The role of saliva in maintaining oral homeostasis

JA D )A R E V I E W

A R T I C L E S

D ental practitioners are becoming more cognizant o f the importance o f saliva as they treat a greater num ber o f older patients, especially those with medical problems requiring a variety o f medications that have xerostomia as a side effect. This article discusses salivary com position and fu n ctio n in a broad perspective, relating them to clinical concerns and current research. Understanding the role o f saliva in m aintaining health, as well as its relation to oral disease, is vital to the competent dental practitioner.

The role of saliva in maintaining oral homeostasis

Irw in D. M an d el, DDS

t the m om ent an infant takes its first breath of life, a residential , microbial com m unity begins to form on the tongue an d o ral m ucous m em branes. L ater, w ith the e ru p tio n of teeth, a d d itio n a l m icro o rg an ism s immigrate and establish colonies on the sheltering tooth surfaces. As time passes and the crevice deepens between the teeth and the gingiva, still another flora takes root in this protected niche. T he bacteria, with the advantage of several billion years of evolution, use every topographical, physical, and meta­ bolic o p p o rtu n ity the m outh provides to m a in ta in th eir presence. L earn in g the m echanism s involved in bacterial c o lo n iz a tio n an d p la q u e m a tu ra tio n , and characterizing them at a molecular level is a productive research area for o ral ecologists. E q u ally in terestin g is the latest research in the counterforce— the host response. Long before there were toothbrushes, floss, a n d o ral w ater irrig a to rs, the evolutionary process created protective mechanisms in the m outh for self-defense and self-sustenance against the hundreds of species of m icroorganism s and their 50 b illio n (or m ore) descendants that make their home in the mouth. The major

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responsibility for the defense of the mouth rests with the salivary glands, the original slow -release device fash io n ed by an ancient technology. T he salivary secre­ tions and other exocrine gland fluids, such as tears and nasal secretions, share im m u n o lo g ic and n o n im m u n o lo g ic means for protecting mucosal surfaces. Saliva, however, also contains un iq u e p ro te in s an d p ep tid es for h e lp in g to m aintain the integrity of the teeth against a constant barrage of physical, chemical, and microbial trauma. During the past 25 years, dental researchers have been developing a more detailed picture of the salivary components and their func­ tion in the maintenance of oral homeo­ stasis. Xerostomia

T h e sim plest way to com prehend the role of saliva in its protective capacity is to exam ine the effect on the m outh w hen it is in short supply. An aging population has an increasing incidence of salivary gland dysfunction caused by local and systemic disease, immunologic disorders, radiation, chemotherapy, and also by the side effects of hundreds of m edications. T h u s, xerostom ia (dry

m outh) has become a significant clinical problem. Patients with xerostomia have reported complaints such as: “My m outh and throat are dry, rough, sticky. I am hoarse—it’s so hard to talk. I can’t wear my dentures—my m outh is always sore. I have to sip fluids frequently so my tongue w on’t stick to the sides or roof of my m outh. E atin g is d ifficu lt and som etim es im possible. I c a n ’t tell the position of food in my mouth. My fillings are falling out and my teeth are crum bling away.” T hese p a tie n ts have to sip w ater frequently, and keep a water bottle or glass of water w ith them at all times. T his reduction in salivary flow results in dram atic increases in: the levels of S trep to co ccu s m u ta n s in p la q u e and saliva and in caries; abrasion and erosion; p la q u e ac cu m u la tio n and g in g iv a l in flam m atio n ; oral m o n ilia sis.1,2 T h e q u a n tita tiv e im pact on the oral flora has been studied best in patients receiving irradiation for cancer of the head and neck. With increasing amounts of radi­ a tio n and a co n c o m ita n t decrease in salivary flow rate, there is a dram atic increase in S mutans, Lactobacillus, and Candida, and a decrease in S sanguis.3 The palatal mucosa and the dorsum of

