SMOKING

J Clin Periodontol 2005; 32 (Suppl.
6): 180–195 Copyright r Blackwell Munksgaard 2005
Richard M. Palmer1, Ron F. Wilson1,

Mechanisms of action of Adam S. Hasan1 and David A. Scott2
1
King’s College London, Guy’s Hospital
environmental factors – tobacco Campus, London Bridge, London SE1 9RT,

UK; 2School of Dentistry, University of
Louisville, Louisville, KY 40292,USA
smoking
Palmer RM, Wilson RF, Hasan AS, Scott DA. Mechanisms of action of environmental
factors – tobacco smoking. J Clin Peridontol 2005; 32 (Suppl. 6): 180–195.
r Blackwell Munksgaard 2005.
Abstract
Aim: To review the potential biological mechanisms underlying the effects of tobacco
smoking on periodontitis.
Main findings: Smoking has major effects on the host response, but there are also a
number of studies that show some microbiological differences between smokers and
non-smokers.
Smoking has a long-term chronic effect on many important aspects of the
inflammatory and immune responses. Histological studies have shown alterations in
the vasculature of the periodontal tissues in smokers. Smoking induces a significant
systemic neutrophilia, but neutrophil transmigration across the periodontal
microvasculature is impeded. The suppression of neutrophil cell spreading,
chemokinesis, chemotaxis and phagocytosis have been described. Protease release
from neutrophils may be an important mechanism in tissue destruction. Tobacco
smoke has been found to affect both cell-mediated immunity and humoral immunity.
Research on gingival crevicular fluid has demonstrated that there are lower levels of
cytokines, enzymes and possibly polymorphonuclear cells in smokers. In vitro studies
have shown detrimental effects of nicotine and some other tobacco compounds on
fibroblast function, including fibroblast proliferation, adhesion to root surfaces and
cytotoxicity.
Key words: smoking; periodontitis; bacteria;
Conclusion: Tobacco smoking has widespread systemic effects, many of which may neutrophils; lymphocytes; fibroblasts
provide mechanisms for the increased susceptibility to periodontitis and the poorer
response to treatment. Accepted for publication 1 April 2005
Tobacco smoking, mostly in the form of this knowledge to the pathogenesis of contains thousands of different com-
cigarette smoking, is recognized as the periodontitis. Therefore, many of these pounds (Table 1). Many of these are
most important environmental risk fac- mechanisms may be implied or specu- directly noxious/poisonous to living
tor in periodontitis, and, with respect to lative. This review will attempt to build organisms and cells, and nicotine may
this, there are large number of support- on previous reviews in the periodontal be unfairly blamed for most of these
ing epidemiological studies which will literature and make attempts to primarily properties. Moreover, it is also very
not be the focus of this review. Over the consider evidence that directly pertains important to appreciate that most of
last decade, there have also been a to the periodontal tissues, citing more the harmful effects of tobacco products
number of excellent reviews that have general papers only where necessary. will result from systemic exposure
considered the biological basis and It is fair to say that much of the work through absorption in the lungs rather
pathogenic mechanisms in addition to in the periodontal and medical literature than topical absorption in the oral cavity
the clinical and epidemiological aspects has concentrated on the effects of nico- (Palmer et al. 2000).
(Barbour et al. 1997, Tonetti 1998, tine in tobacco. While nicotine is the A regular heavy smoker exposes him-
Kinane & Chestnutt 2000, Johnson & primary psychoactive component, and self/herself to these compounds many
Hill 2004, Mullally 2004). It has usually addiction to it is the main reason for times per day for several minutes at a
been necessary to rely on the vast body people subjecting themselves to fre- time. Although increasing evidence is
of medical literature that describes the quent and high doses over many years, being presented for the harmful effects
noxious effects of smoking, and to apply one must appreciate that tobacco smoke of passive smoking, the periodontal
180
Effects of tobacco smoking on periodontitis 181
Table 1. Some constituents of tobacco smoke plaque than non-smokers suggested that ences in the microflora. However, a
(http://www.ash.org.uk/) more severe periodontal disease in smo- number of studies have indicated that
Particulate phase Gas phase kers might be because of greater accu- smoking has little effect on the subgin-
mulations of plaque (Kristoffersen 1970, gival microflora. Preber et al. (1992)
Nicotine Carbon monoxide Preber et al. 1980). However, other sampled a single site with a probing
‘‘Tar’’ (composed Ammonia studies indicated that, when controlling pocket depth X6 mm and compared
of many chemicals) for other factors, smoking did not appear 83 smokers and 62 non-smokers for
Benzene Dimethylnitrosamine to increase the amount of plaque (Alex- the presence and proportion of Actino-
Benzo(a)pyrene Formaldehyde
ander 1970, Sheiham 1971). In addition, bacillus actinomycetemcomitans, Por-
Hydrogen cyanide
Acrolein studies in which the development of phyromonas gingivalis and Prevotella
plaque and inflammation was observed intermedia using cultural methods.
in an experimental gingivitis model They showed no significant differences
literature is generally confined to active showed that the rate of plaque formation between the two groups of subjects.
smoking. Many smokers develop the was similar between smokers and non- A more recent cultural study (van der
habit in their teenage years and continue smokers (Bastiaan & Waite 1978, Berg- Velden et al. 2003) showed similar
it throughout their life. No other drug is strom 1981, Bergstrom & Preber 1986, results. The authors reported sampling
administered so frequently or over such Lie et al. 1998a). the deepest sites in four quadrants
a time period as smoking. This is to and analysing for A. actinomycetemco-
emphasize the fact that the detrimental mitans, Tannerella forsythensis (Bac-
effects on the periodontium are derived Effect of smoking on the oral flora teroides forsythus), Fusobacterium
from long-term chronic exposure and nucleatum, P. gingivalis, P. intermedia
Studies of the relationship between
bear little relationship with the effects and Micromonas micros (Peptostrepto-
smoking and the oral flora are limited
that can be measured on a single expo- coccus micros) before and after treat-
in comparison with those that have estab-
sure. The importance of measurement ment. No significant differences in the
lished a link with more severe perio-
and validation of exposure to tobacco prevalence of the various bacteria were
dontal disease. The majority of studies
smoke is considered in the review by seen between 30 smokers and 29 non-
have investigated the difference in the
Scott et al. (2001). Cotinine, a metabo- smokers before treatment. Stoltenberg
subgingival microflora between smoking
lite of nicotine, can be measured in the et al. (1993) used an immunofluorescent
and non-smoking subjects with perio-
serum/plasma and saliva, and is a better method to examine eight samples per
dontal disease (Table 2). However, a
measure of tobacco smoke exposure as subject to establish the presence or
study of the microbiota of the oral
it has a longer half-life than nicotine absence of A. actinomycetemcomitans,
mucous membranes and saliva failed to
(18 h compared with 1–2 h). Smokers Eikenella corrodens, F. nucleatum,
establish a statistically significant trend
would be expected to have serum coti- P. gingivalis and P. intermedia. No
for smokers to harbour greater propor-
nine levels of over 14 ng/ml, and this significant differences were reported
tions of putative periodontal pathogens in
could be as high as 1000 ng/ml. Resting between the 63 smokers and 126 non-
these oral locations (Mager et al. 2003).
plasma nicotine levels are much lower smokers, although the presence of some
Similarly, an experimental gingivitis
(5–50 ng/ml), and are maintained by the test bacteria and smoking were sepa-
study showed no differences between
individual to satisfy their craving for rately associated with increased risk of
smokers and non-smokers in the altera-
nicotine. Because nicotine is so rapidly probing depths X3.5 mm. Two recent
tions to supra- and subgingival micro-
absorbed from the lung and transport to studies have used DNA identification
flora during the change from relative
the brain is rapid, very high peak levels techniques to investigate differences
health to experimentally induced gingi-
can be measured in the brain. It is between smokers and non-smokers.
vitis (Lie et al. 1998b). However, a study
important to understand these variations Darby et al. (2000) investigated the
of the microflora of the gingival crevice
in relation to levels tested in in vitro prevalence of A. actinomycetemco-
in 25 smokers and 25 non-smokers with
experiments. mitans, T. forsythensis, P. gingivalis,
a relatively healthy periodontium
Tobacco smoking affects the oral P. intermedia and Treponema denticola
showed a higher prevalence of infection
environment and ecology, the gingival in 10 smoking and 23 non-smoking
with at least one of the tested pathogens
tissues and vasculature, the inflamma- patients with adult periodontitis using
in smokers (Shiloah et al. 2000).
tory response, the immune response and PCR. The authors also reported findings
the homeostasis and healing potential of from 12 smokers and 12 non-smokers
the periodontal connective tissues. This with generalized early-onset perio-
Effect of smoking on the subgingival
review will follow this line and will microflora in periodontitis
dontitis. In neither group did they
clearly differentiate between the effects observe differences in the micro-
of whole tobacco smoke and nicotine The vast majority of studies of the flora which could be attributed to
and chronic and acute exposure where influence of smoking on the periodontal smoking. Bostrom et al. (2001) used
appropriate. microflora have been cross-sectional checkerboard DNA–DNA hybridization
investigations of patients with chronic technology to detect the presence of a
periodontitis (Table 2). Given the con- wide range of species in 33 smokers and
Effect of Smoking on Plaque vincing evidence for differences in the 31 non-smokers. No influence of smok-
Effect of smoking on plaque development
clinical and immunological status of the ing on the occurrence of any species was
subgingival environment in smokers and observed.
Early observational reports that smokers non-smokers, it would be reasonable to The earliest reported evidence of
showed a higher prevalence of dental propose that they should exhibit differ- microbiological differences between
Table 2. Microbiological studies of periodontitis in smokers and non-smokers
182
References Number of Smoking Sampling and sites Laboratory Organisms investigated Results: smokers
smokers/non-smokersn history procedures included versus non-smokers
Mager et al. (2003) 47/182 84 subjects ND Swab eight oral mucous DNA Pg, Pi, Mm, Si, Sn, Td and others Non-significant trends
periodontally healthy membrane sites to higher levels of pathogens in smokers
van der Velden et al. 30/29 Cotinine X5ng/ml Paper points to four deepest sites Culture Aa, Tf, Fn, Pg, Pi, Mm No difference
(2003)
Palmer et al.
Bostrom et al. (2001) 33/31 X20 cig/day X32 Paper points to four sites DNA Aa, Tf, Cr, Ec, Fn, Pg, No difference
years X5 mm Pi, Mm, Pn, Si, Sn, Td
Eggert et al. (2001) 86/163 NDz Paper points to two deepest sites IA Aa, Pg, Pi Higher proportions of Pi in smokers
Haffajee and Socransky 50/124 ND Curette Mesio-buccal of all DNA Aa, Cr, Csp, Ec, En, Fn, Higher prevalence of Tf, En, Fn, Pi, Mm,
(2001) teeth Pi, Mm, Pn, Tf, Pg, Si, Sn, Td Pn, Pg, Td in smokers at sites 44 mm
Van Winkelhoff et al. 88/90 ND Paper points to four deepest sites Culture Aa, Tf, Cr, Fn, Pg, Pi, Pn, Mm Higher prevalence of Pi/Pn and higher
(2001) proportions of Fn, Mm in smokers
Darby et al. (2000) 22/33 ND Curette four sites X5 mm PCR Aa, Tf, Pg, Pi, Td No difference
Shiloah et al. (2000) 25/25 healthy subjects X15 cig/day X3 Paper points to healthy sites DNA Aa, Cr, Ec, Fn, Pg, Pi, Td Higher prevalence of infection
years with at least one pathogen in smokers
Kamma et al. (1999) 30/30 early onset X20 cig/day Paper points to two sites Culture Aa, Tf, Cr, Ec, Fn, Pg, Higher prevalence and proportions
periodontitis X5 mm Pi, Mm, Si of Tf, Cr, Pg, Mm and others in smokers
Lie et al. (1998b) 11/14 experimental X7 cig/day Paper points to pooled supra- Culture Aa, Cr, Fn, Pg, Pi, Mm No differences
gingivitis and sub-gingival and others
Umeda et al. (1998) 21/146 ND Paper points to four deepest sites PCR Aa, Tf, Pg, Pi, Pn, Td Higher prevalence of Td in smokers
Zambon et al. (1996) 798/628 smokers ND Paper points two pooled samples IF Aa, Tf, Cr, Es, Fn, Pg, Pi Higher prevalence of Aa, Tf, Pg in smokers
included former smokers from six sites
Stoltenberg et al. (1993) 63/126 ND Curette IF Aa, Ec, Fn, Pg, Pi No difference
Preber et al. (1992) 83/62 ND Paper points to one site X6 mm Culture Aa, Pg, Pi No difference
n
All subjects with chronic adult periodontitis unless otherwise stated.
Aa, Actinobacillus actinomycetemcomitans; Cr, Campylobacter rectus; Ec, Eikenella corrodens; En, Eubacteria nodatum; Fn, Fusobacterium nucleatum; Pg, Porphyromonas gingivalis; Pi, Prevotella
intermedia; Mm, Micromonas micros; Pn, Prevotella nigrescens; Sn, Selenomonas noxia; Si, Streptococcus intermedius; Td, Treponema denticola; Tf, Tannerella forsythensis; Csp, Capnocytophaga sputigena;
ND, No details; IA, Commercial immunoassay; PCR, Polymerase Chain Reaction; IF, Immunofluorescence; DNA, DNA–DNA Hybridization; cig/day, cigarettes per day
reported.
important additional
tistically greater quantity of P. interme-
media/P. nigrescens and a higher

