Smoking and periodontal disease : biological mechanisms

Smoking is a major risk factor in the onset of many pathologies and is directly responsible for 60,000 deaths in France (^{fig. 1}) ; smoking begins in children and by the age of 18, 58 % are smokers (^{fig. 2}) (from the Consensus Conference on Smoking Cessation, Hôpital Pitié-Salpêtrière, October 1998). Tobacco smoke has an extremely complex composition and contains over 7,000 substances, in the form of gases (carbon monoxide, hydrocyanic acid, ammonia, formaldehyde, benzene, toluene, etc.) or particles (tar, nicotine, arsenic, aldehydes, etc.) ^{(Pretet, 1986)}. The combination of these substances induces cancer, diseases of the cardiovascular system, diseases of the lungs, alterations to the immune system, as well as many other changes to our physiology. These include an increase in blood sugar, cortisone, the secretion of beta-endorphins and an increase in platelet aggregation associated with peri pheral vasoconstriction that potentiates the risk of cerebro-vascular accidents. Headaches, as well as hearing, memory, visual and behavioural problems may also occur ^{(Godeau et al., 1996} ; ^{Lagrue, 1997)}. The oral cavity does not escape the deleterious effects of smoking which plays a major role in the aetiology and progression of periodontal disease. The effect of smoking is to modify the oral bacterial flora, the local inflammatory response and the periodontal connective tissue structure. It reduces blood supply to the gingiva, the volume of saliva that is secreted and also the composition of saliva.

It is now acknowledged that smoking constitutes a major risk for the development of periodontal disease. In a study conducted by the American National Centre for Health Statistics involving 13,652 individuals, the relationship between smoking and periodontitis was confirmed ^{(Tomar and Asma, 2000)}. Smokers presented a 4 times greater risk of suffering periodontitis compared with non-smokers. The frequency of disease was proportional to the quantity of cigarettes consumed. For smokers of less than 9 cigarettes per day, the prevalence was 2.79 times higher than for non-smokers and 5.88 times higher for smokers of more than 31 cigarettes. The results of this study were adjusted to take into account other factors that could have affected the result : age, sex, hygiene, education, etc. The study concluded that 74.8 % of periodontitis in smokers is attributable to smoking. That represents 42 % of periodontitis in the American population of 6.4 million patients ^{(Tomar and Asma, 2000)}. A study of 257 patients extending over 10 years in Sweden confirmed these findings. The prevalence of periodontitis, loss of attachment and alveolar bone loss are intimately linked to smoking ^{(Bergström et al., 2000)}. Gingivitis may be less obvious in smokers and this could delay the diagnosis and treatment of periodontitis ^{(Bergström, 1990} ; ^{Danielsen et al., 1990)}. In contrast, acute necrotizing ulcerative gingivitis is associated with smoking ^{(Mac Gregor, 1989)}. The type and the quantity of tobacco consumed increase the amount of alveolar bone loss ^{(Krall et al., 1999)} in healthy patients or those with periodontitis and increase the loss of attachment and depth of the pockets (^{Grossi et al., 1995} ; ^{Mac Gregor, 1989)} (^{fig. 3}). It is found that 45 % of those who have smoked for more than 10 years suffer from severe periodontitis ^{(Grossi et al., 1994)}. A longitudinal study involving 690 American patients showed that the percentage of sites with moderate or severe alveolar bone loss was twice as great amongst smokers ^{(Krall et al., 1999)}. Some mediators of inflammation such as interleukin 1β and prostaglandin E2 stimulate bone loss associated with periodontitis. These mediators are liberated by phagocytic cells and their production is increased under the influence of lipopolysaccharides from Gram negative bacteria which, themselves, are potentiated by nicotine ^{(Paine et al., 1996)}. Although we can now take for granted the bacterial aetiology of periodontitis, smoking does not statistically alter the quantity of bacterial plaque ^{(Preber and Bergström, 1986)}. In contrast, the bacterial flora of the mouth is changed. Smokers have an increased risk, proportional to the consumption of cigarettes, of being infected with Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Bacteroides forsythus and have a more abundant pathogenic subgingival flora (^{fig. 4}) ^{(Grossi et al., 1994)}. In contrast, there are no differences between smokers and non-smokers in relationship to Campylobacter rectus, Fusobacterium nucleatum or Prevotella intermedia ^{(Zambon et al., 1996)}. Both the general immune system ^{(Choy et al., 1985)} and the local response to bacterial attack are altered ^{(Mac Farlane et al., 1992)}. There is a reduction in the chemotaxis of polymorphonuclear leucocytes (PMNs) accompanied by an increase in cellular adhesion molecules (CAM) in serum. These molecules are increased in smokers and enter into competition with those on endothelial and epithelial cells (^{Kounderouse et al., 1996}). PMNs have reduced mobility because of a reduced oxygen intake due to the reducing action of nicotine ^{(Kenney et al., 1975)}. These PMNs have a reduced capacity for phagocytosis and they more readily release the lysosomal enzymes that are responsible for enhancing periodontal inflammation ^{(Kenney et al., 1977)}. Cigarette smoking also affects humoral or specific cell responses. In long term smokers, there is a reduction in serum IgG, IgM, IgA ^{(Johansson et al., 1991)}, in the level of T4 lymphocytes ^{(Costabel et al., 1986)} and an in vitro reduction in the growth, proliferation and activity of T8 lymphocytes ^{(Johansson et al., 1991)}. A number of authors suggest that this action on the immune system could be due to the effects of antigens contained in tobacco ^{(Hersey et al., 1983)}.