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the tongue are p articu larly vulnerable to Candida habitation. Clinically, the increased susceptibility to caries is first seen on exposed cementum in the form of root caries on both buccal and lin g u a l surfaces. In tim e, enam el caries increases as w ell and involves surfaces u su a lly re sista n t to decay, such as the interproxim al areas of the m an d ib u la r a n te rio r teeth and the incisal surfaces. W ith chronic xero­ stomia, the caries becomes circumferential w ith minim al localization and an almost total involvement of the enamel.4 In animals, the opportunity for exper­ imental studies has generated substantial lite ra tu re on the effect of su rg ical d esaliv atio n or saliv ary g la n d d u ct ligation on caries.5 In these studies, young ro d en ts were given a sta n d a rd h ig h carbohydrate diet. W hen all the m ajor glands were removed or the ducts ligated, there was consistently a more rapid onset and increase in the num ber and extent of the carious lesions com pared w ith the control group. Recently, the desal­ ivated rodent model has been extended to the study of root caries.6 Mature rats, w ho u su a lly have little caries on a sta n d ard c a rio g e n ic d iet, developed extensive root surface caries (as well as coronal caries) when their major salivary g lands were rem oved an d they were infected with Actinomyces viscosus and S mutans. It appears that with salivary deprivation, anim als and hum ans have a comparable cariogenic response. Patients with xerostomia are not only prone to caries b u t are also m ore sus­ ceptible to loss of tooth structure from chemical erosion and m echanical abra­ sion; unless extra atte n tio n is paid to oral hygiene, there is a greater tendency for plaque accum ulation and a resultant increase in gingival inflam m ation. Few rep orts in the lite ra tu re address p e ri­ o d o n ta l disease in xero sto m ia. T h e re la tio n s h ip of saliv a to p e rio d o n ta l disease has not been studied extensively. Although the effect of salivary depri­ vation on gingival h ealth is not com ­ pletely clear, the to n g u e an d m ucosa are adversely affected. T h e m ucous m em branes are dry, cracked, fissured, have a loss of elasticity, an d frequent u lc e ra tio n is fo u n d , especially u n d e r dentures. T h e tongue is often p ain fu l and highly sensitive to spices and flavors. At the sam e tim e, th ere are fre q u e n t reports of the loss of norm al taste acuity.7 Based on these subjective complaints, clinical observations, and anim al studies, it is apparent that insufficient salivary

flow has two general effects: an im pair­ m ent in the p re p a ra tio n of food for mastication, deglutition, digestion, and enjo y m en t; an d a h e ig h ten e d suscep­ tibility of both the hard and soft tissues to a variety of destructive processes.

Composition of saliva

U ntil recently, most study was devoted to the digestive functions of saliva, and saliva was described as one of the digestive juices composed of water, salts, amylase, and mucin. T he common view of saliva was derived largely from exam ination of the expectorated fluid, whole saliva. Whole saliva, usually collected by chew­ ing paraffin, not only contains the fluids of the m ajor and m inor salivary glands, but also includes food remnants, bacteria and their products, shed cells and gingival crevicular fluid and its contents. T o study the many glandular constit­ uents effectively, collecting devices are used to gather secretions from the parotid g lan d s, su b m a n d ib u la r-su b lin g u a l glands, and m inor salivary glands.8 By the late 1960s, w ith co llectin g devices and application of the new forms

Table 1

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of electrophoresis, it became evident from the nearly 60 bands disclosed that salivary secretions are hig h ly com plex flu id s.9 T h o u g h low in total p ro te in concen­ tration, more than 40 proteins have been identified in salivary secretion, an d a growing num ber have been isolated and characterized (Table l) .10 W hat appeared 20 years ago as a form idable task has been yielding very gracefully to the new technologies. D uring the identification stage, two major characteristics of salivary proteins emerged: that the acinar products consist m ainly of “fam ilies” of molecules, and th a t the fam ilies have genetic p o ly ­ m o rp h ism .10 T hese characteristics are most evident in the proline-rich proteins (PRPs), which can account for as much as 60% to 70% of the to tal p ro te in in s u b m a n d ib u la r an d p a ro tid saliva. Proline-rich proteins are com posed of four acidic and nine basic components, and the latter branch includes the major p a ro tid g ly c o p ro te in .11 R ecent d a ta 12 suggest that the peptide moieties of the P R P s are derived from six genes on ch rom osom e 12 th a t have u n d e rg o n e tra n sc rip tio n a l m o d ifica tio n th ro u g h differential RNA splicing.

