CLINICAL
CLINICAL
The role of saliva in
oral and systemic health
Juliette Reeves
Saliva is a vital body fluid, without it, continued healthy
functioning of the oral cavity would not be possible. The
multiple functions of saliva relate both to its fluid characteristics
and specific components. As a fluid, saliva facilitates mastication,
bolus formation, swallowing, lubrication of the mucosa and
speech. Specific components of saliva contribute to antimicrobial
activity, buffering actions, digestion, and the protection and
maintenance of mucous membrane.
Its major components, water and mucin, serve as a cleansing solvent and
lubricating fluid. In addition it contains digestive enzymes: lingual
lipase and ptyalin (salivary amylase), mucins, and electrolytes (sodium,
potassium, chloride). It maintains the normal antimicrobial factors,
epidermal growth factor, minerals, and buffering systems. It maintains
normal balance of the oral flora, protecting mucosa from overgrowth
of potentially pathogenic organisms, most
notably Candida species. The viscosity
of saliva is much higher than that
of plain water due to the presence
of various glycoproteins and
immunoglobulins. These and other
chemical characteristics give
saliva its coating and
lubricating properties.
The importance
of saliva,
however,
extends
beyond its
local effects
on the oral
tissues. In addition
to being important
in speech and
swallowing saliva is
also a vital part of
the human defence
Volume 52 No 5 of 6 September 2013
system, containing secretory IgA and components such as lyzosyme,
lactoferrin, histatins along with salivary peroxidase systems. Saliva
contributes to the first line of oral defence and after swallowing, saliva
has a mucosal protective capacity within the gastrointestinal tract1.
Another defence mechanism, the antioxidant system, exists in saliva and
appears to be of paramount importance. Antioxidants are present in all
body fluids and tissues and are critical in protecting against damaging
reactive oxygen species (ROS) and reactive nitrogen species (RNS) that
cause oxidative stress and DNA mutations2.
Saliva contains a wide range of antioxidants including uric acid, albumin,
vitamins A C and E along with antioxidant enzymes such as reduced
glutathione, oxidised glutathione, superoxide dismutase (SOD) and
catalase1. Over production of ROS and decreased clearance by ROS
scavenging antioxidants results in oxidative stress and tissue damage3.
The antioxidant capacity of saliva appears to protect against oral cancers4,
and has been implicated in the progression of periodontal disease5,
susceptibility to periodontal disease and systemic inflammation associated
with diabetes6 and recurrent aphthous ulceration7.
Saliva and oral cancer
In the UK incidence rates for oral cancer have increased by 26% in males
and 30% in females.8-11 The salivary antioxidant system has an essential
anti-carcinogenic role in the oral cavity and plays a pivotal role in the
pathogenesis of oral squamous cell carcinoma (OSCC)12. In addition Wu
et al4 demonstrated that saliva plays an important role in cigarette related
nicotine induced DNA damage.
Free radical ROS and RNS which induce oxidative and nitrative stress
are key contributors to the development OSCC13. RNS in the form of
nitrosamines and ROS such as superoxide radicals, hydroxyl radicals and
hydrogen peroxide play a key role in cancer developments as they can
cause DNA alterations and enhanced expression of genes that cause
normal cells to become cancerous (proto-oncogenes).
Salivary nitrosamine production results from dietary nitrates which are
absorbed from the gastrointestinal tract. In the oral cavity salivary nitrates
are converted to nitrites which then react with amines to form
27
CLINICAL
carcinogenic nitrosamines.14 15
Principal sources of ROS and RNS include smoking, alcohol, smoked
preserved foods and various beverages.
In addition to antioxidants, saliva also contains nitrosamine inhibitory
agents along with another crucial anti-cancer salivary enzyme glutathione
S-transferase.16 The salivary composition of patients with OSCC has been
found to be substantially altered with respect to free radical induced
mechanisms, with salivary RNS levels significantly higher and all salivary
antioxidants significantly reduced17.
More recently Hershkovich et al18 looked at the increased prevalence of
oral cancer among older people and suggested this may be due to an age
related reduction in protective salivary antioxidant mechanisms and age
related magnitude of oxidative stress from ROS and RNS exposure. A
decrease in salivary secretion and reduced ability to flow and arrive at the
sites where salivary protection is required adds to the reduced antioxidant
protective capacity of saliva.19 The reduction in saliva flow may be as a
result of age related changes to salivary gland function and/or multiple
medication use in the elderly.20
The development of oral cancer is multifactorial; however, whilst ROS
and RNS are involved in the initiation and progression of OSCC, both
are inhibited by antioxidants21. What is not clear is whether an increase
in ROS and RNS activity results in depletion of antioxidant availability
or if the opposite is true. In either case the pathogenesis of oral cancer
is related to the close contact between saliva and the mucosal tissues,
demonstrating the vital role salivary antioxidants may play in the
prevention of oral cancer.
