Markers of Inflammation Changes at the Molecular and Cellular Level

In฀ 79฀ children฀ exposed฀ to฀ ETS,฀ concentrations฀ of฀ IgE฀ and฀ interleukin-4฀ IL-4฀ and฀ eosinophil฀counts฀were฀higher฀in฀cases฀where฀the฀children฀experienced฀more฀frequent฀respi- ratory฀illness฀average฀3.4฀illnessesyear.฀In฀contrast,฀the฀children฀of฀non-smoking฀parents฀ only฀experienced฀1.2฀episodes฀of฀respiratory฀illnessyear฀and฀their฀IgE,฀IL-4฀and฀eosinophil฀ values฀were฀unchanged฀Table฀ 9.3 . Many฀studies฀have฀shown฀that฀cigarette฀smoking฀is฀associated฀with฀elevated฀concentra- tions฀of฀total฀serum฀IgE.฀Few฀studies,฀however,฀have฀examined฀total฀IgE฀in฀relation฀to฀passive฀ smoking฀exposure,฀especially฀in฀adults.฀In฀a฀cross-sectional฀study,฀Miyake฀et฀al.฀investigated฀ the฀association฀of฀active฀and฀passive฀smoking฀exposure฀with฀levels฀of฀total฀serum฀IgE฀in฀ Japan฀ [67] .฀They฀examined฀981฀pregnant฀women฀in฀Osaka฀and฀found฀out฀that฀current฀smok- ing฀of฀at฀least฀15฀cigarettes฀a฀day฀and฀8.0฀or฀more฀pack-years฀of฀smoking฀were฀independently฀ related฀to฀an฀increased฀prevalence฀of฀elevated฀total฀serum฀IgE฀฀aORs฀3.40฀and฀2.51,฀95฀CIs฀ 2.12–5.47฀and฀1.55–4.06,฀respectively,฀and฀both฀cigarette฀smoking฀status฀and฀pack-years฀of฀ smoking฀were฀signiicantly฀positively฀associated฀with฀total฀serum฀IgE฀levels,฀especially฀in฀ subjects฀with฀a฀positive฀familial฀allergic฀history.฀There฀was฀no฀measurable฀association฀of฀ exposure฀to฀ETS฀at฀home฀or฀at฀work฀with฀total฀serum฀IgE฀concentrations฀among฀those฀who฀ had฀never฀smoked.฀It฀was฀concluded฀that฀there฀is฀a฀positive฀relationship฀between฀active฀smok- ing฀and฀total฀serum฀IgE฀levels;฀however,฀this฀study฀failed฀to฀substantiate฀a฀positive฀association฀ of฀ETS฀exposure฀with฀total฀IgE.฀Investigations฀with฀more฀precise฀and฀detailed฀exposure฀mea- surements฀are฀warranted฀ [67] . Another฀study฀assessed฀the฀correlation฀of฀ETS฀exposure฀with฀the฀expression฀of฀pro- inlammatory฀mediators฀in฀airway฀secretions,฀including฀IFN-g฀and฀IL-12,฀as฀well฀as฀IL-5฀ and฀IL-13,฀in฀allergic฀asthmatic฀schoolchildren฀and฀healthy฀control฀subjects฀ [68] .฀By฀using฀ the฀nasopharyngeal฀aspiration฀technique,฀airway฀secretions฀were฀collected฀from฀24฀atopic฀ children฀with฀asthma฀age,฀6–16฀years฀and฀26฀healthy฀control฀subjects,฀and฀the฀concentra- tion฀of฀cytokines฀was฀measured฀with฀immunoenzymatic฀methods.