Results of the analysis indicated a sta-
two single or two pooled samples.
and P. intermedia, to investigate differ-
the deepest site in each quadrant. The

smokers with non-smokers using cultur-
never-smokers. They reported a higher
smokers. Umeda et al. (1998) carried
reported that the risk of subgingival
mycetemcomitans, T. forsythensis and
sence of a number of putative perio-
cated a higher prevalence of P. inter-

workers compared treated and untreated
same year, van Winkelhoff and co-
98 were past smokers and 124 were
jects, of whom 50 were current smokers,
DNA–DNA hybridization in 272 sub-
number of species using checkerboard
pockets. No other differences were
only 21 smokers, their published report
in 199 subjects. Despite including
out a study of risk indicators for
never-smokers. Immunofluorescent mi-
rent or former smokers and 628 were
by Zambon et al. (1996). The authors
al methods. Samples were taken from

regard to the other organisms. In the
deepest sites in each patient, either as
bouring T. denticola in periodontal
harbouring six periodontal pathogens
smokers. In particular, the authors
dia in smokers, but no differences with

smokers. Samples were taken from the
ences between 86 smokers and 163 non-
Eggert et al. used a commercial kit,
observation.
(o4 mm) in current smokers was an
periodontal pathogens at shallow sites
Higher prevalence of colonization of
stated that current smokers displayed an
smokers was 2.3 times that of non-
investigated a substantial population of
comparison of untreated subjects indi-

which identified the presence of A.
P. gingivalis in the current or former
1426 subjects, of whom 798 were cur-
actinomycetemcomitans, P. gingivalis
prevalence of eight species in current
investigated the prevalence of a large
2001. Haffajee and Socransky (2001)
reasonably sized sample populations of
Three studies reported findings from
increased risk (Odds ratio 4.6) for har-
infection with T. forsythensis in current
smokers than in the other two groups.

