Advances in Natural and Applied Sciences. Correlation between Stress and Pro-Inflammatory Cytokines in Erosive Oral Lichen Planus Patients

Advances in Natural and Applied Sciences, 9(23) July 215, ages: 28-34 AENSI Journals Advances in Natural and Applied Sciences ISSN:1995-772 EISSN: 1998-19 Journal home page: www.aensiweb.com/anas Correlation between Stress and ro-inflammatory Cytokines in Erosive Oral Lichen lanus atients Maha M Mahmoud Assistant professor, Alexandria University. Oral Medicine, eriodontology, Oral Diagnosis and Radiology Department,aculty of Dentistry.Alexandria, Egypt A R T I C L E I N O Article history: Received 12 March 215 Accepted 28 June 215 Available online 22 July 215 Keywords: Erosive Lichen planus,proinflammatory cytokines, stress A B S T R A C T Background: The etiology of oral lichen planus (OL) remains uncertain. However, most evidence suggests that it is a T-cell mediated autoimmune reaction precipitated by endogenous or exogenous factors in persons with a genetic predisposition to the development of L. Certain precipitating factors have been identified including stress. IL-8 and TN-α are found to be in a higher serum level in patients with OL than in normal subjects and to be involved in the pathogenesis of OL Objective: The aim of the present study was to find a relation between stress and pro-inflammatory cytokines in erosive oral lichen planus patients (EOL). Subjects and Methods: 3 patients with EOL were participated in the present study. atients were divided according to their stress scores using Hospital Anxiety and Depression scale (HADS) into three groups, group A, with high stress score, group B with moderate stress scores, and group C with normal stress score. Lesion size, visual analogue score (VAS), and serum levels of IL-8 &TN- α were assessed for all groups. Results : A statistically significant increase in group A compared to group B and group C respectively in relation to lesions size, VAS scores and serum level of IL-8 &TN- α. Conclusion: The study highly suggested a positive correlation between psychological stress, immune system over-activity with increased production of pro-inflammatory mediators and OL clinical manifestations. 215 AENSI ublisher All rights reserved. To Cite This Article: Maha M Mahmoud., Correlation between Stress and ro-inflammatory Cytokines in Erosive Oral Lichen lanus atients. Adv. in Nat. Appl. Sci., 9(23): 28-34, 215 INTRODUCTION Lichen planus (L) is a chronic autoimmune disease caused by type IV hypersensitivity reaction to antigenic alteration observed in the mucosal lining and skin (Lavanya N 211).While the cutaneous lesions of L usually self-regress, the lesions found in the oral cavity are chronic, rarely undergo spontaneous remission and are potentially premalignant (Eisen D 25). ifty percent of patients with skin lesions also manifest oral mucosal lesions, and 25% of patients with oral lichen planus (OL) present only oral lesions (Ghislaine 21). Oral lichen planus tends to persist for many years with periods of exacerbation and quiescence. During periods of exacerbation, the area of erythema or erosions increases, with concomitant increase in pain and sensitivity. On the contrary, during periods of quiescence, the area of erythema or erosion decreases with decrease in pain and sensitivity (Sandhu 214). Exacerbation of OL has been linked to periods of psychological stress and anxiety, a predictable correlation with any condition that is related to an immune system imbalance (.Soto 24, Rojo-Moreno 1998). The etiology of OL remains uncertain. However, most evidence suggests that it is a T-cell mediated autoimmune reaction precipitated by endogenous or exogenous factors in persons with a genetic predisposition to the development of L (Shirasuna 214). This results in altered response to self-antigens with subsequent damage to basal keratinocytes. Certain precipitating factors have been identified and these include genetic background, dental materials, drugs, stress, trauma, infections, chronic liver disease, diabetes and hypertension (Robertson 1992, Klanrit 23, Luis-Montoya 25). IL-8 and TN-α are found to be in a higher serum level in patients with OL than in normal subjects and to be involved in the pathogenesis of OL (Rhodus 25). Authors proved that serum IL- 8 level is a sensitive marker in monitoring the disease activity of OL. Others. (owell 1986, Mahood 1983, Wang 211) found that the elevated TN- α serum levels may be associated with the induction and/or perpetuation of the apoptotic events in the OL epithelium and that TN-α concentrations varied in different clinical types of OL, being particularly elevated in the case of the Correspondingh Author: Maha M Mahmoud, Assistant professor, Alexandria University. Oral Medicine, eriodontology, Oral Diagnosis and Radiology Department,aculty of Dentistry.Alexandria, Egypt E-mail: mahamahmoud@hotmail.com

