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.
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.
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.
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.
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.
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.
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.