Saliva and periodontal disease
The aetiology of periodontal disease is based on an imbalance between
bacterial challenge from species that colonise the oral cavity and host
response to these bacterial pathogens.22 Three primary species have been
identified as periodontal pathogens: Aggregatibacter actinomycetemcomitans
(AA), Tannerella forsythia (Bacteroides forsythus) and Porphyromonas gingivalis
(PG). Of these PG shows extensive proliferation in chronic periodontally
diseased patients.23
In response to bacterial invasion, the host immune response releases proinflammatory cytokines (IL-1, Il-6, Il-8, TNF) which recruit Polymorphonuclear
leukocytes (PMNs) to the site of infection.22 PMNs are the primary host
defense against periodontal pathogens. PMNs in periodontal patients
display an increase in number, adhesion and oxidative activity, releasing
ROS species such as superoxide. As the superoxide released is not target
specific oxidative damage to the surrounding tissues occurs24. These
mechanisms have identified ROS involvement in the aetiology of periodontal
disease along with lowered antioxidant levels implicating oxidative stress
in the pathology of periodontal disease.5 25
Several studies have demonstrated increased oxidative stress and depleted
antioxidant availability in periodontitis patients.26 Individuals with periodontal
disease have a significant increase in the activities of antioxidant systems in
gingival tissue compared to healthy controls, demonstrating a correlation
between oxidative stress biomarkers and periodontal disease.27 When high
levels of extracellular ROS exist antioxidant levels are suggested to play an
important role in the onset and development of inflammatory oral diseases.28
Chappel et al29 studied the antioxidant capacity of saliva in diseased and
healthy control groups and found significantly lower antioxidant capacity
28
in diseased patients compared to the controls. Further study revealed lower
concentrations of glutathione in serum and in gingival crevicular fluid.30
More recent study has confirmed that patients with chronic periodontal
disease exhibit decreased salivary delivery of antioxidants and poor
periodontal health is associated with reduced salivary antioxidant status
and increased oxidative damage.31
Although it remains unclear whether the decreased saliva and/or plasma
antioxidant status is a cause or a result of periodontal disease, the presence
of salivary antioxidants surrounding the gingival crevice may be of major
importance in dampening down inflammatory processes initiated by
bacterial infection. The extent of dietary influence on salivary antioxidant
status is unclear, however recent studies have indicated that nutritional
supplementation may improve pocket depth and that inadequate antioxidant
levels may be managed by higher intake of fruit and vegetables or by
phytonutrient supplementation.32 33
An improved understanding of the role salivary antioxidants play in
periodontitis and the influence of nutrition on salivary antioxidant status
may lead to the development of nutritional protocols for the treatment
of periodontal disease.
Recurrent aphthous ulceration
Recurrent aphthous ulcers (RAU) represent a very common but poorly
understood mucosal disorder. It is estimated that at least 1 in 5 individuals
has at least once been afflicted with aphthous ulcers. Patients with RAU
experience oral pain ranging from mild to intensely painful that interferes
with normal activities.34
The exact cause is unknown however attacks may be precipitated by local
trauma, stress, food intake, drugs, hormonal changes and vitamin and
trace element deficiencies. Local and systemic conditions and genetic,
immunological and microbial factors all may play a role in the
pathogenesis of RAU.35
More recently RAU has been associated with markers of increased oxidative
stress and decreased antioxidant status that may play a crucial role in its
pathogenesis.36 37 All of the above mentioned conditions can disturb the
oxidant/antioxidant balance and can accelerate the formation of ROS.
In health mucous membranes are protected from oxidative damage by
general host defences and specific immune responses. The antioxidant
system has been shown to protect biomembranes from oxidative damage
by quenching ROS activity2.
More recently lowered salivary antioxidant status has been reported in
patients suffering from RAU.7 38 39 In recent years, there are increasing
reports and literature regarding application of natural anti oxidant
products for the management of RAS.40
In addition dietary and nutrient deficiency plays an important role as an
initiating factor in RAU41, particularly antioxidant vitamins and minerals
as they are involved in antioxidant defense system.36
In conclusion, the evidence shows that there is increased oxidative stress
and levels of both plasma and salivary antioxidants are decreased in patients
with RAU. It has yet to be established whether it is the antioxidant system
impairment in RAU patients is the cause or consequence of recurrent
aphthous ulceration. Nevertheless these findings re-enforce the importance
of salivary antioxidants as a protective mechanism of oxidative damage
to oral mucous membrane.
DENTAL HEALTH
CLINICAL
Conclusion
The available evidence to date implicates pro-inflammatory mediated
oxidative stress in the pathogenesis of oral diseases and that local antioxidant
status may be important in determining the susceptibility, disease progression
and prevention of oxidative damage to mucous membranes. The presence
of salivary antioxidants surrounding the gingival crevice may be of major
importance in dampening down inflammatory processes initiated by
bacterial infection. Further research is needed to understand the influence
of nutrition on salivary antioxidant status that may lead to the development
of a nutritional strategy for the treatment and prevention of
inflammatory oral diseases.
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22. Lamont RJ, Jenkinson HF. Life below the gum line: Pathogenic mechanisms of Volume 52 No 5 of 6 September 2013
The Wrigley Oral Healthcare Programme
This article has been supported by an educational grant from the Wrigley
Oral Healthcare Programme, which is dedicated to improving standards of
oral health in the UK and Ireland by providing dental professionals with
the tools and knowledge to communicate the clinically proven* benefits of
chewing sugarfree gum to their patients.
To find out more about the Wrigley Oral Healthcare Programme’s sampling
and CPD offering in the UK, please visit: www.wrigleyoralhealthcare.co.uk
**Alcantara E, Leveille G, McMahon K, Zibell S. Benefits of Chewing Gum: Oral
Health and Beyond. Nutrition Today, Volume 43, Number 2, March/April 2008
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