฀among฀smokers,฀being฀encountered฀in฀11฀of฀ men฀and฀9฀of฀women.

5.3.2 Important Risk Factors for COPD

For฀ more฀ than฀ 60฀ years฀ now,฀ COPD฀ has฀ been฀ recognised฀ as฀ a฀ consequence฀ of฀ cigarette฀ ฀smoking,฀especially฀since฀more฀than฀80฀of฀all฀COPD฀patients฀are฀smokers฀and฀also฀die฀as฀a฀ result฀of฀this฀condition฀ [17] .฀Mortality,฀morbidity฀and฀pulmonary฀function฀have฀been฀assessed฀ in฀various฀retrospective฀and฀prospective฀studies฀in฀tens฀of฀thousands฀of฀patients฀ [141,฀142] .฀ FEV 1 ฀is฀already฀reduced฀in฀25-year-old฀smokers฀and฀this฀effect฀increases฀over฀time.฀A฀close฀ association฀exists฀between฀cumulative฀cigarette฀consumption฀and฀declining฀pulmonary฀func- tion฀ [116,฀143] .฀In฀this฀context,฀the฀tar฀and฀nicotine฀yields฀of฀the฀cigarettes฀smoked,฀the฀use฀ of฀ilter฀tips฀and฀the฀method฀of฀smoking฀are฀important,฀but฀not฀crucial฀factors฀ [144] .฀Initially,฀ smokers฀have฀a฀normal฀forced฀expiratory฀volume;฀diminished฀FEV 1 ฀with฀clinical฀signs฀of฀ dyspnoea฀develops฀in฀only฀15–30฀of฀cases฀within฀a฀few฀years฀ [128,฀145] . The฀smoking-related฀changes฀co-exist฀alongside฀allergic฀processes,฀some฀of฀which฀are฀ also฀genetically฀determined฀in฀the฀sense฀of฀an฀“asthmatic฀constitution”฀ [146] .฀Methacholine฀ as฀a฀bronchoconstrictor฀or฀b 1 -mimetics฀as฀bronchodilators฀are฀important฀predictors฀for฀the฀ smoking-related฀deterioration฀of฀pulmonary-function฀ [147–149] .฀Bronchial฀hyperrespon- siveness฀is฀an฀important฀risk฀factor฀for฀the฀development฀of฀COPD.฀In฀addition฀to฀decreases฀ in฀pulmonary฀function฀indices,฀IgE฀levels฀and฀eosinophil฀and฀leucocyte฀counts฀have฀been฀ shown฀to฀be฀increased฀in฀smokers;฀these฀variables฀returned฀to฀normal฀on฀smoking฀cessation฀ [148] .฀In฀cases฀where฀smokers฀were฀aware฀that฀they฀had฀an฀allergic฀constitution,฀they฀were฀ more฀often฀prepared฀to฀stop฀smoking฀than฀non-allergic฀individuals฀ [150] .฀Overall,฀how- ever,฀it฀is฀not฀clear฀whether฀eosinophilia฀or฀increased฀IgE฀levels฀in฀smokers฀are฀risk฀factors฀ or฀markers฀for฀pulmonary฀obstruction฀ [150,฀151] .

5.3.2.1 Genetic Factors

COPD฀is฀known฀to฀show฀familial฀clustering฀and฀genetic฀factors฀have฀been฀observed.฀This฀ does฀not฀include฀a 1 -antitrypsin฀deiciency,฀which฀leads฀to฀a฀clearly฀accelerated฀decline฀in฀ pulmonary฀function฀more฀in฀smokers฀than฀in฀non-smokers฀ [145] .฀Irrespective฀of฀smoking฀ status,฀smokers฀with฀an฀antiprotease฀deiciency฀display฀considerable฀heterogeneity฀in฀terms฀ of฀severity฀of฀bronchial฀obstruction฀ [128,฀152] .

5.3.2.2 Occupational and Environmental Factors

A฀wide฀range฀of฀vapours,฀dusts฀and฀gases฀have฀a฀harmful฀effect฀on฀pulmonary฀function,฀ leading฀to฀the฀increased฀occurrence฀of฀chronic฀bronchitis฀cough฀and฀sputum.฀Broncho- obstructive฀reactions฀with฀a฀reduction฀in฀FEV 1 ฀are฀also฀known฀to฀occur฀in฀response฀to฀exog- enous฀factors.฀The฀severity฀of฀COPD฀is฀clearly฀intensiied฀in฀cigarette฀smokers฀in฀developed฀ countries฀ [126] .฀Even฀severe฀air฀pollution฀or฀exposure฀to฀cement฀ [153] ฀may฀have฀an฀additive฀ effect฀on฀the฀condition,฀irrespective฀of฀the฀harmful฀effects฀of฀cigarette฀smoke฀ [147] .

