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DISCOVERY! |
Department of Cariology, Institute of Dentistry, University of Turku, Lemminkaisenkatu 2, FIN-20520 Turku, Finland; jorma.tenovuo{at}utu.fi
KEY WORDS: antimicrobial • saliva • mucosal surfaces
INTRODUCTION
Among the many functions of human saliva, its digestive and protective properties have attracted the most interest. Research on these functions is not that old, perhaps partly because saliva has not been one of the "popular" body fluids. The pithy expression by Mandel (1990) was that "saliva lacks the drama of blood, the sincerity of sweat and the emotional appeal of tears". Despite the absence of charisma, however, research on salivary functions and the underlying molecules has been intensive for the last three decades. This is particularly true for the protective function, which not only resists infectious diseases but also involves lubrication, maintenance of mucosal and tooth integrity, and, not least, the ecological balance—an important evolutionary force during human existence before plaque control (Mandel, 1989).
The diversity and the orchestration of the many protective agents in saliva started to become clearer during 1960s to '70s, when new molecules with multiple functions were repeatedly revealed and explored. Deep interest in these aspects grew out of the emerging interest in the use of saliva for diagnostic purposes, of both local and systemic diseases (Ferguson, 1987; Mandel, 1990; Aguirre et al., 1993). Simultaneously, the drama of saliva became apparent: in its absence. Developing sialochemistry provided useful instructions for saliva collection, storage, and treatment, but yet today, on an individual level, we often face the question: How much saliva is enough?
Appreciation of research on the protective functions of saliva coincided with the era of rapidly growing knowledge of the protection of the mucosal surfaces. Parallel tracks were followed: one to uncover the secrets of the secretory immune system, one to reveal the concerted action of the newly characterized non-immunoglobulin secretory products. Later it became apparent that these two tracks led to the same complex labyrinth of defense of both soft and hard tissues. Thanks to dental research, we now know a great deal about the interactions and amplifications of these two major defense systems, not only in the oral cavity but also relative to other human mucosal surfaces.
HOW DID MY INVOLVEMENT BEGIN?
After being engaged as a test subject and a young researcher in the Turku Sugar Studies in the early 1970s (Scheinin and Mäkinen, 1975), I lost my heart to research on saliva-mediated protection with the observation that xylitol consumption increased the peroxidase activity in saliva (Mäkinen et al., 1976). Although this observation was later verified in a few studies (Mäkinen, 1985), its relevance has remained obscure. However, much more importantly, these observations started a long and fruitful collaboration of research on salivary antimicrobial systems among various groups, first the Turku (Finland)–Birmingham (Alabama) axis, and later with groups from Atlanta, South Carolina (Roland Arnold), Umeå, Sweden (Britta and Firoz Rahemtulla, Thorild Ericson, Jan Carlsson et al.), Memphis, TN (Edwin Thomas), Rostock, Germany (Holger Jentsch), and Rochester, NY (William H. Bowen et al.). Simultaneously, some other very strong and pioneering groups worked on the same field, boosting healthy 'competition' on research of salivary antimicrobials. These groups included, e.g., Seymour J. Klebanoff (myeloperoxidase), Larry Tabak and Michael Levine (mucins), Frank Oppenheim (histatins), Greg Germaine (lysozyme), Henk Hoogendoorn (lactoperoxidase), Joel Rudney (interactions), and later many others as well. Bruno Reiter, a milk biochemist from Redding (UK), and Lennart Björck (Uppsala, Sweden) should also be mentioned for their simultaneous pioneering work of the antimicrobial effects of the non-immune systems in bovine milk.
From the clinical point of view, it turned out to be important that a strong center around both immune and non-immune defense systems developed in Birmingham, AL. This group of enthusiastic people, who uncovered many secrets of the secretory immune system, consisted in the early '80s of such excellent scientists as Jerry McGhee, Jiri Mestecky, Sue Michalek, Michael W. Russell, Noel Childers, and many others close to and in collaboration with the non-immune group led by Kenneth M. Pruitt. This latter group focused its interest mainly on salivary peroxidase systems, and this research was strongly enhanced when, first, Britta and Firoz Rahemtulla moved from Sweden to Birmingham and, later, I spent approximately 1.5 years (1980-1982) there prior to establishing my own research group in Turku, Finland. Dr. Marianne Lenander-Lumikari from my group in Turku also spent a year (1990) in Birmingham and has subsequently become one of the top scientists in the area of salivary non-immunoglobulin antimicrobial agents.