Besides the inflammatory cells, the fibroblast, the cell that is the key to the physiopathology of the gingival connective tissue, is also affected by nicotine in that its structural integrity and function is compromised. Studies using radioactive nicotine show that it is non-specifically bound to fibroblasts, absorbed and then released into the extracellular environment ^{(Hanes et al., 1991)}. Fibroblasts cultured in the presence of nicotine (in concentrations greater than 3.9 mmol) show vacuolisation of the cytoplasm, alterations to the plasmid membrane with reduction in their capacity for adhesion and disorganisation of their microtubules and vimentin filaments ^{(Alpar et al., 1998)}. The volatile components of smoke, such as acrolein and acetaldehyde, have identical effects : reduction in the proliferation and adhesion of fibroblasts, vacuolisation of the cytoplasm and an increase in intracellular lysosomes ^{(Cattaneo et al., 2000)}. These deleterious effects on cells lead to the presence of many atypical fibroblasts, mitotic defects and reduction in cell proliferation ^{(Tipton and Dabbous, 1995)}. These effects on fibroblast cell division add to the possibility of malignant changes in the oral mucosa induced by cigarette smoke, directly mediated by reductions in epidermal growth factor (EGF) and thus the activity of protein kinase ^{(Wang et al., 1996)}. Not only the structure, but also the functions of gingival fibroblasts are affected. Nicotine upsets the equilibrium between the production and degradation of the extracellular matrix produced by the fibroblast. The synthesis of fibronectin and type 1 collagen is reduced, whereas the production of collagenase (MMP1) is increased. The reduced synthesis of fibronectin modifies cell migration and tissue repair ^{(Tipton and Dabbous, 1995)}. The reduction in the synthesis of collagen is a consequence of the decrease in the expression of alpha-2 integrin chains during gingival fibroblast culture, which is nicotine dose dependent ^{(Leonardi et al., 1999)}. The adhesion and proliferation of periodontal ligament fibroblasts in culture are reduced following a raising of the level of nicotine or its main metabolite, cotinine, in the culture medium. After 3 to 5 cell passages at a nicotine concentration of 1 mg/ml or more, fibroblast cell proliferation and adhesion are both inhibited in vitro. For a greater number of passages (11 to 13), a concentration of 0.5 mg/ml has the same effect. Cotinine has the same effect as that of nicotine but at a much lower concentration (10 µg/ml) ^{(James et al., 1999)}. Taken together, these reports show the importance of fibroblasts and their integrity in the progression of periodontitis and the capacity for local repair ^{(Tipton and Dabbous, 1995)}.

