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Saliva
Of all the organs in the
craniofacial-oral-dental complex, it is perhaps the salivary glands
and their remarkable secretory product, saliva, that forge the
strongest link between oral and systemic health. Salivary function is
extremely sensitive to changes in our general well-being, ranging from
subtle effects of over-the-counter cold medications to the devastation
of life-threatening disease.
Even the ancients recognized an association between the human
condition and saliva, which served as judge and jury in cases of
wrong-doing. A suspect was given a mouthful of dry rice. If his
anxiety reduced his saliva flow so that he could not swallow it, the
verdict was guilty as charged. To this day, "cotton mouth" betrays all
of us at some point in our lives, signaling to the world that our
nerves have taken control.
Gatekeeper
With its vast antimicrobial arsenal, saliva represents a remarkable
evolutionary selective advantage for the host against invading
pathogens such as HIV, the fungus Candida albicans, and a host of
bacteria associated with oral and systemic diseases. Secretory
antibodies, for example, directed against viral pathogens such as
poliovirus and cold viruses, as well as the anti-HIV agent SLPI, are
found in saliva. Large salivary glycoproteins called mucins appear to
have antiviral properties as do cystatins, a family of cysteine-rich
proteins that are active against herpes viruses.
Saliva also contains histatins, anti-fungal proteins that are potent
inhibitors of candida, which is normally kept in check at extremely
low levels in the mouth. When the oral balance is upset, however, by
HIV infection or other immunosuppressive and debilitating disorders,
antifungal defenses are overwhelmed and candida flourishes
uncontrolled.
Reinforcing saliva's antiviral and antifungal activity are salivary
constituents that thwart bacterial attack. These enzymes destroy the
opposition by various mechanisms, including degrading bacterial
membranes, inhibiting the growth and metabolism of certain bacteria,
and disrupting vital bacterial enzyme systems.
Functioning in concert, these and other protective factors in saliva
help to maintain the oral environment in optimal working order and
restore it to more normal conditions when disturbed. But protection of
the oral tissues reflects only one dimension of this versatile fluid
and its constituents. Research has found a new role for saliva as an
effective laboratory tool.
New Diagnostics
Long known primarily for its protective and lubricating properties,
saliva is now meeting the demand for inexpensive, noninvasive, and
easy-to-use diagnostic aids for oral and systemic diseases, and for
assessing risk behaviors such as tobacco and alcohol use. Detection of
HIV by the presence of virus-specific antibodies in saliva, for
example, has led to the development of commercially available test
kits. These offer the sensitivity of a blood test, but without the
discomfort of a needle stick.
The strong correlation between HIV antibodies in saliva and serum has
spurred the use of saliva as a monitor for other viral antibodies and
antigens. Experimental salivary assays have already been developed for
detecting antibodies for measles, mumps and rubella. Saliva is also
reliable in diagnosing viral hepatitis A, B and C in laboratory tests.
As an investigational diagnostic aid and potential monitor of disease
progression, saliva has been used increasingly in systemic disorders
that affect salivary composition and gland function, including
Alzheimer's disease, Sjögren's syndrome, cystic fibrosis, diabetes,
and diseases of the adrenal cortex. Saliva is also proving to be an
effective tool to monitor levels of hormones and therapeutic
medications -- as well as the presence of illicit drugs.
Research opportunities abound to develop more sensitive and specific
assays to measure and understand changes in saliva beyond oral and
systemic diseases to areas such as genetic defects, nutritional
status, and age-specific changes.
Salivary Gland Dysfunction
Although viewed as champions of the oral cavity, the salivary glands
are not spared insult or disease. The parotid, submandibular, and
sublingual glands that comprise the major salivary glands are directly
affected by a variety of conditions, including infection (such as
mumps), obstructions, developmental disorders, and tumors. Two major
diseases, cystic fibrosis (CF) and Sjögren's syndrome, can devastate
these vital glands.
In cystic fibrosis, a defect in chloride ion transport causes exocrine
gland secretions, including saliva, to be thick and viscid and leads
to chronic lung disease and pancreatic insufficiency. Studies of
salivary acinar (salt and water secreting) cells, a convenient model
for exploring mechanisms of chloride ion transport, have greatly
expanded the understanding of exocrine gland transport systems in
human salivary glands. The identification of the defective gene in
cystic fibrosis has also led to clinical trials using gene therapy to
treat this disorder.
