br Please cite this article in press as Ankita K
Please cite this article in press as: Ankita K, et al. Assessment of salivary endothelin-1 in patients with leukoplakia, submucous fibrosis, oral cancer and healthy individuals – a comparative study. J Stomatol Oral Maxillofac Surg (2019), https://doi.org/10.1016/ j.jormas.2019.02.024
in patients with gastritis, gastric and duodenal ulcers, which may contribute to the formation of peptic ulcer diseases in humans.
Hoffman et al. in 2011  separated their patients according to their sex and hypertension history; there was no significant association with the ET-1 levels. Cheng et al. in 2011  analysed the systemic diseases of the participants in each group; cardiovascular diseases, bone and joint diseases, gastrointestinal diseases, hypothyroidism and diabetes. Due to the small sample size of each group, they did not analyse the statistical correlation between the salivary ET-1 level and the systemic diseases of participants. Looking at the association between hypertension and salivary ET-1 levels; our study did not include cases with a history of any systemic diseases, which can contribute to the limitation of the study.
4.3. Endothelin-1 and habit history
Lam et al. 2004  assessed the levels of ET-1 in patients with a history with smoking. In their study, the smokers show significantly higher salivary levels of IR-ET than those of the non-smokers. Very few studies have analysed for the habit history and its correlation with ET-1 levels in saliva of the participants. In our study, within the study group, there was a positive correlation (rbi = 0.41, P = 0.12) of salivary ET-1 level with Smokeless form of tobacco in the leukoplakia group. None of the cases in this group had a history of consuming smoked form of tobacco, therefore we couldn’t comment on its association with salivary ET-1.
4.4. Endothelin -1 and periodontitis
Yamamoto et al. in 2003  found that the expression of ET-1 in gingival 3X FLAG Peptide was strongly induced by the P. gingivalis infection. However, Pradeep et al. in 2008  conducted a study where it was found that the gingival crevicular fluid samples in all the groups tested negative for the endothelin-1 molecule. These results were not in accordance with those of a previous study by Yamamoto et al. in 2003 . So to conclude as mentioned by Hoffman et al. [10, the levels of ET-1 in periodontitis might affect its mean levels in the result data. However, our study did not assess for the periodontal status of the patients for evaluation of ET-1 levels, which accounts for a drawback.
4.5. Endothelin- 1 and oral fibroblasts
Hinsley et al. in 2012  stated that the significance of the tumour stroma in carcinogenesis and progression of disease is increasingly recognised, and represents an attractive target for emerging therapeutic approaches. The predominant cell type in the stroma, fibroblasts, frequently undergo a number of changes in response to signals released by malignant epithelial cells including increased proliferation, migration and acquisition of a contractile, myofibroblastic phenotype. In OSCC, the presence of myofibro-blasts in the tumour stroma was recently identified as the strongest negative prognostic indicator, and myofibroblasts were shown to promote cancer cell invasion. They showed that ET-1 stimulation of fibroblasts increases their migration and confers on them a more contractile phenotype. This is associated with an increased ability to stimulate oral cancer cell invasion but is not concomitant with the acquisition of markers of myofibroblastic transdifferentiation, suggesting ET-1may synergise with other factors to generate the reactive, myofibroblast rich stroma associated with aggressive oral malignancies.
Lieu et al in 2016  found that the proteome analysis in saliva of normal buccal mucosa, SMF and OSCC revealed a number of potential biomarker and they seem to have large prognostic value for patient survival, which suggest that SMF and OSCC biomarkers
are potential targets for therapeutical intervention. Therefore, ours was the first study to hypothesize that ET-1 levels can be expressed in SMF patients and the mean levels of salivary ET-1 were significantly high when compared to that of normal controls.
The limitation of the present study is that, lesser number of samples was being considered for analysis. Although significant levels have been found in assessing salivary ET-1 levels in OPMD and OSCC, the findings of the study cannot be generalised owing to smaller sample size. Studies on larger populations to validate the results of the present pilot study are therefore necessary.
5. Conclusions and future directions