Tobacco also modifies the composition of the oral environment. Salivary flow and the composition of saliva are modified. In moderate smokers, an increased salivary flow is observed because of stimulation of the autonomic nervous system by nicotine, whereas in heavy smokers there is reduced salivary flow ^{(Lueza, 1977)}. The concentration of salivary nicotine varies from 70 µg/ml to 1,500 µg/ml in smokers, whereas in non-smokers it is 1.3 µg/ml ^{(Godeau et al., 1996)}. The salivary pH is more alkaline in smokers (pH 7.1) than non-smokers (pH 6.8) ^{(Kenney et al., 1975)}. Also, the number of bacteria in saliva is reduced by 40 % in smokers. Formaldehyde could be responsible for this reduction, affecting particularly the acidophilic bacteria. Therefore, smoking could have an anti-cariogenic effect ^{(Lueza, 1977)}. On the other hand, there is an association between smoking and subgingival calculus. The prevalence of calculus is increased in smokers by a mean of 20 % and this is independent of age, the amount of plaque and of gingival inflammation ^{(Bergström, 1999)}. The organic antibacterial composition of saliva is altered. The quantity of IgA drops in heavy smokers ^{(Little, 1982)}. The concentration of lactoferrin, which is associated with thiocyanates and hydrogen peroxide in attacking Gram positive and Gram negative organisms and yeasts, is also reduced ^{(Gregory et al., 1991)}. In contrast to the effect on the organic composition, the inorganic components in the saliva of smokers seem to be increased. Thus, the antibacterial sulphocyanates increase by 2 to 4.5 times ^{(Bowers et al., 1987)}. Potassium is present at higher levels, as is calcium after smoking a cigarette, but the basal level of salivary calcium in smokers is reduced. Calcium and phosphorus concentrations increase along with the early formation of plaque ^{(Mac Gregor et al., 1986)}. Collectively these anionic changes could play a role in the increased formation of calculus in smokers ^{(Kowalski, 1971)}. Another oral fluid, gingival exudate, is affected by smoking. In patients during the course of periodontal treatment, the nicotine level is 5 to 6 times higher than in saliva ^{(Holmes, 1990)}. In patients with healthy gums, smoking stimulates an increase in gingival fluid of 90 %. This increase reflects the variations in blood flow ^{(Mac Laughlin et al., 1995)}. Nevertheless, nicotine is rapidly absorbed during smoking and causes the liberation of adrenalin by the suprarenal glands and noradrenalin from the walls of arteries. This liberation of catecholamines brings about a peripheral vasoconstriction and therefore a reduction in the flow of gingival exudate. This diminution of blood flow explains the reduction in bleeding on probing in smokers compared with non-smokers ^{(Bergström and Preber, 1986)}.

Periodontal diseases have a multifactorial aetiology. By altering the equilibrium of the oral environment, smoking aggravates pathological changes in the periodontium not only in connection with the development of disease but also in its effect on the success of treatment. Of the French population, 58 % are smokers, including 7 % of 12 year-olds. This remains a major risk factor for many diseases and is the principal cause of premature death in the industrialized countries (from the Consensus Conference on Smoking Cessation, Hôpital Pitié-Salpêtrière, October 1998). Periodontal disease is yet another to be added to the long list of those linked to smoking.