patients with chronic periodontitis in
cated a higher prevalence of A. actino-
samples per subject. The results indi-
dontal pathogens from two pooled
croscopy was used to identify the pre-
smokers and non-smokers was provided
proportion of F. nucleatum and M. Effect of Smoking on the Periodontal light smokers responded with a signifi-
micros in the smokers. Tissues cant increase in blood flow, paralleling
In contrast to the findings of Darby Effect of smoking on gingival blood flow
the changes observed by Baab & Öberg
et al. (2000), Kamma et al. (1999) have (1987) but the heavy smokers showed no
reported some microbiological differ- There is little or no evidence that smok- response, indicating a high level of tol-
ences between 30 smokers and 30 non- ing induces gingival vasoconstriction. erance. The increase in blood flow to the
smokers with early-onset periodontitis. Early studies of ANUG recognized that gingiva and forehead skin following an
Plaque collected from the deepest pock- many affected individuals were smokers episode of smoking in 13 casual consu-
ets in each quadrant were pooled into (Pindborg 1947) and it was hypo- mers of tobacco was confirmed by Mav-
two samples and cultured to identify the thesized that the necrotic lesion may ropoulos et al. (2003). The same group
presence and proportions of nine bacter- have been caused by vasoconstriction had previously reported an increase in
ial species. Their results showed a high- induced by nicotine and stress (Kardachi blood flow to these tissues following the
er prevalence and proportion of & Clarke 1974). This hypothesis was topical application of tobacco snuff to
T. forsythensis, Campylobacter rectus, implicated in periodontitis, and a sub- the vestibular sulcus (Mavropoulos et al.
P. gingivalis and M. micros in samples sequent paper by Clarke et al. (1981) is 2001). Blood pressure and heart rate
from smokers. often cited as evidence. In their expe- increased and blood flow to the thumb
riment, they attempted to indirectly decreased, confirming the systemic effect
Conclusions
measure blood flow by measuring tem- of the topically absorbed nicotine. This is
perature from a thermistor inserted into in contrast to cigarette smoking, where
There are problems associated with the gingival sulcus of a rabbit. The the effects are mediated by systemic
microbiological investigations of the rabbit was subjected to 10 intra-arterial absorption from the lung.
oral flora that may affect the interpreta- infusions of nicotine into the carotid at There has also been a study where
tion of the results of the studies review- 30 min. intervals. They reported that the Laser Doppler blood flow has been
ed here. Estimates of the number of gingival blood flow increased immedi- recorded in subjects who quit smoking.
species that regularly colonize the sub- ately following the infusion, but that Morozumi et al. (2004) examined 11
gingival environment vary between 400 recovery fell below baseline levels. periodontally healthy regular smokers
and 600. At least half of these are There was a gradual decline in thermis- who successfully quit smoking as ver-
unculturable and many have yet to be tor voltage to the 7th infusion but there ified by serum cotinine analysis. These
reliably speciated. Inevitably, those was a gradual increase thereafter. The researchers managed to improve the re-
whose biotypes have been most exten- reported values were not related to producibility of LDF recordings to allow
sively characterized are most often in- temperature or blood flow and were measurement at time intervals over an 8-
vestigated. Sampling methods vary not analysed statistically. week period. They showed that the gin-
widely, and, together with undoubted Baab & Öberg (1987) were the first gival blood flow had significantly
differences from site to site within the researchers to question the vasoconstric- increased at 3 days following quitting
mouth, such variations may affect the tive action of nicotine (from cigarette and that further small increases occurred
results of studies. Identification of orga- smoking) on gingival tissues. In a Laser up to 4 and 8 weeks. This study provides
nisms by different methods such as Doppler Flow (LDF) study of 12 young important information on the recovery of
culture, immunofluorescence and DNA- regular smokers, they showed that gingi- healthy gingival tissue post-quitting.
based techniques gives rise to poten- val blood flow rose by about 25% during
tially different outcomes. Under these smoking, was maintained for 5 min. and Oxygen tension in the gingival tissues
circumstances, it is imperative that stu- then gradually declined to baseline
dies with adequate numbers of subjects values. This was associated with an Tobacco smoke contains carbon mon-
are performed in order to overcome the increase in heart rate and systolic and oxide, which is detectable in the
background of extreme variation, which diastolic blood pressure. They confirmed breath of smokers and can be used to
will potentially mask the effects of that the blood flow to the skin of the assess compliance in quit-smoking pro-
smoking on the oral microflora. Of those forearm did decrease slightly, demon- grammes (Scott et al. 2001). Oxygen
that appear to satisfy these require- strating the differences in response saturation of haemoglobin is affected
ments, some early studies tended to between peripheral skin responses and and attempts have been made to mea-
show no differences. However, there those in the head and neck. It was sure this in the gingival tissue of smo-
are now a number of studies that suggest interesting to note that 3 of their subjects kers and non-smokers. Hanioka et al.
a trend for smokers to harbour more or felt light headed after smoking, suggest- (2000b) showed variable results. In
greater numbers of potential periodontal ing that the inhalation dose was greater healthy gingiva, smokers did appear to
pathogens than non-smokers without than they normally experienced. have lower oxygen saturation, deter-
increasing the amount of plaque. This The study of Meekin et al. (2000) mined using tissue reflectance spectro-
undoubtedly supports the attractive added further information to this photometry, whereas in the presence of
hypothesis that a significantly different response. They compared the response inflammation, the converse was shown.
subgingival environment in smokers, to smoking a single cigarette in a group The same group of workers (Hanioka
related to an altered immune response, of light/occasional smokers and heavier et al. 2000a) also examined the oxygen
should result in a different microflora. habitual smokers. The changes in gingi- tension in the pockets of 34 non-smo-
Further investigation with the latest val blood were not statistically signifi- kers and 27 heavy smokers with mild to
methods is still required to confirm cant. However. they showed quite moderate periodontitis. They showed
that such differences are directly related dramatic differences in responses of that the pocket oxygen tension was
to smoking. LDF in the skin of the forehead. The significantly lower in smokers (mean
184 Palmer et al.
21.9 mm Hg CI 18.1–25.7) compared (po0.05), despite having similar levels number of vessels expressing ICAM-1
with non-smokers (mean 33.4 mm Hg of plaque (p40.05). The reduced in non-inflamed sites was greater in
CI 30.5–36.31 [po0.0001]). This inflammatory response in this model non-smokers compared with smokers
could have an impact on the pocket has also been confirmed by Danielsen (po0.05). This suggested that the
microflora (see ‘‘The Effect of Smoking et al. (1990) and Lie et al. (1998a). The inflammatory response in smokers with
on Plaque’’). latter group also showed that a reduced periodontitis may not be accompanied
bleeding score (approximately 50%) in by an equivalent increase in vascularity,
Gingival inflammation and bleeding
smokers was apparent on both probing and that reduction in endothelial ICAM-
to the bottom of the pocket and probing 1 expression could affect neutrophil
Some early studies suggested that smo- the marginal gingivae. emigration from the vessels (plus see
kers experienced less gingival bleeding The effect of smoking on gingival ‘‘Evidence from Studies on GCF’’).
than non-smokers (Bergstrom & Flo- bleeding has also been shown in sub- Moughal et al. (1992) described the
derus-Myrhed 1983). This observation jects on a quit-smoking programme. expression of ICAM-1 and E-Selectin
was confirmed in a comparative study of Nair et al. (2003) followed 27 subjects (Endothelial cell leukocyte adhesion
10 heavy smokers (at least 20 cigarettes for 4–6 weeks during a verified success- molecule-1) in the blood vessels of the
per day) and 10 non-smokers who had ful period of quitting smoking. Gingival gingival connective tissue and strong
similar levels of periodontitis (Preber & bleeding assessed with a constant force expression of ICAM-1 in the junctional
Bergstrom 1985). These authors cited probe doubled (from 16% to 32%, and sulcular epithelium. The expression
the potential vasoconstrictive effect of po0.001) during this period, despite of these molecules was similar in both
nicotine previously reported by Clarke some improvement in subjects’ plaque healthy and inflamed tissue of just six
et al. (1981). control. This demonstrates a relatively subjects of undisclosed smoking status
