Exogenous Factors and Lung Cancer

with฀those฀with฀lower฀BMI฀and฀higher฀weight฀gain฀p฀=฀0.06.฀Overall,฀the฀authors฀con- cluded฀ that฀ leanness฀ is฀ a฀ host฀ susceptibility฀ factor฀ that฀ affects฀ DNA฀ adduct฀ formation,฀ which฀could฀underlie฀the฀observed฀relationship฀between฀BMI฀and฀lung฀cancer฀risk฀ [121] . Alcohol฀does฀not฀play฀a฀role฀in฀smokers฀in฀terms฀of฀the฀development฀of฀lung฀cancer.฀ This฀was฀demonstrated฀in฀a฀study฀in฀27,111฀male฀smokers,฀1,059฀of฀whom฀developed฀lung฀ cancer฀over฀a฀period฀of฀7.7฀years.฀Non-drinkers฀were฀at฀increased฀lung฀cancer฀risk฀com- pared฀with฀drinkers฀relative฀risk฀=฀−1.2;฀95฀CI:฀1.0–1.4฀ [122] .฀However,฀additional฀ alcohol฀consumption฀is฀important฀for฀the฀development฀of฀cancers฀in฀the฀oral฀cavity,฀phar- ynx,฀larynx฀and฀oesophagus,฀the฀risk฀being฀twice฀as฀high฀as฀in฀patients฀with฀a฀current฀his- tory฀of฀smoking,฀but฀without฀current฀daily฀drinking฀ [123] . According฀to฀one฀study฀from฀Italy฀ [122] ,฀patients฀with฀lung฀cancer฀and฀HIV฀infection฀ were฀younger฀38฀vs.฀53฀years฀and฀previously฀smoked฀more฀cigarettes฀per฀day฀40฀vs.฀20฀ than฀the฀control฀group฀of฀patients฀with฀lung฀cancer,฀but฀without฀HIV฀infection.฀The฀main฀ histological฀subtype฀was฀AC,฀with฀tumour฀stage฀TNM฀III–IV฀observed฀in฀the฀majority฀ 53฀of฀patients.฀The฀median฀survival฀of฀the฀HIV฀patients฀was฀signiicantly฀shorter฀than฀ that฀of฀the฀control฀group฀5฀vs.฀10฀months. The฀ development฀ of฀ lung฀ cancer฀ in฀ smokers฀ is฀ supported฀ by฀ exposure฀ to฀ asbestos฀ [124] ,฀with฀the฀risk฀being฀increased฀by฀many฀multiples฀20-fold฀increase฀compared฀with฀ non-smoking฀ asbestos฀ workers฀ and฀ 50-fold฀ increase฀ compared฀ with฀ non-smoking฀ and฀ non-asbestos-exposed฀persons฀ [25] .฀Other฀gaseous฀substances฀also฀encourage฀the฀devel- opment฀ of฀ bronchial฀ carcinoma:฀ arsenic฀ compounds,฀ chloromethyl฀ ether,฀ chromium,฀ nickel฀ and฀ polynuclear฀ aromatic฀ compounds฀ act฀ synergistically฀ with฀ cigarette฀ smoke฀ [100] .฀Radon฀exposure฀is฀also฀associated฀with฀an฀increased฀risk฀of฀bronchial฀carcinoma฀ due฀to฀its฀storage฀in฀lung฀tissue฀and฀high-energy฀a-radiation฀ [64] .฀Smokers฀employed฀in฀ uranium฀mining฀have฀a฀tenfold฀increased฀risk฀of฀bronchial฀carcinoma฀compared฀with฀non- smokers฀working฀in฀the฀same฀industry฀ [64,฀125,฀126] .฀Even฀radiation฀from฀underground฀ uranium฀can฀increase฀the฀lung฀cancer฀risk฀in฀cigarette฀smokers฀ [64] .฀Radiation฀levels฀of฀ 50฀up฀to฀140฀Bqm 3 ฀are฀measured฀in฀various฀residential฀areas฀ [127] ,฀leading฀to฀p53฀muta- tions฀and฀increased฀cancer฀risk฀OR฀=฀−1.4;฀CI:฀0.7–2.6;฀OR฀for฀non-smokers฀=฀3.2;฀CI:฀ 0.7–15.5฀ [127] . Finally,฀the฀risk฀for฀bronchial฀carcinoma฀may฀be฀increased฀simply฀as฀a฀result฀of฀urbani- sation,฀mainly฀due฀to฀air฀pollution฀ [34] .฀However,฀this฀idea฀has฀not฀been฀conirmed฀by฀ other฀studies฀ [6,฀18,฀66] . Readers฀are฀referred฀to฀ Chap.฀3 ฀for฀a฀discussion฀of฀bacterial฀endotoxins฀lipopolysac- charides฀contained฀in฀cigarettes฀and฀cigarette฀smoke.