BIBLIOGRAPHY

• ALPAR B, LEYHAUSEN G, SAPOTNICK A, GÜNAY H, GEURTSEN W. Nicotine induced alterations in human primary periodontal ligament and gingiva fibroblast cultures. Clin Oral Invest 1998;2:40-46.
• BERGSTRÖM J. Oral hygiene compliance and gingivitis expression in cigarette smokers. Scand J Dent Res 1990;98:497-503.
• BERGSTRÖM J. Tobacco smoking and supragingival dental calculus. J Clin Periodontol 1999;26:541-547.
• BERGSTRÖM J, ELIASSON S, DOCK J. Exposure to tobacco smoking and periodontal health. J Clin Periodontol 2000;27:61-68.
• BERGSTRÖM J, PREBER H. The influence of cigarette smoking on the development of experimental gingivitis. J Periodontol Res 1986;21:668-676.
• BOWERS DJ, WINETT RA, FREDERIKSEN LW. Nicotine fading behavior contracting and extended treatment : effects on smoking cessation. Addict Behav 1987;12:181-184.
• CATTANEO V, CETTAG, ROTA C, VEZZONI F, ROTA MT, GALLANTI A et al. Volatile components of cigarette smoke : effect of acrolein and acetaldehyde on human gingival fibroblasts in vitro. J Periodontol 2000;71(3):425-432.
• CHOY W, BECKER G, SISKIND GW, FRANCUS T. Effects of tobacco glycoprotein (TGP) on the immune system. J Immunol 1985;134:3193-3198.
• COSTABEL U, BROSS KJ, REUTER C, RÜHLE KH, MATTHYS H. Alterations in immunoregulatory T-cell subsets in cigarette smokers. A phenotypic analysis of bronchoalveolar and blood lymphocytes. Chest 1986;90:39-44.
• DANIELSEN B, MANJI F, NAGELKERKE N, FEJERSKOV O, BAELUM V. Effect of cigarette smoking on the transition dynamics in experimental gingivitis. J Clin Periodontol 1990;17:159-164.
• GODEAU P, HERSON S, PIETTE JC. Traité de médecine. Paris : Flammarion Médecine-Sciences, 1996.
• GREGORY RL, KINDLE JC, HOBBS LC, MALMSTROM HS. Effect of smokeless tobacco use in humans on mucosal immune factors. Arch Oral Biol 1991;36:25-31.
• GROSSI SG, GENCO RJ, MACHTEI EE, HO AW, KOCH G, DUNFORD RG et al. Assessment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontol 1995;66:23-29.
• GROSSI SG, ZAMBON JJ, HO AW, KOCH G, DUNFORD RG, MACHTEI EE, NORDERYD OO et al. Assessment of risk for periodontal disease. I. Risk indicators for attachement loss. J Periodontol 1994;65:260-267.
• HANES PJ, SCHUSTER GS, LUBAS S. Binding, uptake and release of nicotine by human gingival fibroblasts. J Periodontol 1991;62:147-152.
• HERSEY P, PRENDERGAST D, EDWARDS A. Effects of cigarette smoking on the immune system. Med J Australia 1983;2:425-429.
• HOLMES LG. Effects of smoking and/or vitamin C on crevicular fluid flow in clinically healthy gingiva. Med J Australia 1990;21:191-195.
• JAMES JA, SAYERS NM, DRUCKER DB, HULL PS. Effects of tabacco products on the attachement and growth of periodontal ligament fibroblasts. J Periodontol 1999;70(5):518-525.
• JOHANSSON SL, HIRSCH JM, JOHNSON DR. Effect of repeated oral administration of tobacco snuff on natural killer-cell activity in the rat. Arch Oral Biol 1991;36:473-476.
• KENNEY EB, KRAAL JH, SAXE SR, JONES J. The effect of cigarette smoke on human oral polymorphonuclear leucocytes. J Periodont Res 1977;12:227-234.
• KENNEY EB, SAXE SR, BOWLES RD. The effect of cigarette smoking on anaerobiosis in the oral cavity. J Periodontol 1975;46:82-85.
• KOUNDEROUS E, ODELL E, COWARD P, WILSON R, PALMER RM. Soluble adhesion molecules in serum of smokers and non-smokers, with and without periodontitis. J Periodont Res1996;31:596-599.
• KOWALSKI CJ. Relationship between smoking and calculus deposition. J Dent Res 1971;50:101.
• KRALL EA, GARVEY AJ, GARCIA RI. Alveolar bone loss and tooth loss in male cigar and pipe smokers. J Am Dent Assoc 1999;130(1):57-64.
• LAGRUE G. Tabagisme. Le défi actuel. Recherche et Santé 1997;72:25-27.
• LEONARDI R, LANTERI E, STIVALA F, CALTABIANO M, FANGA C, TRAVALI S. Alteration in alpha-2 integrin in immunocytochemical expression on cultured human gingival fibroblasts following nicotine exposure. Minerva Stomatol 1999;48(11):495-499.
• LITTLE JW. Salivary immunoglobulin A levels in normal subjects tobacco smokers and patients with minor aphtous ulcerations. Oral Surg Oral Med Oral Pathol 1982;53:461-465.
• LUEZA M. Influence du tabac sur le milieu buccal. Concours Med 1977;43:80-89.
• MAC FARLANE G, HERZBERG M, WOLFF L, HARDIE N. Refractory periodontitis associated with anormal polymorphonuclear leukocyte phagocytosis and cigarette smoking. J Periodontol 1992;63:908-913.
• MAC GREGOR IDM. Effects of smoking on oral ecology. Clin Prev Dent 1989;11:3-7.
• MAC GREGOR IDM, EDGAR WM. Calcium and phosphate concentrations and precipitate formation in whole saliva from smokers and no smokers. J Periodontol Res 1986;21:429-433.
• MAC LAUGHLIN WS, LOVAT FM, MAC GREGOR IDM, KELLY PJ. The immediate effects of smoking on gingival fluid flow. J Clin Periodontol 1995;22:743-749.
• PAINE JB, JOHNSON JK, REINHARDT RA, DYER JK, MAZE CA, DUNNING DJ. Nicotine effect on PGE2 and IL1-beta release by LPS treated human monocytes. J Periodont Res 1996;31:99-104.
• PREBER H, BERGSTRÖM J. Cigarette smoking in patients referred for periodontal treatment. Scand J Dent Res 1986;94:102-108.
• PRETET S. Les composants du tabac. Impact Prat 1986;109:7-10.
• TIPTON DA, DABBOUS MK. Effects of nicotine on proliferation and extracellular matrix production of human gingival fibroblasts in vitro. J Periodontol 1995;66:1056-1064.
• TOMAR SL, ASMA S. Smoking-attribuatable periodontitis in the United States. J Periodontol 2000;71(5):743-751.
• WANG SL, FENG J, CORREA A, BRIGHAM M, WU-WANG CY. Effects of in vitro treatments of nicotine and benzo (a) pyrene on the epidermal growth factor receptor in hamster buccal pouch. Toxicology 1996;107:31-38.
• ZAMBON JJ, GROSSI SG, MACHTEI EE, HO AW, DUNFORD RG, GENCO RJ. Cigarette smoking increases the risk for subgingival infection with periodontal pathogens. J Periodontol 1996;67:1050-1054.