5.4 Cigarette Smoking and Bronchial Asthma

Cigarette฀smoking฀has฀a฀deleterious฀effect฀on฀physical฀performance฀in฀people฀with฀asthma฀ [154] .฀Passive฀exposure฀to฀cigarette฀smoke฀see฀ Chap.฀9 ฀is฀also฀dangerous฀for฀children฀and฀ leads฀to฀increased฀asthma฀morbidity฀ [4] .฀Asthma฀sufferers฀should,฀therefore,฀be฀strongly฀ advised฀not฀to฀start฀smoking฀or฀to฀stop฀smoking฀as฀quickly฀as฀possible.

5.4.1 Caveats Concerning the Informative Value of Studies

Prospective,฀randomised,฀double-blind฀and฀placebo-controlled฀studies฀to฀investigate฀a฀pos- sible฀association฀between฀cigarette฀smoking฀and฀bronchial฀asthma฀are฀not฀acceptable฀on฀ ethical฀grounds;฀consequently,฀only฀cohort฀and฀case-control฀studies฀are฀available.฀For฀the฀ most฀part,฀such฀studies฀use฀extent฀of฀cigarette฀smoking฀as฀a฀parameter,฀but฀the฀information฀ provided฀by฀patients฀frequently฀fails฀to฀relect฀the฀true฀extent฀of฀consumption.฀Urinary฀and฀ serum฀concentrations-of฀cotinine,฀exhaled฀CO฀and฀nicotine฀levels฀have฀also฀been฀used฀as฀ aids฀to฀assessment฀ [155] .฀One฀further฀source฀of฀bias฀is฀that฀asthmatic฀patients฀with฀severe฀ symptoms฀possibly฀smoke฀less฀than฀those฀with฀no฀appreciable฀sense฀of฀being฀unwell.฀This฀ already฀results฀in฀smoker฀selection฀in฀this฀disease฀group฀ [156,฀157] . Even฀the฀clinical฀diagnosis฀of฀bronchial฀asthma฀is฀problematic฀because฀rhonchi฀and฀ wheezing฀may฀anticipate฀the฀diagnosis฀by฀several฀years฀ [158] ฀and฀furthermore,฀there฀is฀ symptom฀overlap฀with฀COPD฀e.g.฀wheezing,฀dyspnoea,฀emphysema.฀Reversible฀or฀irre- versible฀bronchial฀obstruction฀may฀also฀occur฀in฀both฀conditions.฀b 1 -adrenoceptor฀stimu- lants฀are฀neither฀sensitive฀nor฀speciic฀enough฀to฀permit฀discrimination฀of฀the฀two฀diseases฀ [159] .฀Likewise,฀the฀administration฀of฀histamine฀or฀methacholine฀to฀provoke฀a฀bronchial฀ spasm฀is฀not฀speciic฀for฀bronchial฀asthma฀because฀the฀response฀may฀also฀occur฀in฀chronic฀ bronchitis,฀sarcoidosis,฀bronchiectasis฀or฀rhinitis฀ [160,฀161] . While฀an฀allergic฀disposition฀can฀be฀identiied฀in฀asthmatics,฀the฀parameters฀used฀skin฀ testing,฀IgE฀levels฀and฀eosinophil฀count฀are฀not฀reliable฀assessment฀criteria.฀Immediate- type฀skin฀reactions฀are฀linked฀with฀IgE฀antibodies฀ [162] ฀and฀are฀frequently฀positive฀in฀ asthmatics฀ [163] .฀However,฀IgE฀levels฀are฀neither฀sensitive฀nor฀speciic฀for฀the฀diagnosis฀ of฀asthma฀ [160] ,฀even฀if฀associations฀with฀reduced฀pulmonary฀function฀have฀been฀detected฀ speciically฀in฀asthmatics฀ [164] .฀Eosinophils฀possibly฀play฀an฀important฀role฀in฀the฀inlam- matory฀changes฀seen฀in฀asthmatics฀ [165] .

5.4.2 Cigarette Smoking and Bronchial Asthma in Adults

Despite฀various฀studies฀to฀investigate฀the฀possible฀association฀between฀bronchial฀asthma฀ and฀cigarette฀smoking,฀such฀an฀association฀has฀not฀been฀demonstrated฀ [158,฀166,฀167] .฀ The฀ NHANESI฀ Study฀ included฀ patients฀ from฀ 100฀ different฀ communities฀ in฀ 38฀ US฀