The reduced bleeding on probing was rapid recovery of the inflammatory participating in an experimental gingi-
further demonstrated in a study by Berg- response and corresponds with reported vitis study. Also, in an earlier study
strom & Bostrom (2001). Gingival bleed- changes in some other parameters, such comparing lesions of periodontitis and
ing was lower in 130 smokers (median as the reduction in serum soluble inter- gingivitis in 21 subjects, Gemmell et al.
[interquartile range, IQR] bleeding score cellular adhesion molecule (sICAM) (1994) did not find any differences in
19.0 [13.0]) than 113 non-smokers (med- levels (Palmer et al. 2002). the expression of adhesion molecules on
ian [IQR] bleeding score 32.0 [20.3]), endothelial cells (or lymphocytes), but
with similar levels of periodontitis Effect on the gingival vasculature
there was no account of smoking status.
(po0.001). They were also able to show
a dose–response effect, which was con- The vasculature has also been examined Conclusions
firmed in a much larger study of 12,385 in histological and immunocytochem-
general population subjects from the ical studies. In a very limited study of Smoking has a long-term chronic effect,
National Health and Nutrition Examina- one histological section from three smo- impairing the vasculature of the perio-
tion Survey III by Dietrich et al. (2004). kers and four non-smokers, Mirbod dontal tissues rather than a simple vaso-
This reduced response in smokers has et al. (2001) found that there were a constrictive effect following a smoking
also been elegantly shown in studies high proportion of small vessels com- episode. The suppressive effect on the
using the experimental gingivitis model. pared with large vessels in smokers vasculature can be observed through less
In the first of these studies involving compared with non-smokers, but no gingival redness, lower bleeding on
healthy dental students, 10 smokers difference in the vascular density. The probing and fewer vessels visible clini-
(10–20 cigarettes per day for at least 4 region chosen for study was the con- cally and histologically. This may also
years) and 10 non-smokers abstained nective tissue beneath the external gin- have relevance to the healing response
from cleaning their mandibular anterior gival epithelium, which was therefore with impairment of revascularization.
teeth for 28 days (Preber & Bergstrom remote from the pocket wall/sulcus and
1986). Plaque accumulation did not dif- the inflammatory lesion. Sönmez et al.
fer between the groups, and although (2003) did not show differences in the Smoking and Neutrophil Function
bleeding scores significantly increased density or number of Factor VIII- Tobacco smoke exposure increases the
in the non-smokers, there was no com- labelled vessels in gingival tissues number of neutrophils found in the
parable increase in the smokers. The obtained at the time of periodontal sur- systemic circulation (van Eeden &
development of gingival redness and gery from 38 smokers and 36 non- Hogg 2000, Iho et al. 2003, Sorensen
the volume of gingival crevicular fluid smokers. The orientation and location et al. 2004) and those exiting the pul-
(GCF) were also lower in smokers, of the specimens were not described. monary microvasculature into the lungs
suggesting a suppression of the normal A more comprehensive histological (Chalmers et al. 2001, Seagrave et al.
inflammatory response to plaque. In a comparison of smokers and non-smo- 2004). Despite inducing a significant
follow-up study of experimental gingi- kers was presented by Rezavandi et al. systemic neutrophilia, tobacco smoking
vitis, Bergstrom et al. (1988) evaluated (2002), who labelled the vessels by does not seem to affect the numbers of
the number of visible gingival vessels. immunocytochemical staining to the neutrophils entering the gingival sulcus
There was a tendency for fewer gingival von Willebrand factor, ICAM-1 and and oral cavity. Indeed, limited evi-
vessels at baseline in the smokers and E-Selectin. They reported that a signifi- dence suggests that the numbers of
after 14, and 28 days of plaque accu- cantly larger number of vessels were neutrophils reaching the gingival sulcus
mulation, the smokers had approxi- observed in inflamed tissues of non- in smokers may even be reduced (Eichel
mately half the number of visible smokers than smokers (po0.05). In & Shahrik 1969, Pauletto et al. 2000).
vessels compared with the non-smokers addition, the proportion of the total These findings imply that neutrophil
transmigration across the periodontal proteinase (MMP) release, in neutro- city of neutrophils to destroy plaque
microvasculature is impeded in tobacco phil-mediated tissue injury and bacteria. Several studies have suggested
smokers. It may be relevant to note that degradation is established in several that cigarette smoke constituents may
neutrophils are known to be sequestered disease entitities (Barnett et al. 1998, inhibit the respiratory burst of neutro-
in the pulmonary microvasculature and Scott & Palmer 2002). phils (Drost et al. 1992, Pabst et al.
are hypothesized to contribute to the de- 1995, Sorensen et al. 2004). However,
gradation of lung tissues while trapped Neutrophil-derived degradative proteases such studies utilize different media for
within this vascular compartment (Mac- in tobacco smokers neutrophil suspension/challenge, with
Nee et al. 1989, Terashima et al. 1999). and without cations and glucose, which
Neutrophils are primary mediators of It has long been hypothesized that have a profound effect on the respiratory
protection against periodontal plaque tobacco smoking increases the proteoly- burst. In the Sorensen et al. (2004)
bacteria (Dennison & Van Dyke 1997). tic activity of neutrophils (Donaldson study, a decrease in luminol-dependent
However, neutrophil bacteriocidal ac- et al. 1991). The critical importance enhanced chemiluminescence (ECL)
tivity involves multiple non-specific of neutrophil recruitment and neutro- was demonstrated in smokers. How-
mechanisms, and the inappropriate and/ phil-derived proteolytic enzymes, parti- ever, luminol ECL represents total
or continuous activation of periodontal cularly MMPs and elastase, to the luminescence and does not differentiate
neutrophils is thought to contribute to the tobacco-induced destruction of pulmon- extracellular from intracellular radi-
degradation of gingival tissues and the ary vessels and tissues is well estab- cal release. Furthermore, luminol is re-
progression of inflammatory periodontal lished (Wright et al. 2003, Churg et al. garded as a reporter molecule for hypo-
disease (Deas et al. 2003). 2004). Tobacco smoking leads to sig- chlorous acid production and thus
Neutrophils express functional recep- nificant increases in the circulating bur- reflects myeloperoxidase activity, rather
tors for several components and meta- den of neutrophil elastase and MMPs in than directly measuring superoxide
bolites of tobacco smoke, such as humans (Nakamura et al. 1998, van anion release. Lucigenin is the substrate
nicotine, cotinine (primarily the a3 b4 Eeden & Hogg 2000). Tobacco smoking most commonly used to measure super-
subtype of nicotinic receptors; Benham- has also been shown in human skin to oxide release from NADPH-oxidase
mou et al. 2000) and aryl hydrocarbons decrease the rate of synthesis of specific activity (Koie et al. 2001). Therefore,
(Ackermann et al. 1989). The numbers collagen types, by increasing the pro- results of studies on neutrophil function
of nicotinic receptors expressed by duction of collagen-degrading enzymes, in relation to smoking status require
human neutrophils are increased in smo- and decreasing levels of the major endo- careful interpretation.
kers and decline on cessation (Lebargy genous MMP inhibitor, tissue inhibitors Nguyen et al. (2001) have recently
et al. 1996). of MMP-1 (Knuutinen et al. 2002). demonstrated that gas-phase cigarette
Neutrophils also express several While the tobacco-induced release of smoke may lead to a suppression of
receptors for endogenous factors such proteolytic enzymes from neutrophils has neutrophil NADPH oxidase, but not
as interleukin-8 (IL-8) (Zeilhofer & not been demonstrated definitively in the myeloperoxidase activity, that is at least
Schorr 2000), ICAM-1 (Selby et al. periodontal tissues themselves, neutro- partially mediated by volatile reactive
1992, Scott et al. 2000) and tumour phils are considered to be a major source a,b-unsaturated aldehydes, such as acro-
necrosis factor-a (TNF-a) (Akgul & of the elastase and MMPs associated lein. Other researchers have confirmed
Edwards 2003), whose natural agonists with periodontal disease destruction suppression of the oxidative burst in
have been reported to be dysregulated in (Soder et al. 2002, Persson et al. 2003). neutrophils treated with aqueous-phase
tobacco smokers in the periodontal Furthermore, tobacco smoke and compo- smoke extract, coupled with a signifi-
environment and elsewhere [(IL-8: Fre- nents are known to stimulate the release cant hindrance of phagocytotic ability
driksson et al. 2002, Iho et al. 2003); of such enzymes from neutrophils in vivo (Zappacosta et al. 2001).
ICAM-1 (Fraser et al. 2001; Palmer and in vitro (Seow et al. 1994, Seagrave However, other studies appear to