■ Proteins of parotid and submandibular saliva.

Salivary protein families 1. Proline-rich 2. Histidine-rich 3. Cysteine-containing 4. Tyrosine-rich 5. Amylase 6. Mucin 7. Salivary peroxidase

Acid, basic, basic glycoprotein Neutral, basic Cystatin S, cystatin SN Statherin Glycosylated, nonglycosylated MG 1 (> 106), MG 2 (> 2 x 10s) (SAPX 1, 2, and 3)

Other acinar proteins 1. Lactoferrin 2. Secretory com ponent 3. Zinc-binding protein-gustin 4. Parotid—aggregating glycoproteins High-m olecular weight (440,000) Low-molecular weight (60,000) 5. Epidermal growth factor—(urogastrone) 6. Antileukoprotease Ductal, stromal, or origin unknown 1. Lysozyme 2. Secretory IgA 3. Kallikrein 4. Vitam in B-12-binding protein 5. Vitam in D-binding protein 6. Fibronectin

7. 8. 9. 10. 11. 12. 13.

Nerve growth factor Lipase Ribonuclease Carbohydrases Esterases Amino peptidases Phosphatases

Serum proteins 1. Album in, IgG

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Although not as well studied, other families include the histidine-rich pep­ tides, both neutral and basic13; cysteinecontaining phosphoproteins, acidic and neutral, which appear to be identical to cystatin S and SN14; and tyrosinerich peptides, mainly statherin.15 Even the “grandfather protein,” amylase, is a “patriarch” with two main family branches, glycosylated and nonglyco­ sylated, and six to eight isoenzymes.16 In addition, mucin has recently been shown to be secreted in two forms, as the traditional high-molecular weight macromolecule (> 106) designated MG1, and the lower-molecular weight (2 x 105) designated MG2.17 Salivary peroxidase (SAPX) exists in several genetically determined forms that differ in molecular weight.18 A number of other proteins produced by acinar cells include: lactoferrin19; secretory component20; a parotid zincbinding protein, gustin21; several aggre­ gating glycoproteins in parotid saliva22,23; epidermal growth factor (urogastrone)24,25; and antileukoprotease.26 Another group of salivary proteins originates in the ductal cells, in the interstitial tissue, or are of undetermined origin. This group includes lysozyme, secretory IgA, kallikrein, vitamin B-12, vitamin D binding proteins, fibronectin, and a variety of enzymes.9,10,27 Lipase is produced by the von Ebner glands of the tongue.28 Even in a completely healthy gland, low but measurable amounts of serum proteins can leak into the secretions, mainly albumin and IgG, but many other proteins can also be found if the tech­ niques of measurement are sufficiently sensitive.9 Nonprotein-bound hormones and drugs—both prescribed and illicit— can also enter saliva. Saliva is also being used increasingly for monitoring pur­ poses as an external measure of homeostasis.29,30 Not only the proteins but also the salivary electrolytes—the nonelectrolytes such as urea and ammonia and the lipids, both associated and covalently bound— 31,32 are important components of the various oral defense systems. How these systems operate and how they interact with each other—their orchestration and regulation—are areas of active research.33" 36

Protective properties of saliva

Lubrication. From an evolutionary view­

point, the oldest function of the salivary 300 ■ JADA, Vol. 119, August 1989

glands has been to supply lubricatory molecules, not only to coat the food, but also the oral soft and hard tissues.37 The lubricatory film allows food to travel easily through the digestive system, and provides smooth tissue surfaces with minimal friction. Without appropriate lubrication, food is retained and impacted around the teeth, making eating difficult and unpleasant, and increasing plaque formation. It has always been assumed that the mucin glycoproteins are solely respon­ sible for the lubricatory properties of saliva. And indeed, both MG1 and MG2 can provide fluid layers with high-film strength. It has recently been shown, however, that the basic proline-rich glycoproteins of parotid saliva, when complexed with albumin (present in low concentration in saliva), can also be an extremely effective lubricant and could serve on teeth (as part of the pellicle) as well as on mucous membranes.38 Maintenance of mucous membrane integrity.