฀It฀was฀shown฀that฀IL-13฀ levels฀were฀highly฀increased฀in฀patients฀with฀asthma฀฀p฀฀0.005,฀and฀parental฀tobacco฀ smoke฀ resulted฀ in฀ a฀ signiicant฀ increase฀ in฀ airway฀ IL-13฀ secretion฀ in฀ these฀ children฀ Group n฀ Infections year TLC฀฀ cmm 3 EC฀฀ cmm 3 IL-4฀฀ pgml IgE฀฀ IUml Children฀with฀ frequent฀฀ infections 41 4.5฀±฀1.1 a ฀ 7,889฀±฀989 a 651฀±฀121 a 1.8฀±฀0.5 605฀±฀365 Children฀with฀ infrequent฀ infections 29 2.0฀±฀0.6 6,771฀±฀1131 364฀±฀85 1.31฀±฀0.45 557฀±฀354 All฀children฀of฀ smoking฀parents 70 3.4฀±฀0.8 b 7,426฀±฀899 b 482฀±฀96 b 1.6฀±฀0.46 b 587฀±฀359 b Children฀of฀ non-smoking฀ parents 50 1.2฀±฀0.6 6,040฀±฀530 239฀±฀51 0.8฀±฀0.5 189฀±฀21 Table 9.3 ฀฀฀Recurrent฀respiratory฀tract฀infections:฀a฀comparison฀of฀selected฀inlammatory฀variables฀ in฀children฀aged฀9–11฀years฀of฀smoking฀and฀non-smoking฀parents฀ [66] TLC฀total฀leucocyte฀count;฀EC฀eosinophil฀count;฀IL-4฀interleukin-4;฀IgE฀immunoglobulin฀E a p฀฀0.05,฀between฀children฀of฀smoking฀parents b p฀฀0.05:฀group฀vs.฀control compared฀with฀that฀seen฀in฀non-exposed฀children฀and฀healthy฀control฀subjects฀median,฀ 860฀ vs.฀ 242฀ and฀ 125฀ pgml,฀ respectively.฀ Furthermore,฀ a฀ positive฀ correlation฀ between฀ IL-13฀levels฀and฀serum฀IgE฀concentrations฀rs฀=฀0.55฀was฀found฀in฀children฀with฀allergic฀ asthma.฀The฀study฀indicated฀that฀ETS฀augments฀the฀expression฀and฀secretion฀of฀IL-13฀in฀ allergic฀asthma฀and฀that฀nasopharyngeal฀aspiration฀is฀a฀suitable฀method฀to฀assess฀cytokine฀ measurements฀ in฀ the฀ airways฀ of฀ children.฀ Measurements฀ of฀ IL-13฀ in฀ secretions฀ might฀฀ be฀taken฀into฀account฀as฀a฀non-invasive฀marker฀of฀airway฀inlammation฀and฀to฀assess฀the฀ detrimental฀effects฀of฀ETS฀ [68] .

9.2.5 ETS and Drug Metabolism

The฀inluence฀of฀passive฀smoking฀in฀children฀and฀adults฀on฀the฀metabolism฀of฀medicinal฀ drugs฀and฀toxic฀substances฀cannot฀yet฀be฀gauged.฀Where฀the฀parents฀had฀a฀minimum฀1-pack day฀habit,฀ETS-exposed฀children฀displayed฀intensiied฀metabolism฀of฀medicines฀such฀as฀ theophylline.฀Compared฀with฀children฀without฀ETS฀exposure,฀total฀body฀clearance฀of฀theo- phylline฀was฀signiicantly฀elevated฀1.36฀±฀0.09฀vs.฀0.90฀±฀0.04฀mlminkg;฀p฀฀0.0001฀and฀ serum฀concentrations฀were฀signiicantly฀lower฀55.3±2.8฀vs.฀73.2±3.3฀µgml;฀p฀฀0.00001.฀ Hospital฀stay฀times฀were฀also฀longer฀in฀the฀group฀exposed฀to฀passive฀smoking฀4.4฀±฀2.6฀vs.฀ 2.9฀±฀1.3฀days;฀p฀฀0.05฀ [69] .฀These฀indings฀suggest฀that฀the฀metabolism฀of฀other฀medici- nal฀drugs฀may฀also฀be฀accelerated฀in฀children฀exposed฀to฀ETS.