et al. 2002, Rezavandi et al. 2002); and et al. 2004). Seow et al. (1994) examined show that tobacco constituents can exa-
TNF-a (Fredriksson et al. 2002)]. the effects of nicotine on neutrophil cerbate aspects of the respiratory burst
Thus, multiple receptor-agonist cou- function at concentrations achievable in in human neutrophils. Iho et al. (2003)
ples have been identified, suggesting oral tissues and showed an enhancement suggest that nicotine can increase IL-8
that tobacco smoke is capable of affect- of neutrophil degranulation. production by neutrophils (which would
ing neutrophil function both directly and It is, therefore, entirely possible that be expected to recruit further neutro-
indirectly. For example, circulating tobacco may contribute to the progres- phils) and enhance the production of
soluble circulating soluble ICAM-1 is sion of periodontal disease at least in reactive species, particularly ONOO .
a physiologically active, immunomodu- part through the induction of protease Additionally, the work of Gillespie et al.
latory molecule whose concentrations release from periodontal neutrophils. (1987) showed a potentiated release of
increase in a predictable dose-dependent superoxide from neutrophils in rats
manner in tobacco smokers and rapidly Neutrophil respiratory burst
exposed to either cigarette smoke or to
return to baseline on smoking cessa- i.p. -injected nicotine.
tion (Palmer et al. 2002). The major The respiratory burst represents the On balance, the literature would sug-
natural ligands for ICAM-1 are the b2- combined oxygen-dependent processes gest that smoking affects the NADPH-
integrin complexes, which are expressed by which neutrophils kill phagocytosed oxidase respiratory burst, but, because
by human neutrophils and other leuco- bacterial cells through the generation of of differences in neutrophil handling
cytes. The importance of the engage- multiple reactive oxygen and reactive and reporter substrates, it is not possible
ment of b2-integrin complexes, which nitrogen species. A compromised to conclude whether NADPH-oxidase
stimulates elastase and matrix metallo- respiratory burst may reduce the capa- responses are enhanced or suppressed.
186 Palmer et al.
Furthermore, many of the studies do not Similarly, Gillespie et al. (1987) found affects multiple functions of neutrophils
examine the activity of the NADPH- that i.p. injection with 0.2 mg/kg nicotine and may shift the net balance of neu-
oxidase in smoker and non-smoker reduced fMLP-induced neutrophil che- trophil activities into the more destruc-
patient neutrophils simultaneously. motaxis, in contrast to the potentiating tive direction.
This is vital for assay consistency actions of a lower dose (0.02 mg/kg
because ex-vivo neutrophil responsive- nicotine). In an ex vivo study, Sorensen
ness varies widely from day to day. et al. (2004) demonstrated increased che- Smoking and Lymphocyte Function
motaxis in the peripheral blood neutro-
phils of smokers, but this decreased again The immune system of mammals has
Neutrophil migration and chemotaxis evolved to protect the host. Innate and
when the same subjects quit smoking.
Early studies suggested detrimental When studying chemotaxis in neutro- adaptive immunity operate together, and
effects of tobacco smoke extract on phils, it should be kept in mind that neu- there are innate immune mechanisms
migration of oral neutrophils (Eichel & trophils respond to multiple chemotactic that help to focus and facilitate adaptive
Shahrik 1969, Kraal et al. 1977). The stimuli, the mechanisms of all, none, or immune responses. In order to protect
actin cytoskeleton is critical in facilitat- some which may be affected by tobacco the host, the adaptive immune system
ing neutrophil motility that is required smoke exposure. Therefore, variable must be able to recognize antigens and
for extravasation across the periodontal results are to be expected, depending then mount an appropriate response.
microvasculature and subsequent migra- on the experimental system used. Antigens are recognized by lympho-
tion of neutrophils towards inflamma- cytes. T lymphocytes recognize antigens
tory stimuli. Recently, Ryder et al. Neutrophil priming (hyper-reactivity) presented in association with human
(2002) have shown that tobacco smoke lymphocyte antigens by antigen-pre-
Koethe et al. (2000) have suggested that, senting cells such as dendritic cells,
exposure may impair f-actin kinetics.
in vitro, components of tobacco smoke macrophages and B cells. Following
This is in keeping with the earlier data
that are present in CSC can have a antigen presentation and appropriate
of Drost et al. (1992), who observed that
profound influence on neutrophil effec- costimulation, effector cells are formed.
smoke-exposed neutrophils exhibited
tor function. CSC induced a greater than This process involves clonal selection of
reduced deformability, an effect
twofold increase in fMLP receptor the T cell clones bearing T cell receptors
mediated through the actin component
expression on the neutrophil surface, that can recognize epitopes on antigen,
of the cytoskeleton. This reduced neu-
rendering the cells ‘‘primed’’, resulting and clonal proliferation, thereby ensur-
trophil deformability was accompanied
in a twofold increase in the release of ing there are sufficient numbers of the
by a compromised ability to traverse
both superoxide and elastase on subse- appropriate T cells available to combat
micropore membranes similar in dimen-
quent stimulation with fMLP. infection and protect the host. In the
sion to capillaries.
Tobacco-induced increases in fMLP effector phase, activated T cells differ-
Seow et al. (1994) examined the
receptor numbers have been noted by entiate into cytotoxic T cells, and T
effects of nicotine on neutrophil func-
others (Matheson et al. 2003). In the helper cells. Cytotoxic T cells express
tion at concentrations achievable in oral
periodontal environment, where there is CD8 molecules on their cell surface with
tissues. The results showed a dose-
a plentiful source of fMLP, priming of T cell receptor (TCR), while T helper
dependent suppression of both chemo-
gingival neutrophils by tobacco smoke cells typically express CD4 in associa-
taxis and phagocytosis. Earlier, Bridges
components could lead to an increase in tion with TCR and have either a T helper
& Hsieh (1986) had fractionated cigar-
the local burden of potentially degrada- cell (Th1) or pro-inflammatory pheno-
ette smoke condensate (CSC) and
tive elastase and superoxide in response type activating macrophages and stimu-
demonstrated that the more polar frac-
to the plaque bacteria – a hyperinflam- lating cytotoxicity, whereas T helper 2
tions were potent inhibitors of chemo-
matory response. In further support of (Th2) cells are essential for successful
taxis, while the fractions containing
this hypothesis, Gustafsson et al. (2000) antibody responses as they control B cell
nicotine and those containing polycyclic
have shown that the priming capacity of growth and differentiation, as well as
hydrocarbons were weak inhibitors of
TNF-a, measured as generation of immunoglobulin class switching.
neutrophil chemotaxis. Another group
oxygen radicals from stimulated neu-
has shown that neutrophil cell spreading
trophils, is higher in neutrophils from
and chemokinesis, but not chemotaxis
smokers compared with neutrophils T lymphocytes
itself, are impaired following in vitro
from non-smokers. The same authors
smoke exposure (Selby et al. 1992). There are many studies that show leu-
also showed that smoking potentiated
While MacFarlane et al. (1992) could cocytosis in smokers (Corre et al. 1971,
the generation of radicals in individuals
not demonstrate tobacco-induced che- Hughes et al. 1985). Most studies have
with periodontitis.
motactic defects in neutrophils from examined T cell subsets and report
smokers with refractory periodontitis, Conclusions
different findings: reduced, increased
impaired phagocytosis was evident in or no change in the number of CD4 T
neutrophils from these subjects. Neutrophils are critical cells in the cells (Ginns et al. 1982, Smart et al.
Nowak et al. (1990) observed that the maintenance of periodontal health 1986, Johnson et al. 1990, Loos et al.
influence of nicotine on neutrophil che- because of their multifaceted roles in 2004). Smokers suffer from respiratory
motaxis was dependent on the stimulat- the control of plaque bacteria, but they infections more frequently than non-
ing dose, with low concentrations of may also contribute to the progression smokers. This finding is often inter-
nicotine stimulating neutrophil chemo- of periodontitis in chronic inflammatory preted to mean the effects of smoking
tactic responsiveness to fMLP and high responses. While there are conflicting on immunity are localized to the lung
nicotine concentrations being inhibitory. data, it is clear that tobacco smoking (Finklea et al. 1971), and this is further
supported by finding little correlation protein and some metals (Hoffmann & tus following stimulation with phyto-
between alterations in T cell numbers Wynder 1986). Each compound has its haemagglutinin (PHA) or Mab to CD3
in bronchial alveolar lavage fluid own effects and, while nicotine, ben- and CD28. As smoking status correlates
(BALF) and peripheral blood in smo- zo(a)pyrene and benzo(a)anthracene with the numbers of lymphocytes, the