esophagus because of their ability to effectively bind tannins. Tannin-rich foods, especially sorghum, are consumed in large quantities by populations at high risk for esophageal cancer. It is possible that genetic variants of these salivary proteins may influence the incidence of esophageal cancer in dif­ ferent populations. Numerous proteolytic enzymes are generated in the bacterial plaque around the teeth and in the crevicular area, and from degenerating polymorphonuclear leukocytes, especially in people with periodontitis. These proteases not only affect the periodontal tissues, but can affect the integrity of the mucous mem­ branes and cause ulceration. Mucin coatings are physically protective in this regard. There is also a second line of defense against protease activity— cysteine-containing phosphoproteins, which are identical to cystatin S and cystatin SN.43They are effective inhibitors of cysteine-proteases, such as the cathepsins. This antiprotease activity is further augmented by antileukoprotease, an effective inhibitor both of elastase and cathepsin.26,44

The salivary mucins possess rheological properties that include low solubility, high viscosity, elasticity, and adhesive­ ness. These properties enable mucins to concentrate on oral mucosal surfaces Soft tissue repair. “Licking one’s wounds” where they provide an effective barrier may be more than metaphoric as exper­ against desiccation and environmental imental studies in mice have shown the factors.34 Mucins act as natural “water rate of wound contraction is significantly proofing” that helps maintain oral tissues affected by saliva.45 Epidermal growth in a hydrated state, and protect the factor (EGF) present in the saliva of mice underlying cells from sudden changes and other animal species is thought to in osmotic pressure. 39 be important in the accelerated healing Mucins are important in the control of cutaneous injuries as these animals of permeability of mucosal surfaces.40 lick their wounds.46 Topical application The presence of a salivary film can limit of EGF has been shown to speed epi­ penetration of various potential irritants dermal regeneration of mid-dermal skin and toxins in foods and beverages, as injuries.47 EGF is present in human well as potentially hazardous agents from parotid and submandibular saliva.48 The tobacco smoke and other sources. Several effects of EGF on oral wound healing animal studies suggest that the mucous are yet unproved. layer can help retard the penetration and dissolution of lipotropic carcinogenic Maintenance of ecological balance. Col­ agents.34 No comparable data in humans onization of tissue surfaces (adherence) are available. However, a study on the is critical for survival of many bacteria, effect of human saliva on the mutage­ and interference with this process (bac­ nicity of a series of known and suspected terial clearance, by mechanical, immu­ carcinogens used the Ames test with nologic, and nonimmunologic means) Salm onella typh im u riu m . Saliva was is one of the basic functions of the salivary effective against aflatoxin B, benzopyrene, defense systems.35 Indeed, the ability of and several other suspected carcinogens, saliva to help maintain an appropriate and moderately effective against a con­ ecological balance in the mouth must have been a critical evolutionary force densate of cigarette smoke.41 Salivary proteins may even have pro­ long before this century’s plaque control. tective effects beyond the mouth. A new hypothesis, introduced by Warner and Debridement/lavage. The physical flow Azen,42 suggests that salivary PRPs can of saliva (a hydrokinetic flushing action), have anticarcinogenic effects in the augmented by the movements of the lips

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and tongue, constantly removes numerous potentially harmful bacteria from teeth and mucosal surfaces. This clearance mechanism is similar to the eye’s tearing and blinking, blowing the nose, coughing and expectorating, and its counterparts in the urinary and gastrointestinal tract.

gating proteins in parotid saliva,22,23,27'58,59 lysozyme,60 and parotid basic glyco­ protein.61 Simple mechanisms such as calcium bridging can also contribute. Determin­ ing how these interactions actually occur in the mouth, rather than in the lab­ oratory, is the next challenge.