Over the past 20 years, the 'Birmingham groups' have made a series of findings which have become important for our understanding of the in vivo activity of salivary antimicrobials. These works include:
Of course, many of these examples represent findings which were partly based on concurrent or previously reported observations by many other groups mentioned above.
In Birmingham and later in Turku and several other places, enthusiastic research filled the puzzle piece by piece, and soon the first comprehensive reviews, even books (Pruitt and Tenovuo, 1985), appeared of the structure-function relationships of the major non-immunoglobulin antimicrobial components discovered in human saliva (Tenovuo and Pruitt, 1984; Carlsson, 1987; Mandel, 1989; Tenovuo, 1989; Tenovuo and Lumikari, 1991; Lamkin and Oppenheim, 1993; Rudney, 1995). The methods to detect specifically the studied proteins (Månsson-Rahemtulla et al., 1986; Vilja et al., 1991) and their inhibitory action against target cells (Loimaranta et al., 1998) were also intensively developed and improved by the members and successors of the Birmingham group. A recent major development has been the discovery, purification, and structure-function analyses of histatins, cystatins, and ß-defensins in human saliva during the late 1980s and 1990s (reviewed by Lamkin and Oppenheim, 1993; Nieuw Amerongen and Veerman, 2002).
PROTECTION FOR THE WHOLE BODY?
Although much of the interest in salivary antimicrobials focused on their activity against mutans streptococci and lactobacilli, it soon became obvious that due to their widespread occurrence on all mucosal surfaces, it was worth studying the antimicrobial spectrum more extensively. It appeared, e.g., that the (lacto)peroxidase-mediated oxidation products display significant inhibitory activity against such pathogens as Legionella pneumophila, Salmonella typhimurium, Pseudomonas aeruginosa, Listeria monocytogenes, Staphylococcus aureus, Porphyromonas gingivalis, and Actinobacillus actinomycetemcomitans (Kamau et al., 1990; Ihalin et al., 1998). Furthermore, Candida albicans and C. krusei and many viruses, including HIV, herpes simplex type 1, echovirus (type 11), and respiratory syncytial virus, turned out to be sensitive to the peroxidase system (Pourtois et al., 1990; Mikola et al., 1995). Also, many other salivary antimicrobial agents have recently been shown to display antiviral activity (Shugars, 1999). From these observations, it might be concluded that salivary antimicrobial agents also protect the upper digestive tract, not just the oral cavity (Herrera et al., 1988).
From the clinical point of view, it is interesting to speculate how hyposalivation might also affect the upper part of the gastrointestinal tract, not just oral health. So far, little is known of this important clinical aspect, but it is worth mentioning that pharmacological induction of dry mouth has led to an increased incidence of palatal and oral tumors in experimental animals (Wallenius, 1966). Also, saliva-derived epidermal growth factor plays an important role in the repair and maintenance of the entire gastrointestinal tract (Dutta et al., 1987). These few examples indicate that saliva, with its many protective and antimicrobial agents, is important not only to oral but also to general health, particularly in preventing the oral transmission of several noxious agents. It is important to note that not only is the salivary peroxidase system active against micro-organisms but also it protects host cells from the toxicity of oxygen compounds, such as hydrogen peroxide (Hänström et al., 1983; Tenovuo and Larjava, 1984).
CLINICAL IMPLICATIONS
Based on the above observations, and starting from the first attempts to enhance the activity of salivary peroxidase (Månsson-Rahemtulla et al., 1983), it was quite natural that commercial attempts to use host-derived antimicrobial agents for the prevention of oral diseases also emerged already in the early 1980s. The idea seems sound: to add physiological antimicrobial agents into the mouth that lacks saliva-mediated protection in patients with dry mouth. Many products are already on the market, but although, in clinical trials, these antimicrobial toothpastes, mouthrinses, and moisturizing gels have relieved the symptoms of xerostomia, it is not yet known whether this is because of antimicrobial proteins (lactoferrin, lysozyme, lactoperoxidase) or other properties of the products (Tenovuo, 2002). Interestingly, even in people with normal salivary flow, augmentation of salivary antibacterial proteins and peptides may increase protection against oral diseases (Van Dyke et al., 2002). In the future, the application of genomics and proteomics can markedly expand opportunities, and enthusiastic and pioneering observations similar to those made some 20 years ago are also to be expected. For me, it has been a great privilege to be involved in the discovery of this fascinating area of antimicrobial agents in the human mouth, although much more saliva has to flow until we fully understand its role in the maintenance of both oral and general health.
Received August 14, 2002; Accepted September 26, 2002
REFERENCES
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