kers. Furthermore, the total number of (polycyclic aromatic hydrocarbons) are use of whole-blood culture assays would
lymphocytes is increased in BALF and immunosuppressive (Geng et al. 1995, not allow distinction between impaired/
the CD4 cell subpopulation is reduced 1996), tobacco glycoprotein and metals enhanced T cell responses or impaired/
(Costabel et al. 1986, Wallace et al. present in cigarette smoke are immu- enhanced monocyte responses (Loos et
1994), producing a reduced CD4/CD8 nostimulatory (Francus et al. 1988, al. 2004).
ratio in smokers compared with non- 1992, Brooks et al. 1990). Fur-
smokers, while the CD4/CD8 ratio in thermore, acute or chronic exposure to B cells and immunoglobulins
peripheral blood is similar (Ancochea hydrocarbons may stimulate (Schnizlein
et al. 1993, Wallace et al. 1994). On et al. 1982) or inhibit (White 1986) the B cells recognize antigen once it has
cessation of smoking, the number of immune response. Thus, the net effect is bound to antigen-binding sites of immu-
CD4 cells in peripheral blood returns dependent upon the dose and duration of noglobulin on the B cell antigen recep-
to levels observed in people who have the exposure to the components of tor, namely antibody expressed on the B
never smoked (Ginns et al. 1982, Loos tobacco smoke (Tollerud et al. 1991). cell surface. In order to mount success-
et al. 2004). ful humoral immune responses, B cells
More recently, Loos et al. (2004) T cell function
require T helper cell-derived cytokines
examined 112 adults, 76 with perio- to proliferate and differentiate into plas-
dontitis and 36 control subjects. Sub- The effects of tobacco smoking on T ma cells (as well as for immunoglobulin
jects were classified into non-smokers cell function/proliferation are controver- class switching).
(those who quit within the last 10 years), sial. Some studies show significant In experiments in animals and
light smokers (those who smoked o10 reductions in T cell proliferation com- humans, tobacco smoke has been found
cigarettes/day) or heavy smokers (X10 pared with controls when lymphocytes to affect both humoral immunity and
cigarettes/day). The total leucocyte are stimulated with mitogens, while cell-mediated immunity (Sopori et al.
count was highest among the heavy others show no significant differences 1994, Sopori & Kozak 1998). Chronic
smokers and significantly higher com- between lymphoproliferative responses exposure of rats to nicotine inhibits
pared with non-smokers irrespective of of smokers and non-smokers (Sopori antibody-forming cell responses and
periodontal disease status, and was et al. 1994). Tobacco smoke has been this immunosuppression appears to be
reflected in increased neutrophil num- shown to reduce the proliferative the result of impairment of antigen-
bers but not in lymphocyte or monocyte response of both peripheral blood and mediated T cell signalling (Geng et al.
numbers. Although there was a similar BALF lymphocytes to both T cell mito- 1996, Sopori et al. 1998). These findings
trend towards elevated neutrophil counts gens and antigens (Chang et al. 1990, are supported by reports indicating that
in the controls, moderate and severe Johnson et al. 1990). Nicotine can inhi- serum IgG levels are reduced in smokers
periodontitis, this was not statistically bit T cell proliferation to mitogens in (Gulsvik & Fagerhol 1979, McSharry
significant. However, smoking status in vitro experiments using peripheral et al. 1985, Quinn et al. 1996, 1998) and
acted as a significant covariate for total blood from non-smokers and may even in periodontitis patients; non-smokers
leucocytes, neutrophils, lymphocytes induce T cells, which can suppress T have higher levels of IgG2 compared
and monocytes. Analysis of CD3 T cell function (Petro et al. 1992). It is with smokers (Graswinkel et al. 2004).
cells, CD4 and CD8 T cell subsets, and difficult to duplicate human smoking The effects of cigarette smoking on
CD4/CD8 ratios revealed no significant habits in animals that are often only serum IgA and IgM classes are contro-
differences between controls and perio- exposed to cigarette smoke for just a versial, with some reports indicating sup-
dontitis groups. However, leucocyte few minutes and not years, as is often pression of IgM and IgA levels (Gulsvik
counts are known to vary according to the case in humans. When animals are & Fagerhol 1979), while other studies
ethnic group (Tollerud et al. 1989, 1991), exposed to tobacco smoke, antibody indicate no effect of smoking on either
and in this study it is not clear how well responses have also been found to be class of antibody (Andersen et al. 1982,
the subjects were matched for race, as inhibited in lung-associated lymph McSharry et al. 1985, Graswinkel et al.
they were only grouped as either Cauca- nodes, but not in extra-pulmonary 2004). IgE is greatly elevated in smokers,
sian or non-Caucasian (Loos et al. 2004). lymph nodes (Sopori et al. 1989), sug- and not related to enhanced skin reactiv-
Animal studies have indicated that gesting that the immune response is ity (Burrows et al. 1981, 1982).
chronic exposure of rats to the vapour altered locally. Chang et al. (1990) There are some researchers who
phase of cigarette smoke does not lead showed that antigen-specific T cell profound no suppression of total IgG con-
to significant changes in immune liferation was inhibited following smoke centrations in smokers (Merrill et al.
responses. It is therefore likely that the inhalation in bronchial nodes draining 1985, O’Keeffe et al. 1991, Graswinkel
particulate phase of cigarette smoke the lung, but was unaffected by tobacco et al. 2004). These conflicting findings
confers the immunosuppressive proper- smoke in distant lymph nodes. may reflect differences in the popula-
ties (Hoffmann 1979, Hoffmann & Recently, Loos et al. (2004) investi- tions studied. O’Keeffe et al. (1991)
Wynder 1986). Unfortunately, among gated the proliferative capacity of T examined an older population with a
the numerous possible compounds pre- cells in whole blood lymphocyte culture mean age of 60 years (50–80) in whom
sent, the particulate phase of cigarette assays. No significant differences were IgG2 levels tend to be higher. In addi-
smoke consists of nicotine polycyclic found between the control subjects, tion, in order to determine whether IgG
aromatic hydrocarbons, tobacco glyco- periodontitis patients and smoking sta- subclasses vary in different populations,
188 Palmer et al.
the total IgG needs to be determined and observed effect is determined by the Conclusions
related to IgG subclasses. However, this net immunostimulatory/immunosuppre-
analysis is not always carried out. Stu- ssive properties of tobacco and its com- There are inconsistencies and variations
dies of IgG subclasses in smokers and bustion by-products. in findings reflecting the complex rela-
non-smokers with periodontal disease tionship between smoking, race, perio-
show that IgG2 is depressed in smokers. dontal diagnosis and age. Most studies
Natural killer (NK) cells have focused on peripheral effects,
However, serum IgG2 levels in African
American subjects are unaffected by NK cells, components of the innate mainly on the lung, with little perio-
smoking, except in generalized early- immune system, are large granular dontal-specific research. Furthermore in
onset periodontitis (Quinn et al. 1996). non-T non-B lymphocyte-like cells that many periodontal diseases, the impor-
When Quinn et al. (1998) investigated make up a small proportion of periph- tant antigens are not known and it is
black subjects, they found a reduction in eral blood lymphoid cells. Unlike T and therefore difficult to assess the effect of
IgG1 and IgG4 in chronic periodontitis. B cells, NK cells do not have antigen- smoking on antigen-specific responses
Further evidence that serum immuno- specific receptors, but are able to recog- that are relevant to periodontitis.
globulin subclass concentrations are nize and kill antibody-coated target cells
strongly influenced by periodontal dis- (antibody-dependent cellular cytotoxi-
ease status and race have been provided city) and this is triggered when antibody Evidence from Studies on GCF
by Gunsolley et al. (1997) and Lu et al. bound to the surface of the cell interacts GCF has been the subject of intense
(1993, 1994). Localized juvenile perio- with Fc receptors on the NK cells. The research in periodontology and readily
dontitis patients have elevated levels of mechanism of attack is analogous to lends itself to comparative studies of
IgG2 compared with other race-matched cytotoxic T cells involving the release various conditions. However, the relia-
and periodontal disease groups. In of granules containing perforins and bility of data is sometimes problematic
addition, black patients show increased granzymes. NK cells also produce che- because of the difficulty in measuring
concentrations of all IgG subclasses mokines and inflammatory cytokines and assaying the small volumes ob-
compared with white subjects with the such as interferon-g and TNF-a. tained in many cases and the variations
same periodontal diagnosis (Lu et al. Reduced NK cytolytic activity has in collection protocols (different collec-
1993, 1994). There is clearly a complex been reported in smokers (Ferson et al. tion strips, times and numbers of sam-