Aggregation. In addition to physical means,

saliva can interfere with bacterial adher­ ence by more direct means that depend on molecular interactions. The ability to inhibit bacterial attachment is a major characteristic of the secretory IgA sys­ tem.49 Williams and Gibbons50 demon­ strated that strains of S salivarius that were agglutinated by secretory IgA did not adhere to human buccal epithelial cells. The data on inhibition of oral bacterial attachment to hydroxyapatite by secretory IgA in in vitro experiments are not as clear cut.51 However, the validity of this protective mechanism in caries is supported by the vaccination studies in rodents. In those studies, development of secretory IgA antibodies in saliva against S m utans inhibits the adherence of these cariogenic organisms to teeth and results in very significant protection against caries.52,53 In humans, data are limited but several pilot studies have shown a reduction in the level of infection and duration of colonization of implanted strains of S m utans after perioral immunizations when entericcoated capsules containing formalinkilled organisms were ingested.54,55 In addition to these specific antibodies there are several other macromolecules in saliva (such as mucins), some very specific in action, which mask bacterial adhesions or compete with them for attachment sites on tissues.34 They may also function by clumping or aggregating bacteria to the point where they can no longer effectively adhere to hard or soft tissues and are expectorated or swal­ lowed.56 These molecules provide the host with considerable flexibility and help the secretory fluids to cope with the large number of different bacterial antigens. The degree of effectiveness of salivary-bacterial interaction was pro­ vided by Clark and Gibbons57 with their findings that when S m utans cells are first suspended in saliva and then exposed to hydroxyapatite disks, adsorption to the disks is reduced more than 30 times when compared with untreated bacteria. In addition to secretory IgA and mucins, various other salivary molecules are capable of interacting with oral bacteria. These include several aggre­

Direct antibacterial activity. Saliva has

multiple systems that work to fight bacteria. A group of salivary proteins, lysozymes, histidine-rich peptides, lactoferrin, and salivary peroxidase, working in conjunction with other components of saliva, can have an immediate effect on oral bacteria, interfering with their ability to produce acid and multiply, or killing them directly. Lysozyme. The strongly cationic enzyme,

lysozyme, can cause lysis of oral bacterial cells, especially S mutans and Veillonella, by effectively binding to their cell surface, and interacting with salivary anions of low-charge density (chaotropic ions) such as thiocyanate, perchlorate, iodide, bro­ mide, nitrate, chloride, fluoride, and with bicarbonate. These combinations are thought to destabilize the cell mem­ brane through the activation of autolysins (a self-destruct mechanism).62,63 Lysozyme can also exert an antibacterial effect by inhibiting growth and dechaining,64 as well as by reducing glucose incorporation and lactic acid production.65,66 Another cationic peptide in saliva, the histidine-rich peptide of parotid saliva, also has growth-inhibitory and bactericidal effects on oral bacteria.67 The mechanism of action has not yet been determined.

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Salivary peroxidase. The peroxidase in

the salivary secretions closely resembles bovine milk peroxidase and hence has been called lactoperoxidase. Although it is related antigenically to lactoperox­ idase, there are significant differences in the properties of the enzymes; thus, the term salivary peroxidase is more appropriate. Salivary peroxidase is part of an antibacterial system which catalyzes the oxidation of salivary thiocyanate by hydrogen peroxide produced by oral bacteria such as S sanguis to generate highly reactive oxidizing agents, most prominently hypothiocyanite and hypothiocyanous acid. These products oxidize sulfhydral groups in bacterial enzyme systems involved in glucose transport and glycolysis, thus seriously effecting acid production and growth.70 The antimicrobial effect of salivary peroxidase against S m u ta n s is significantly enhanced by interaction with secretory IgA.71 The protective potential of all of the antibacterial proteins can be extended by interaction with each other and with high molecular weight mucin. This mucin can serve to concentrate a defense force on the mucosa against the external environment, entrapping and incapac­ itating microorganisms.34 When teeth are present, especially if some gingivitis exists, the oral fluids will be augmented by the gingival crevicular fluid.33 This fluid can con­ tribute to the oral defense system by providing: serum antibodies against oral bacteria, especially IgG antibodies; phagocytic cells; and antibacterial pro­ ducts liberated from the phagocytic cells (lysozyme, lactoferrin, myeloperoxidase).