Gene Transfer Technology
Applying the same technology used in the CF trials, scientists have
successfully introduced human and bacterial genes into the salivary
glands of rats. This advance holds potential not only for repairing
diseased or damaged salivary glands, but also for enabling the glands
to produce therapeutic drugs for delivery into the mouth.
The researchers used a common cold virus (adenovirus), altered to
prevent reproduction, and packaged in it either human or bacterial
genes that could make readily detectable proteins. When introduced
through the salivary ducts, the genetically altered virus particles
infected the ductal cells as well as the fluid-secreting acinar cells.
The foreign genes then made their specific proteins that were detected
inside the infected cells and in saliva secreted from the cells,
confirming that this system of gene transfer can be used to make
salivary tissues produce functional proteins.
This advance has already found application in animal studies that
could eventually lead to a new treatment for thousands of people whose
salivary glands are damaged by radiation therapy for head and neck
cancer. While head and neck radiation treatment kills cancerous cells,
it also often destroys vital acinar cells that lie within the
radiation field. Patients are unable to produce adequate saliva,
leading to a host of long-term problems including xerostomia (dry
mouth), mucositis, rampant dental caries, infections of the mouth and
pharynx, and difficulty with swallowing, speech and taste. These
conditions dramatically reduce quality of life and can also be the
source of systemic infections that may threaten patient survival or
interfere with their cancer treatment.
NIDCR scientists have now tricked non-fluid producing ductal cells
into making saliva. Unlike acinar cells, ductal cells frequently are
not destroyed by irradiation. The researchers sought to genetically
re-engineer ductal cells into fluid producers by giving them a gene
for an aquaporin protein, a recently discovered family of proteins
that form pores in cell membranes through which fluid can pass. They
inserted an aquaporin gene into an altered adenovirus and then
infected irradiated rat salivary glands with the virus. Remarkably,
the ductal cells produced fluid.
Although human application is likely several years away, the NIDCR
research team is optimistic about the potential use of gene-mediated
therapeutics for restoring salivary gland function.
Sjögren's Syndrome
Eagerly awaiting clinical advances in salivary gene transfer are many
thousands of people with Sjögren's syndrome (SS), an autoimmune
disorder that primarily affects women. Classic symptoms include dry
mouth, eyes and other mucosal surfaces, accompanied in about half the
cases by a connective tissue disease such as rheumatoid arthritis or
systemic lupus erythematosus. The oral dryness interferes with normal
functions of talking, chewing and swallowing and, deprived of the
protective properties of saliva, puts SS patients at high risk for
dental and oral infections.
Investigators are looking closely at alterations in salivary gland
function associated with Sjögren's syndrome. Because salivary
involvement in this disorder is highly variable, ranging from mild
impairment to total loss of function, early diagnosis is difficult.
Studies are aimed at defining criteria for early and unequivocal
diagnosis and establishing clinically useful markers for salivary
gland disease activity.
The inflammatory cytokine interleukin-6 (IL-6), for example, has been
found at elevated levels in the saliva of SS patients and may serve as
a marker for this disorder. IL-6 and other elevated cytokines are
thought to play a significant role in the pathogenesis of Sjögren's
syndrome; the mechanism, however, is unknown.
Research is also under way to develop a new noninvasive or minimally
invasive means of diagnosing salivary gland involvement in SS using
laser spectroscopy techniques. Currently, definitive diagnosis
requires surgical removal of minor salivary glands. Laser spectroscopy
to detect labeled cells specific to Sjögren's syndrome would not only
obviate the need for surgery, but would also permit repeated testing
of the salivary glands to follow the course of the disease and
effectiveness of therapy.
Xerostomia
Another major source of dry mouth -- medication -- affects most of us
at some time in our lives. More than 400 prescription and
over-the-counter drugs are known to have xerostomic effects. Many of
these medications are taken daily, particularly by older Americans, to
treat chronic conditions such as hypertension and depression. Although
salivary gland function does not normally decline with age, the oral
dryness experienced by many older persons from certain diseases and
long-term medications heightens their risk for oral and dental
infections. As the population ages -- by 2010, 40 million Americans
will be 65 or older -- vulnerability to an array of chronic and
disabling disorders and the oral effects of medications prescribed for
their management will present significant challenges to health care
providers.
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