9.3 Passive Smoking During and After Pregnancy

ETS-exposed฀children฀born฀to฀mothers฀who฀smoke฀during฀pregnancy฀are฀2–4-times฀more฀ likely฀than฀children฀without฀ETS฀exposure฀to฀be฀born฀small฀for฀gestational฀age฀see฀ Chap.฀8 ฀ [70] .฀A฀50–100฀increase฀in฀acute฀respiratory฀disorders฀has฀been฀reported฀in฀children฀as฀a฀ result฀of฀passive฀smoking฀ [71] .฀Children฀born฀to฀mothers฀exposed฀to฀ETS฀during฀pregnancy฀ have฀increased฀number฀of฀nucleated฀red฀blood฀cells฀ [72] ,฀indicating฀reduced฀O 2 ฀supplies฀ during฀pregnancy฀ [73] .฀The฀same฀inding฀has฀been฀made฀in฀children฀born฀to฀women฀who฀ were฀active฀smokers฀during฀pregnancy฀ [69] .฀Infants฀have฀a฀2.5-fold฀increased฀risk฀of฀dying฀ from฀sudden฀infant฀death฀syndrome฀SIDS฀where฀their฀mothers฀continue฀to฀smoke฀after฀ giving฀birth฀ [1,฀74] .฀The฀presence฀of฀nicotine฀and฀cotinine฀in฀children’s฀hair฀after฀birth฀is฀an฀ important฀marker฀of฀foetal฀exposure฀to฀tobacco฀smoke฀Table฀ 9.4 ฀ [56] .฀The฀detected฀pres- ence฀of฀cotinine฀10-50฀to 50฀ngnl฀pericardiac฀luid฀in฀four฀infants฀is฀indicative฀of฀absorp- tion฀due฀to฀passive฀smoking฀ [20] .฀However,฀it฀is฀highly฀improbable฀that฀raised฀nicotine฀and฀ cotinine฀levels฀in฀the฀pericardiac฀region฀are฀contributory฀factors฀in฀SIDS฀ [20] . While฀there฀are฀suficient฀data฀regarding฀the฀negative฀effect฀of฀exposure฀to฀the฀constitu- ents฀of฀tobacco฀smoke฀on฀newborn฀infants’฀birth฀weights,฀it฀is฀still฀unclear฀whether฀this฀effect฀ may฀originate฀in฀early฀pregnancy.฀Therefore,฀Hanke฀et฀al.฀evaluated฀the฀impact฀of฀exposure฀ to฀tobacco฀smoke฀components฀in฀early฀pregnancy฀20–24฀weeks฀on฀foetal฀biometry฀ [75] .฀ The฀study฀population฀comprised฀183฀women฀consecutively฀enrolled฀at฀20–24฀weeks฀of฀ pregnancy฀at฀the฀two฀antenatal฀care฀units฀and฀ultrasound฀biometric฀measurements฀of฀foetal฀ bi-parietal฀diameter฀BPD,฀abdominal฀circumference฀AC฀and฀femur฀length฀FL฀were฀ performed.฀Also,฀serum฀cotinine฀concentration฀was฀determined฀at฀20–24฀weeks฀of฀gesta- tion฀ by฀ gas฀ chromatography฀ with฀ mass฀ spectrometry฀ detector฀ GCMS฀ to฀ assess฀ ETS฀ exposure฀during฀the฀previous฀evening฀and฀the฀morning฀of฀the฀same฀day฀blood฀collection฀ at฀1,200–1,300฀h.฀ETS฀exposure฀passive฀smoking฀was฀assumed฀to฀occur฀when฀the฀level฀ of฀serum฀cotinine฀ranged฀from฀2฀to฀10฀ngml.฀The฀authors฀demonstrated฀that฀a฀statistically฀ signiicant฀negative฀association฀was฀present฀between฀the฀BPD฀and฀serum฀cotinine฀concen- tration.฀A฀similar฀association฀was฀identiied฀for฀subjects฀with฀serum฀cotinine฀concentra- tions฀below฀10฀ngml฀corresponding฀to฀passive฀smoking฀฀p฀=฀0.06.