5.3 Cigarette Smoking and COPD

COPD฀is฀the฀sixth฀most฀common฀disease฀worldwide,฀four฀places฀ahead฀of฀bronchial฀carci- noma฀rank฀10.฀In฀about฀20฀years’฀time,฀COPD,฀a฀condition฀that฀is฀smoking-related฀for฀the฀ most฀part฀and฀is฀characterised฀by฀increasing฀exacerbations฀necessitating฀hospital฀interven- tion,฀will฀have฀risen฀to฀third฀place฀in฀the฀league฀table฀of฀diseases.฀In฀Germany,฀3–4฀of฀the฀ ฀population฀over฀the฀age฀of฀18฀years฀develop฀COPD฀and฀in฀55-year-olds,฀prevalence฀is฀already฀ 10–12.฀For฀COPD฀alone,฀a฀disease฀that฀is฀chiely฀encountered฀among฀smokers,฀the฀costs฀of฀ treatment฀will฀continue฀to฀escalate. Chronic฀bronchitis฀is฀characterised฀by฀chronic฀cough฀and฀excessive฀sputum฀secretion฀ over฀a฀period฀of฀at฀least฀3฀months฀and฀up฀to฀several฀years.฀This฀form฀of฀bronchitis฀may฀ occur฀both฀with฀and฀without฀accompanying฀ventilatory฀disorders฀arising฀primarily฀as฀a฀ result฀ of฀ airspace฀ dilatation฀ distal฀ to฀ the฀ terminal฀ bronchiole฀ without฀ obvious฀ ibrosis.฀ COPD฀is฀said฀to฀be฀present฀where฀emphysema฀and฀airlow฀obstruction฀occur฀in฀addition฀to฀ chronic฀bronchitis. An฀ epidemiological฀ survey฀ of฀ COPD฀ is฀ problematic฀ because฀ the฀ disease฀ criteria฀ are฀ deined฀differently.฀In฀the฀USA,฀it฀is฀estimated฀that฀14฀million฀people฀suffer฀from฀the฀disease฀ [128] .฀In฀recent฀decades,฀this฀igure฀has฀risen฀continuously,฀especially฀among฀women฀ [128] .฀ In฀1992,฀more฀than฀90,000฀US฀Americans฀died฀from฀COPD,฀making฀it฀the฀fourth฀common- est฀cause฀of฀death.฀The฀disease฀is฀still฀contracted฀by฀more฀men฀than฀women,฀but฀the฀propor- tions฀are฀set฀to฀even฀out฀as฀a฀delayed฀response฀to฀the฀increasing฀number฀of฀female฀smokers.฀ The฀COPD฀death฀rate฀for฀females฀increased฀by฀382฀from฀1968฀through฀1999.฀In฀the฀same฀ period,฀the฀rate฀for฀males฀increased฀by฀27฀ [129] .฀COPD฀becomes฀more฀common฀with฀ increasing฀age฀and฀smoking฀habits,฀and฀age-related฀lung฀changes฀have฀been฀identiied.

5.3.1 Pathophysiology of COPD

Cigarette฀smoking฀triggers฀a฀wide฀range฀of฀harmful฀effects฀see฀Table฀ 5.4 ฀as฀follows: • ฀ Cilia฀loss฀and฀mucous฀gland฀hyperplasia฀in฀the฀main฀bronchi • ฀ Inlammation,฀epithelial฀changes,฀ibrosis,฀secretory฀congestion฀in฀the฀more฀peripheral฀ airways • ฀ Hypertrophy฀of฀the฀bronchial฀musculature,฀vascular฀changes • ฀ Alveolar฀destruction฀with฀loss฀of฀airways฀flexibility,฀elastic฀recoil฀and฀gas฀exchange฀ surface฀area. Changes฀in Findings Central฀airways Cilia฀loss,฀mucous฀gland฀enlargement,฀goblet฀cell฀increase,฀regression฀of฀ cilia฀pseudostratiied฀epithelium฀to฀squamous฀metaplasia,฀carcinoma฀ in฀situ฀and฀possibly฀bronchogenic฀carcinomas Peripheral฀airways Inlammation฀and฀atrophy,฀goblet฀cell฀metaplasia,฀squamous฀metaplasia,฀ mucus฀congestion฀blockade,฀smooth-muscle฀hypertrophy,฀ ฀peribronchial฀ibrosis Alveoli฀and฀ capillaries Destruction฀of฀peribronchial฀alveoli,฀reduction฀in฀small฀arteries,฀ pathological฀composition฀of฀bronchoalveolar฀lavage฀luid,฀increased฀ IgA฀and฀IgG,฀increase฀in฀activated฀macrophages฀and฀neutrophils Immune฀system Increased฀leucocyte฀count฀in฀periphery,฀eosinophilia,฀increased฀IgE฀ levels,฀reduced฀responsiveness฀to฀allergy฀tests,฀reduced฀reactions฀to฀ inhaled฀antigens Table 5.4 ฀฀฀Effects฀of฀smoking฀on฀the฀lung฀ [130]