relationship between immunoglobulin 1979, Tollerud et al. 1989). NK cells ples) and processing methodology.
subclass, race, age, periodontal diagno- from BALF of smokers show reduced Some studies express GCF concentra-
sis and smoking. cytolytic activity compared with BALF tions and some ‘‘total amounts’’ of a
NK cells of non-smokers (Takeuchi substance per unit sample time. The
B cell function
et al. 1988). Some workers have found latter has been recommended in studies
no differences between NK cells in that attempt to identify markers of
B cell numbers are similar in smokers smokers and non-smokers (Hughes et active disease (Lamster et al. 1986,
and non-smokers (Sopori et al. 1989). In al. 1985). Others have found that the Chapple et al. 1999). However, for
peripheral blood, there is a decrease in effect of smoking on NK cells is rever- studies that address pathogenesis, it is
proliferative response to polyclonal B sible and cytolytic activity may increase vital to measure GCF volumes and
cell activators (B cell mitogens) and even within a short period of a month of examine concentrations as well as total
antigens (Sopori et al. 1989), suggesting smoking cessation (Meliska et al. 1995). amounts of the analtye under investiga-
that B cell function is impaired in This contrasts with the findings of Tol- tion. This is because studies have shown
smokers. On cessation of smoking, B lerud et al. (1989), who found that the a significant relationship between pock-
cell function returns to normal (Mili numbers of NK cells in peripheral blood et depth and GCF volume and the latter
et al. 1991, Reynolds et al. 1991). do not recover on cessation of smoking. is a major confounder of analyte con-
Sopori et al. (1989) showed that in These discrepancies may, in part, reflect centration in association studies of
smoke-exposed animals, there is a differences in methodology, identifica- periodontitis (Brock et al. 2004). Final-
reduction in antigen-induced proliferation and determination of NK cell num- ly, the comparative contribution of ser-
tion. This can first be detected in lym- bers and NK cell cytotoxicity. um- and tissue-derived products in a
phoid tissue with prolonged exposure to In Caucasian subjects, there is a sig- GCF sample is impossible to determine.
tobacco smoke, suggesting that B cell nificant decrease in the proportion of Smoking may result in lower resting
function may be affected by combustion circulating NK cells in smokers that GCF flow rate (Persson et al. 1999); the
by-products of tobacco smoke. Tobacco may persist for some time after the increase in GCF during an experimental
glycoprotein (a polyphenolic protein in cessation of smoking. Tollerud et al. gingivitis may be less in smokers (Berg-
tobacco) is a potent B cell mitogen (1989) found that in contrast to Cauca- strom & Preber, 1986), and an episode
(Francus et al. 1988) and stimulates sian smokers, African-American smo- of smoking may produce a transient
production of immunoglobulin classes kers had numbers of NK cells similar increase in GCF flow rate (McLaughlin
(IgM, IgG and IgA). In vitro studies in to non-smoking African Americans. et al. 1993). In a study examining sub-
which smokeless tobacco was used to While this may at first appear surpri- jects on a quit-smoking programme,
stimulate murine splenic and mesenteric sing, there are a number of reported Morozumi et al. (2004) showed that
lymph node cells indicated that this differences between ethnic groups in GCF flow was greater at 5 days post-
form of tobacco could induce the pro- terms of white blood cell counts, num- quitting. These apparently contradictory
duction of polyclonal IgM (Hockertz bers of T and B cells and immuno- findings can be related to the acute and
et al. 1994). Therefore, although there globulin levels (Tollerud et al. 1989, chronic effects of smoking on blood
are B cell mitogens in tobacco, the 1991,1994). flow (see ‘‘Effect of smoking on gingi-
val blood flow’’) and the inflammatory va and oral rinse samples for elastase higher levels of activity within the tissue
response (see ‘‘Gingival inflammation activity. Elastase activity was lower in or effects on gingival fluid flow
and bleeding’’). the smokers, as were neutrophil counts. dynamics.
Alavi et al. (1995) showed significantly
Cytokines lower concentrations of GCF elastase in Smoking and fibroblast function
smokers compared with non-smokers
Bostrom et al. (1998) showed higher with similar levels of disease and GCF The effects of nicotine and some other
levels of TNF-a in GCF in smokers volumes (functional elastase: smokers components of tobacco smoke have
(n 5 30) and former smokers (n 5 19) 30.21 17.6 ng/ml, non-smokers 73.77 been tested in in vitro studies on gingi-
compared with non-smokers (n 5 29), 75.26 ng/ml, po0.05 and elastase val and periodontal ligament (PDL)
with comparable levels of moderate/ complexed with a1-antitrypsin smokers fibroblast lines. All published studies,
severe periodontitis. The smokers had 8.97 6.54 ng/ml, non-smokers 25.71 with the exception of the study of Pea-
significantly less bleeding on probing, 22.07 ng/ml, po0.001). Although cock et al. (1993), have demonstrated
and the GCF samples were collected PMN numbers were reduced in smo- detrimental effects, which could have
using a washing technique and therefore kers’ GCF, this was not significant. significant impact in the inflammatory
volumes were not accurately determined Significantly lower concentrations of destructive process and the healing
(this was compensated by using measure- a-2-macroglobulin and total amounts response. However, most of these stu-
ment of serum albumin). No attempt was of a-1-anti-trypsin have been reported dies used concentrations of nicotine and
made to compare GCF levels with those in heavy smokers with moderate to cotinine that were far higher than those
found in the serum. In a follow-up study severe periodontitis by Persson et al. expected in plasma of smokers (nicotine
of a comparable group of subjects using (2001). 5–50 ng/ml, 0.03–0.3 mmol/l; cotinine
similar protocols, Bostrom et al. (1999) Molé et al. (1998) examined levels of 50–500 ng/ml, 280–2800 nmol/l), and
confirmed the presence of higher levels of sICAM-1 in GCF (paper strip for 2 min.) the concentrations used by some are
TNF-a in a smaller group of smokers. and showed higher levels at sites of difficult to verify because of lack of
However, no differences were found in inflammation, but smoking status was information. In an early descriptive
the levels of IL-6, which were frequently not taken into account. Following earlier study, Raulin et al. (1988) suggested
below the detection levels of their ELI- reports of higher levels of sICAM-1 in that cell orientation and attachment of
SA. The same research group (Bostrom the serum of smokers (Koundouros et al. human foreskin fibroblasts to glass or
et al. 2000) compared levels of IL-1b and 1996) regardless of their periodontal dentine surfaces were affected by nico-
IL-1ra in pooled GCF washing samples in status, Fraser et al. (2001) examined tine at concentrations comparable with
22 smokers and 18 non-smokers. No levels of this molecule in the GCF of plasma levels (25–50 ng/ml), with more
significant differences were found. How- smokers and non-smokers. They con- striking changes at higher concentra-
ever, Rawlinson et al. (2003) found levels firmed higher systemic serum levels of tions (200–400 ng/ml). Nicotine at com-
of IL-1b and IL-1ra to be significantly sICAM-1 (smokers 331 ng/ml, non- parable levels was found on root
lower in GCF from diseased sites in smokers 238 ng/ml; p 5 0.008) but, in surfaces of periodontally affected teeth
smokers compared with non-smokers, contrast, levels in GCF were signi- extracted from smokers, and the levels
using a 3 min. paper strip sample mea- ficantly lower in smokers (smokers could be reduced following root planing
sured with a Periotron 6000 and collected 83 ng/ml, non-smokers 212 ng/ml; (Cuff et al. 1989).
following the discarding of a 30 s sample. p 5 0.013). The smokers had signifi-
Petropoulos et al. (2004) showed that cantly lower sICAM-1 levels in GCF
the concentration of IL-1a in GCF of Gingival fibroblasts
compared with serum (in contrast to the
smokers was approximately half that non-smokers), although levels of coti- Hanes et al. (1991) showed that gingival
found in non-smokers (po0.01), which nine were comparable (which would fibroblasts bound nicotine, which was
supported their previous observations indicate that this molecule is unaffected subsequently taken up and then released
(Shirodaria et al. 2000) and confirmed in transit from the circulation to the into an in vitro culture system. They did
a wide site-to-site variation. This group periodontal pocket). not demonstrate the presence of specific
did not show differences in polymor- receptor binding for nicotine. Peacock
phonuclear cell (PMN) numbers be- et al. (1993) were the only researchers to
tween smokers and non-smokers eluted Conclusions
show a positive effect of nicotine on the
from Durapore collection strips left in It would seem logical to expect that proliferation and attachment of gingival
place for 10 s. In a 10-day experimental factors that are associated with tissue fibroblasts to plastic. They used a series
