Public Release:  A new study sheds light on how the tongue restores its ability to taste following surgery

Findings could lead to advances for thousands who have lost their ability to taste after treatment for cancer, other disorders of the mouth

American Physiological Society

(December 9 , 2002) - Bethesda, MD - Surgery and a wide range of cancer treatments on the tongue can be devastating for both its short- and long- term considerations. A recent study conducted at Duke University, for example, found that patients who experience taste and smell loss because of the disease and its treatments are at high risk for weight loss and nutritional deficits that can compromise their overall treatment success. Even among patients who are eating the same volume of calories, those with taste and smell distortions may avoid foods with high nutritional value, such as fresh fruits and vegetables. Eliminating such nutritious foods can further depress immune function.

Why We Lose Taste

The causes of taste loss vary. Chemotherapy drugs are known to alter taste and smell by blunting the normal turnover rate of taste and smell receptors on the tongue and in the nasal passages. Radiation treatments can also damage taste and smell receptors, giving food a metallic flavor. Tumors themselves also secrete a protein that suppresses appetite in some patients. Often it is the need to perform surgery on the tongue itself.

Key to our ability to taste are the taste receptor cells within the mushroom-shaped protrustions on the anterior tongue, which are innervated by the chorda tympani (CT) nerve. One function of this nerve, in addition to conduction of neural impulses to the central nervous system, is to maintain the structural and functional fitness of associated taste receptor cells.

When the CT is unilaterally cut, as may be required by surgery, taste buds degenerate and gustatory function is abolished on that side. However, taste receptor cells eventually reappear following reinnervation, or resupply of the nerve, and normal taste function is restored. Previous research demonstrated that taste receptor cells that regenerate under dietary sodium restriction find their function dramatically different from the normal post-regeneration state. Specifically, dietary sodium restriction in combination with CT section selectively affects taste responses to sodium.

From the results discussed above, it is apparent that important events subsequent to unilateral CT section occur if adult rats are placed on a sodium-deficient diet. However, the timing of such events is unknown because the sodium-restricted diet was always instituted immediately after sectioning. To begin determination of the relevant physiological processes responsible for the dramatic response alterations, it is necessary to know when the diet has its influence.

The Study

Against this backdrop, Lynnette Phillips McCluskey from the Department of Physiology, Medical College of Georgia, Augusta, GA; and David L. Hill, at the Department of Psychology, University of Virginia, Charlottesville, VA, conducted a study entitled, "Sensitive Periods for the Effect of Dietary Sodium Restriction on Intact and Denervated Taste Receptor Cells." Their findings are published in the November 2002 edition of the American Journal of Physiology--Regulatory, Integrative and Comparative Physiology.

Methodology

The researchers sought to determine the period of vulnerability of CT function to dietary sodium restriction following nerve sectioning.

· Their first goal was to define the onset of the "sensitive period" for the regenerated and intact CT nerves by systematically varying when rats were placed on the low-sodium diet. Responses were recorded from both CT nerves starting at 50 days after unilateral CT section. The period of 50 days was chosen because the sectioned CT nerve regenerates during that period (i.e., demonstrates robust neural responses to multiple stimuli). Moreover, at 50 days post sectioning, the hypersensitivity to sodium in the uncut nerve is evident when dietary restriction is instituted immediately after nerve section. Such a strategy has been extremely useful in developmental studies of taste function, and knowing when the diet is effective will further subsequent determination of the underlying mechanisms.

· The second goal was to investigate taste bud degeneration in sodium-restricted and control rats during the corresponding functional sensitive period(s). To accomplish this, a monoclonal antibody to keratin 19 was used to immunohistochemically label taste buds at various times after unilateral CT section. Keratins are intermediate filament proteins expressed in a range of epithelial tissue, with specific sequences present during various states of differentiation and tumorigenesis. Keratin 19-like immunoreactivity has been demonstrated in rat fungiform taste buds, which contain the taste receptor cells innervated by the CT nerve. Importantly, keratin 19 is restricted to fusiform cells located within the limits of the taste bud, and the immunopositive cells are thought to represent mature, functional taste receptor cells.

Results

The findings demonstrate that two distinct functional "sensitive periods" exist for the regenerated nerve. This research reveals that effects of CT cut and sodium restriction on sodium taste function in the two sides of the tongue are likely to be due to different mechanisms. The intact CT is susceptible to sodium restriction in the first week after sectioning, while the regenerated nerve is sensitive to the diet in the first two weeks after sectioning. This work presents a narrowed time period to focus further attention on possible mechanisms involved in changes in sodium sensitivity and eliminates an effect of sodium restriction on the number of taste buds as a candidate mechanism.

Although recording from the CT nerve assessed alterations in sodium taste function, it is likely that the initial site of these changes is in taste receptor cells. The effects of dietary sodium restriction and CT section were largely specific to sodium, suggesting that sodium transduction through ENaC on taste receptor cells is responsible. However, the possibility that additional functional alterations in the CT nerve contribute to changes in taste responses cannot be ruled out.

Conclusions

· This study finds that upregulation of immune function with systemic LPS reverses the dramatic decrease in sodium sensitivity exhibited by the intact CT shortly after contralateral denervation.

The authors suggest that sodium restriction leads to abnormalities in immunederived factors liberated by neural damage. In fact, there is evidence to suggest that macrophages are present in both the denervated and intact taste epithelium following CT sectioning, but their numbers are substantially lower in sodium-restricted compared with control rats. The soluble products of immune cells may then modulate changes in the number or function of ENaCs in the intact population of taste receptor cells.

· Macrophages and other leukocytes secrete an array of cytokines and growth factors that are known to influence injured neural and epithelial cells. More specifically, the proinflammatory cytokine tumor necrosis factor increases amiloride-sensitive sodium transport in the alveolar epithelium of murine lung In contrast, the anti-inflammatory cytokine transforming growth factor prevents aldosterone-stimulated sodium transport through ENaC in the collecting duct of rat kidney. LPS-stimulated macrophages (or macrophage-conditioned media) also inhibit ENaC activity and mRNA levels in rat distal lung epithelial cultures. Thus, leukocytes and cytokines regulate ENaC function in nonlingual epithelial cells and may do so in taste receptor cells as well.

· The basic mechanism of changes in the function of denervated taste receptor cells is also likely to involve channel function. However, the difference in the periods of sensitivity to sodium restriction indicates that processes diverge in the regenerated and intact nerves before the effects on channel function. A current challenge is to determine the cellular events that are responsible for this remarkable functional plasticity exhibited by both the regenerated and intact nerves as well as to investigate behavioral implications.

Next Steps

In future work, the researchers hope to determine mechanisms responsible for altered CT responses to sodium, including the identification of sites where the effects of CT section and sodium restriction initially take place. Although the mechanism for dietary related differences in sodium taste function following nerve section has yet to be discovered, there is an indication that the immune system may play a role in maintaining normal sodium responses in intact taste receptor cells contralateral to denervated taste receptor cells.

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Source: November 2002 edition of the American Journal of Physiology--Regulatory, Integrative and Comparative Physiology.

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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