฀After฀controlling฀for฀ pregnancy฀duration,฀maternal฀pre-pregnancy฀weight฀and฀infant’s฀gender,฀we฀found฀that฀ serum฀cotinine฀levels฀at฀20–24฀weeks฀of฀gestation฀was฀inversely฀associated฀with฀infant฀ birth฀weight฀฀p฀=฀0.004.฀For฀the฀subjects฀with฀serum฀cotinine฀levels฀below฀10฀ngml,฀a฀ borderline฀association฀฀p฀=฀0.09฀with฀infant฀birth฀weight฀was฀found.฀It฀was฀concluded฀that฀ maternal฀exposure฀to฀tobacco฀smoke฀in฀early฀pregnancy,฀as฀measured฀by฀serum฀cotinine฀ concentrations฀at฀20–24฀weeks฀of฀gestation,฀adversely฀affects฀foetal฀BPD฀ [75] . In฀children฀with฀low฀birth฀weight฀following฀ETS฀exposure,฀the฀vasodilator฀response฀ following฀forearm฀cuff฀occlusion฀and฀release฀was฀still฀reduced฀at฀age฀9–11฀years฀compared฀ with฀that฀in฀normal฀birth฀weight฀children฀born฀to฀non-smoking฀mothers.฀The฀physiological฀ vasodilator฀response฀is฀triggered฀by฀NO฀release฀from฀endothelial฀cells฀ [76] .฀Among฀other฀ things,฀this฀harmful฀effect฀has฀its฀origins฀in฀the฀prenatal฀period฀and฀is฀related฀to฀the฀smok- ing฀behaviour฀of฀the฀mother-to-be฀during฀pregnancy;฀it฀manifests฀itself฀as฀early฀as฀the฀irst฀ decade฀of฀life฀as฀a฀prelude฀to฀later฀atherogenic฀changes.฀Evidently,฀in฀the฀developmental฀ phases฀characterised฀by฀rapid฀growth฀such฀as฀the฀foetal฀period,฀the฀endothelial฀cells฀also฀ undergo฀adverse฀changes฀which฀limit฀physiological฀function฀ [77] . Urinary฀cotinine฀levels฀were฀determined฀in฀199฀ETS-exposed฀children฀between฀the฀ages฀ of฀4฀months฀and฀4฀years฀with฀obstructive฀bronchitis.฀Compared฀with฀healthy฀children฀of฀the฀ same฀age,฀urinary฀cotinine฀levels฀were฀found฀to฀be฀5.7฀µgl,฀instead฀of฀4.4฀µgl.฀The฀risk฀of฀ developing฀bronchitis฀was฀increased฀in฀line฀with฀the฀extent฀of฀passive฀smoking฀and฀the฀rise฀ in฀urinary฀cotinine.฀This฀risk฀was฀increased฀threefold฀at฀a฀urinary฀cotinine฀concentration฀of฀ 20฀ µgl฀ [78] .฀ Similar฀ results฀ have฀ been฀ reported฀ in฀ 69฀ children฀ [79] .฀ The฀ incidence฀ of฀ Nicotine฀ngml Cotinine฀ngml฀ Active฀smoking฀women฀n฀=฀36 19.2 4.9 6.3 4.0 Newborns฀of฀active฀smoking฀women ฀ 2.4 0.9 2.8 0.8 Passive฀smoking฀women a ฀n฀=฀23 ฀ 3.2 0,8 0.9 0.3 b Newborns฀of฀passive฀smoking฀women ฀ 0.28 0.05 0.6 0.15 Non-smoking฀women฀n฀=฀35 ฀ 1.2 0.4 0.3 0.06 Newborns฀of฀non-smoking฀women ฀ 0.4 0.09 0.26 0.04 Table 9.4 ฀฀฀Hair฀concentrations฀mean฀±฀SEM฀of฀nicotine฀and฀cotinine฀in฀women฀and฀their฀newborn฀ infants฀ [56] a฀ Deined฀as฀regular฀and฀steady฀gestational฀exposure฀to฀other฀person’s฀cigarette฀smoke,฀either฀at฀ home฀or฀in฀the฀workplace b p฀฀0.01฀when฀compared฀to฀newborns฀of฀active฀smoking฀women฀and฀newborns฀of฀non-smokers