Lactoferrin. Lactoferrin, the exocrine gland

equivalent of transferrin (the ironbinding protein of blood), has been shown to possess bacteriostatic properties for various aerobic and facultative orga­ nisms. The bacteriostatic properties are attributed to the ability of the unsaturated protein to bind two iron atoms per molecule. This ability of a host protein to withhold iron from invading bacteria has been termed “nutritional immunity.” Nutritional immunity is an important protective mechanism against bacteria that require ferric iron for metabolism as it can effectively compete with the bacterial iron-binding molecules. Lac­ toferrin is capable of both a bacteriostatic and a bactericidal effect on S m utans that is distinct from simple iron depri­ vation.68,69

Antifungal activity. It has been recently

shown that the parotid fluid has an antifungal capacity, reflecting properties of both the neutral and the basic histidinerich peptides. Pollock and others72 showed that the basic peptides could cause a > 99% loss of viability of C albicans at levels of 25 n g /m h , levels commensurate with salivary concentra­ tions. Oppenheim and others73 found that the neutral histidine-rich peptide was a potent inhibitor of C albicans germination at levels as low as 2 ;um/ mL. Antiviral activity. In addition to its ability

to help keep the oral bacterial flora in balance, saliva can have a modulating influence on viruses. Antibodies (secretory

M andel: ROLE OF SALIVA IN MAINTAINING HOMEOSTASIS ■ 301

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IgA) can directly neutralize viruses. Oral mucosal antibodies have proved effective against rhinovirus and poliovirus, and may help in h ib it the tran sm issio n of hum an im m unodeficiency virus (HIV) via saliv a.74 M ucins are also effective a n tiv ira l m o lecu les.75 Salivary m ucin can also p ro te c t a g a in s t the herpes simplex virus,76 and may contribute to an anti-HIV effect as well.77 Most of the studies on the antimicrobial p ro p erties of saliva focused on in te r­ actions w ith specific o ral o rganism s. Perhaps a m ajor fu n ctio n of saliva is to prevent the establishment of unwanted species in the first place, a type of bacterial exclusion act which would be yet another new research frontier. Maintenance Of pH. Saliva helps m aintain a relatively n eu tral p H in the m outh, in the b ac te ria l p la q u e an d , d u rin g swallowing, in the esophagus as well.78 In the b a c te ria l p la q u e , w here acids constitute the metabolic waste products of bacteria using carbohydrates for energy, saliva helps regulate p H in several ways. B icarbonate, p h o sp h ate, an d peptides rich in histidine are direct buffers after d iffusion in to the p laq u e. U rea from saliva is converted by bacterial urease to ammonia, which can neutralize acid. Amino acids and peptides can be decarbo x y lated to form m o n o am in es an d polyam ines, a process th a t effectively consumes hydrogen ions.79 Arginine and a rg in in e p ep tid es can form am m onia as well as the polyamine putrescine and, thus, can effectively elevate plaque p H .80 T he ability of saliva to affect plaque pH can be shown in clinical experiments in which plaque p H is being monitored by intraoral telemetry. Introduction of sugar in solution, confections, or baked goods results in a rapid and prolonged pH fall in the interproxim al plaque being m easured. T h e sim p le e x p ed ien t of chewing paraffin, or “ sugar-free” (sor­ bitol, m annitol, xylitol, aspartame) gum, and in a sense, pum ping saliva into this area, results in a ra p id rise of p H to a neutral level.81 Maintenance of tooth integrity. In addition to countering plaque acidity, saliva helps to protect the teeth in other ways. The physical flow of saliva (the hydrokinetic property) coupled with m uscular activity, aids in the clearance of sugars in solution and carbohydrate rem nants, ju st as it does for bacteria. Small decreases in the re stin g salivary flow rate can greatly prolong sugar clearance tim e,82 and is 302 ■ JÀDA, Vol. 119, August 1989

