Nitric Oxide and Oral Diseases
Nitric Oxide

Author: erika brachet contul
Date: 27/06/2007


NO formed in saliva may serve as an anti-bacterial agent, or be involved in saliva production itself (acting as a nonadrenergic, noncholinergic neurotransmitter). But NO has been shown to play a role in the pathogenesis of a number of oral diseases.

An overview of oral diseases in which NO has been implicated is discussed below.

1. Sjögren's syndrome
It's an example of inflammatory autoimmune disease that affect exocrine tissue. It is generally believed that destruction of the acinar parenchyma is caused by lymphocytic infiltration of the gland. It is possible that aberrant NO production in the acinar cells may contribute to inflammatory damage and acinar cell atrophy, favoring the disease progression. iNOS gene expression was found to be up-regulated in labial salivary glands from patients with Sjögren's syndrome and could be caused by cytokine release from lymphocytes infiltrating the glands. NO production from iNOS is long-lasting and leads to production of relatively high NO concentrations, which might ultimately lead to tissue destruction. It has been shown that nitrite (NO2-, the oxygenation product of NO) levels in saliva and serum are markedly increased in patients with Sjögren's syndrome. Surprisingly, it is the resident salivary gland cells rather than immigrant inflammatory cells that are responsible for raised nitrite concentrations in the saliva of patients with Sjögren's syndrome.

2. Periodontal disease
NO synthesis is increased in periodontal disease, as a result of macrophage infiltration in the periodontal tissues. It is probable that bacterial plaque is responsible for NOS2 activation, since no NOS2 activity is found in the gingival tissues of sterile animals. Recent studies have also demonstrated that gingival fibroblasts in chronic periodontitis have significantly higher NOS2 expression than those in healthy gingival tissue.
It is possible that the induction of NOS2 occurs in response to bacterial LPS, or as a result of cytokines which are formed in periodontal disease. NO might play a role in the pathogenesis of both periodontitis and subsequent bone loss, either directly, or indirectly by modulating the production of other pro-inflammatory cytokines.
NOS2 inhibitors reduce gingival fibroblast NO production, and it was postulated that pharmacological inhibition of NO might be therapeutically valuable in the management of this disease.

3- Odontogenic Cyst and Periapical Lesion
-The radicular cysts rapresent 60% of the odontogenic cysts. They result from chronic periapical inflammation, and it is not surprising that NOS2 was expressed in this condition.
- NO has also been implicated in the pathogenesis of apical infection. again, inflammation-induced NOS2 accounts for NO production.

4. Oral Carcinoma
Transition from a normal somatic cell to a cancer cell is usually the result of many genetic changes, including the activation of oncogenes or inactivation of tumor suppressor genes. these changes allow the cell to escape normal control mechanisms which control cell proliferation, migration, differentiation and cell death. Since high concentrations of NO cause genetic mutations, it could be postulated that long-term NO exposure (from NOS2 activity during chronic inflammation) could have an active role in carcinogenesis.
*The ways through which NO could promote carcinogenesis are:
a - DNA damage can be due to NO-induced deamination;
b - nucleic acid transition and/or trasversion;
c - NO has a great affinity for the thiol group in amino acids, and has a result can inactivated DNA ligase (a DNA repair enzyme), which contains large numbers of cysteine residue;
d - It has been hypothesized that NO induces mutations of the p53, c-mic and p21 oncogenes, thereby facilitating tumor progression.
NO may promote carcinogenesis by inactivating the tumor suppressor gene, p53.
In normal cells exposed to high NO concentrations, the tumour-suppressor gene, p53, promotes apoptosis via the p21 pathway, in an attempt to safeguard against potential NO-mediated DNA damage. The mutations of p53, a common finding in oral cancer, can lead to unchecked NOS2 activity with potentially detrimental effects.
e - Although eNOS in tumor facilitates angiogenesis

Expression of various NOS isoforms is increased in both benign (pleomorphic adenoma) and malignant (adenocarcinoma) salivary gland tumor as well as in other oral cancer types such as oral squamous cell carcinoma.

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