gingivitis study, Giannopoulou et al. destruction should be higher in smokers of nicotine concentrations close to nor-
(2003) claimed higher levels of IL-8 than non-smokers. This is blatantly not mal serum levels (4–64 ng/ml, assuming
and lower levels of IL-4 in smokers the case for many of these factors when that the units described were mm/ml).
GCF at baseline and the end of the assayed in the GCF. For the most part, Significant inhibition of proliferation of
period. However, they did not measure research has demonstrated that there are gingival fibroblasts at very high concen-
GCF volume and reported the total lower levels of cytokines, enzymes and trations of nicotine of 10–75 mg/ml was
amount per 20 s sample. possibly PMNs. This correlates with the demonstrated by Tipton and Dabbous
lower levels of inflammation observed (1995), who also showed reduction in
Other factors
clinically and within the tissues. The the production of type 1 collagen and
GCF could be viewed as an end product fibronectin and an increase in the col-
Pauletto et al. (2000) did not directly of the destructive process, and lower lagenase activity in the culture media.
measure GCF levels but examined sali- levels of factors may simply indicate Tanur et al. (2000) examined the effects
190 Palmer et al.
of nicotine on the attachment of gingival PDL fibroblast attachment to root sur- Selective inhibition of polymorphonuclear
fibroblasts to glass and non-diseased faces that were obtained from patients 7 neutrophil activity by 2,3,7,8-tetrachlorodi-
root specimens. Concentrations of 25– days after thorough root planing. Cell benzo-p-dioxin. Toxicology Applied Pharma-
100 ng/ml affected the orientation of attachment was significantly less on root cology 101, 470–480.
cells. Higher concentrations produced surfaces obtained from heavy smokers Akgul, C. & Edwards, S. W. (2003) Regulation
of neutrophil apoptosis via death receptors.
cytoplasmic vacuolation and attachment compared with non-smokers and healthy
Cell Molecular Life Sciences 60, 2402–2408.
to the surfaces was more easily dis- controls. Alavi, A. L., Palmer, R. M., Odell, E. W.,
rupted. Inhibition of collagen produc- Coward, P. Y. & Wilson, R. F. (1995)
tion by gingival fibroblasts could also be Conclusions
Elastase in gingival crevicular fluid from
demonstrated when they were grown in Smoking has a detrimental effect on smokers and non-smokers with chronic
the presence of epithelial cells that had clinical healing of non-surgical and sur- inflammatory periodontal disease. Oral Dis-
previously been exposed to 50–500 mg/ gical treatment modalities in perio- eases 1, 103–105.
ml nicotine (Giannopoulou et al. 2001). Alexander, A. G. (1970) The relationship
dontology (as reviewed by Kinane & between tobacco smoking, calculus and pla-
There is some evidence that gingival Chestnutt 2000). The biological basis
fibroblasts from smokers may be less que accumulation and gingivitis. Dental
for this is undoubtedly multifactorial as Health 9, 6–9.
susceptible to the cytotoxic effects of smoking affects the vasculature and Ancochea, J., Gonzalez, A., Sanchez, M. J.,
high levels of nicotine (Checchi et al. revascularization, the inflammatory Aspa, J. & Lopez-Botet, M. (1993) Expres-
1999), possibly because of the develop- response and fibroblast function, as out- sion of lymphocyte activation surface anti-
ment of tolerance. Gingival fibroblasts lined above. It is not possible to estimate gens in bronchoalveolar lavage and
were exposed to acrolein and acetalde- the in vivo potential of these effects peripheral blood cells from young healthy
hyde, present in the volatile fraction of based upon the data from these in vitro subjects. Chest 104, 32–37.
tobacco smoke, by Cattaneo et al. experiments, which usually test high Andersen, P., Pedersen, O. F., Bach, B. &
(2000) and Poggi et al. (2002). These Bonde, G. J. (1982) Serum antibodies and
levels of nicotine and do not take the immunoglobulins in smokers and nonsmo-
substances inhibited cell attachment and other noxious compounds into account.
cell proliferation at concentrations of kers. Clinical & Experimental Immunology
Nevertheless, it is likely that smoke 47, 467–473.
3 10 5 M for acrolein and 10 3 M products will affect fibroblast re- Baab, D. A. & Öberg, P. A. (1987) The effect of
for acetaldehyde. They observed cellu- cruitment and adhesion to root surfaces. cigarette smoking on gingival blood flow in
lar changes at the light and electron humans. Journal of Clinical Periodontology
microscopical levels, which included 14, 418–424.
disruption of cell orientation, presence Overall Conclusions Barbour, S. E., Nakashima, K. Zhang, J. B.,
of large vacuoles and dense residual Tobacco smoking has widespread sys- Tangada, S., Hahn, C. L., Schenkein, H. A.,
bodies in the cytoplasm. The same temic effects, many of which may pro- Tew, J. G. (1997) Tobacco and smoking:
group showed significant reduction in vide mechanisms for the increased environmental factors that modify the host
cell viability and disruption to the susceptibility to periodontitis and the response (immune system) and have an im-
microtubules, intermediate filaments pact on periodontal health. Critical Reviews
poorer response to treatment. As an
and actin (Poggi et al. 2002). Oral Biology and Medicine 8, 437–460.
environmental factor, smoking interacts Barnett, C. C. Jr., Moore, E. E., Mierau, G. W.,
with the host and the bacterial challenge. Partrick, D. A., Biffl, W. L., Elzi, D. J. &
PDL fibroblasts The host genetic and environmental Silliman, C. C. (1998) ICAM-1–CD18 inter-
interaction is of the utmost importance. action mediates neutrophil cytotoxicity
PDL fibroblast growth and attachment As knowledge of the genetic susceptibil- through protease release. American Journal
to tissue culture plates was inhibited by ity to periodontitis increases, this will of Physiology 274, C1634–C1644.
nicotine at high concentrations (over provide further opportunities to explore Bastiaan, R. J. & Waite, I. M. (1978) Effect of
1 mg/ml) and no effects were seen at this relationship with tobacco smoking tobacco smoking on plaque development and
concentrations comparable with plasma (Kornman et al. 1997, Fraser et al. 2003, gingivitis. Journal of Periodontology 49,
levels in smokers (James et al. 1999). Meisel et al. 2003, Berglundh et al. 480–482.
Cotinine tested at lower concentrations Benhammou, K., Lee, M., Strook, M., Sullivan,
2003, Ryder et al. 2004). It is quite B., Logel, J., Raschen, K., Gotti, C. &
(up to 10 mg/ml) failed to demonstrate a possible that many of the pathogenic Leonard, S. (2000) [(3)H]Nicotine binding
significant effect. Vacuolation of PDL mechanisms involved in tissue degrada- in peripheral blood cells of smokers is corre-
fibroblasts exposed to high concentration in periodontitis in tobacco smokers lated with the number of cigarettes smoked
tions of nicotine was observed by Gian- could be quite different from those per day. Neuropharmacology 39, 2818–2829.
nopoulou et al. (1999) and significant involved in non-smokers. Berglundh, T., Donati, M., Mahn-Zori, M.,
inhibition of proliferation at concentra- Hanson, L.-A. & Padyukov (2003) Associa-
tions of 100 ng/ml to 2 mg/ml. Nicotine tion of the 1087 IL10 gene polymorphism
Acknowledgements with severe chronic periodontitis in Swedish
at high concentrations (5–25 mM) was
also shown to be cytotoxic by Chang The authors would like to acknowledge Caucasians. Journal of Clinical Perio-
et al. (2002). They confirmed that PDL the very helpful input to this paper from dontology 30, 249–254.
Professor Iain Chapple, University of Bergstrom, J. (1981) Short-term investigation
cell proliferation was inhibited in a
on the influence of cigarette smoking upon
dose-dependent manner, as was protein Birmingham, UK.
plaque accumulation. Scandinavian Journal
synthesis. An interesting observation of Dental Research 89, 235–238.
was the protective effect of the anti- Bergström, J. & Bostrom, L. (2001) Tobacco
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Clinical Relevance
mation. Extensive clinical trials periodontitis in smokers but may
Epidemiological and clinical stu- have also shown poorer responses also reveal important information
dies have confirmed that tobacco to non-surgical and surgical treat- about the pathogenic mechanisms
smoking is a major risk factor in ment in smokers. The me- in non-smokers. Future research
periodontal disease. Smoking is chanisms whereby smoking affects needs to consider the recovery of
associated with more attachment the inflammatory and immune res- these responses in subjects who quit
loss, bone loss and tooth loss, but, ponses have direct relevance in smoking.
paradoxically, less signs of inflam-

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J Clin Periodontol 2005; 32 (Suppl.

6): 180–195 Copyright r Blackwell Munksgaard 2005

Richard M. Palmer1, Ron F. Wilson1,

environmental factors – tobacco Campus, London Bridge, London SE1 9RT,

tistically greater quantity of P. interme-

media/P. nigrescens and a higher

the deepest site in each quadrant. The

cated a higher prevalence of P. inter-

al methods. Samples were taken from

dia in smokers, but no differences with

comparison of untreated subjects indi-

smokers than in the other two groups.

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