an im p o rtan t factor in the destructive caries often seen in x erostom ia. T h e b io ch em ical p ro te c tio n of the to o th begins im m ediately after its e ru p tio n in to the m o u th . A lth o u g h the crow n of the too th is fully form ed m o rp h o ­ logically when it erupts, it is incomplete cry stallo g rap hically. In te ra ctio n w ith saliva provides a posteruptive m aturation th ro u g h the diffusion of ions such as calcium, phosphorus, m agnesium , and fluoride, as well as other trace com po­ nents, in to b o th the surface and su b ­ surface e n am el.83 T h is en rich m en t of the crystal structure increases hardness, decreases perm eability, and in anim al models, increases resistance to caries.84 O nce a to o th begins to fu n ctio n in the m o u th , its developm ental cuticle or pellicle is rapidly worn away. T he o rig in al pellicle is replaced by a con­ stantly replenished salivary film. T he acquired coating or pellicle of selectively adsorbed proteins w ith a high affinity for h y d ro x y ap atite (largely p h o sp h o ­ proteins, album in, and high-m olecular weight m ucin—MG1 coupled with neu­ tral lip id s, glycolipids, and p h o sp h o ­ lipids) forms a primitive membrane and provides a protective barrier, a lubricating film against excessive wear, a diffusion b a rrie r a g a in st acid p e n e tra tio n , and a lim itation against mineral egress.85,86 Because of the involvement of pellicle com ponents in the initial colonization of plaque known as bacterial adherence, in su ffic ie n t a tte n tio n has been given to the protective properties of the pellicle. Enam el has no capacity for renew ing its surface structure; the form ing cells are lo st on e ru p tio n . In a sense, the pellicle supplies that regeneration capa­ bility and is an im portant property of saliva. Saliva is saturated, or even supersat­ urated w ith calcium phosphate salts.87 R esearch d u rin g the last decade has stu d ied how o ral hom eostasis exists w ithout unwanted precipitation or crys­ tallizatio n of calcium p h o sphate salts w ithin the salivary glands, the m outh, and on the tooth surfaces. T his regulation of the io n ic en v iro n m en t is provided largely by the tyrosine-rich peptide called staterin th a t can in h ib it spontaneous precipitation from supersaturated solu­ tions. Additional regulation is provided by the a n io n ic P R P s, the n e u tra l histid in e-rich peptides, and the acidic cy stein e-co n taining pro tein s (cystatin S), which can inhibit crystal growth and the transform ation of dicalcium p h o s­ phate dihydrate to more basic forms of

7^ ftfi— on calcium phosphate. ' The stabilized su p ersatu ratio n of saliva (and plaq u e fluid) provides the thermodynamic driv­ ing force both for initial protection of the enamel surface and for remineralizing early subsurface lesions. It is this rem in­ eralizing potential that fluoride enhances so effectively in the co n sta n t b a ttle betw een dem in eralizatio n and re m in ­ eralization occurring under plaque. C onsidering the variety of protective components in saliva, it is understandable that people w ith severe salivary insuf­ ficiency suffer difficulties with soft and hard tissues. T eeth are especially v u l­ nerable. In people with normal salivary flow, however, little inform ation exists on how q u a n tita tiv e an d q u a lita tiv e differences in the salivary protective systems affect the levels of oral disease. There is still m uch unfinished business in salivary research. Summary Saliva is a complex fluid w ith constit­ uents th at provide an effective m eans of protection against a constant barrage of p o te n tia lly h a rm fu l m icrobes a n d irritan ts. T h is is evidenced by people w ith xerostom ia. Saliva p ro tects soft tissues against desiccation, penetration, ulceration, and p o tential carcinogens, an d can encourage soft tissue rep air. A major protective function is its ability to m ain tain an appropriate ecological balance in the m outh by debridem ent/ lavage, aggregation and reduced bacterial adherence by a com bination of im m u­ nologic and n o n im m u n o lo g ic m eans, and direct antibacterial activity by a series of systems fu n c tio n in g singly an d in combination. Saliva also contains an ti­ fungal and antiviral systems. Saliva is im p o rtan t in m ain tain in g a relatively neutral oral pH , possesses a number of effective m echanism s for re g u la tin g plaque pH , and helps neutralize reflux acids in the esophagus. Saliva’s role in m aintaining tooth integrity is a reflection of: mechanical cleaning and carbohydrate clearance, p o steruptive m a tu ra tio n of enam el, reg u latio n of the ionic e n v i­ ronm ent in plaq u e fluid to provide a rem ineralizing potential w ithout spon­ taneous precipitation, and pellicle depo­ sition and lim itation of acid diffusion.

------------- J!£OA ------------This paper is based largely on the 1986 Seymour J. Kreshover Lecture at the National Institute of Dental Research, Sept 24, 1986. Some sections have appeared in Dr. M andel’s paper, “ Functions of

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