29 Maha M Mahmoud, 215 Advances in Natural and Applied Sciences, 9(23) July 215, ages: 28-34 erosive/atrophic form of the disease. Moreover, other investigators (ujita29, Bai 27, 29, Liu 214) identified the positive influence of inflammatory cytokine, including, TN-α, and IL-8 in the prognosis of OL. the psychosomatic stressors being discussed as one of the causative factors Since the description of lichen planus ( Wilson 1869 ). Later on, authors found a significant difference in the mental disturbance between OL and non-ol patients ( Hampf 1987 ). More recently, it was found that OL patients exhibited greater anxiety than controls, but could not establish a causal relationship between them (Rojo-Moreno 1998). A sycho-neuro-immunological researches demonstrated clinically relevant interrelations between psychological stressors & the onset and progression of chronic diseases. Disturbances in the interaction between the nervous, immune and endocrine systems have been hypothesized to be implicated in several autoimmune diseases (Koraya 23). Several studies supported the opinion that psychological distress can participate with the onset, exacerbation or recurrence of OL (Soto 24, McCartan 1995, Chaudhary 24, Kalman 24, Rabiei 212). While others could not confirm such association. They reported that stressful events usually preceded developmental of OL (Allen 1986, Goldberg1997, Takai 1995, Rojo-Moreno 1998, Rodestrom 21). Thus the current study was performed to evaluate serum pro-inflammatory cytokines levels correlating them with stress profile in patients with erosive oral lichen planus (EOL). Subjects and methods: Thirty participants were selected from the outpatient clinic of oral medicine & periodontology department, faculty of dentistry, Alexandria University. All selected patients were diagnosed with erosive oral lichen planus lesions (EOL) clinically and confirmed by histopathological examination according to modified WHO criteria (van der Meij and Van der Wall 23). patients were otherwise systemically healthy. Any psychiatric illness, and those who are taking anti-depressives as well as any systemic medications for the previous 3 months of sample collection were excluded patients with other skin, mucosal or systemic diseases and regnant women or women using oral or injectable contraceptives were excluded. Materials: AviBion Human TN-α ELISA Kit AviBion Human IL-8 ELISA Kit Methods : 1- ull history was obtained including name, age, onset, symptoms, medical history, drug history, any extra-oral lesions and any previous treatments for L. 2-atients were informed about the nature and objectives of the study, read, approved and signed a written informed-consent form. 3-atients with EOL were evaluated according to Hospital Anxiety and Depression Questionnaire(HADS (Zigmond 1983). accordingly, the selected thirty patients will be divided into three groups as follow: Group A:1 patients with EOL with ( HADS)scores of 11 considered abnormal or high stress value. Group B: 1 patients with EOL with ( HADS) scores of 8-1, considered as borderline or moderate stress value. Group C: 1 patients with EOL with ( HADS) scores of -7 considered as normal or low stress value. 4- Clinical examination: Lesion scores: Lesions were examined clinically according to the criteria of Thongprasom et al 23, where : Score No lesion/normal mucosa Score1 Mild white striae only Score2 White striae with erythematous area < 1cm 2 Score3 White striae with erythematous area >1cm 2 Score4 White striae with erosive area < 1cm 2 Score5 White striae with erosive area > 1cm 2 A ruler and a sterile graduated (figures 1&2)periodontal probe will be used to measure the size of the most sever erythematous area in mm Visual Analogue Scale (Huskisson 1976). The severity of pain and pain sensation will be evaluated according to following scales Scale : no pain: VAS= Scale 1: mild pain: < VAS 3.5 Scale 2: moderate pain: 3.5 <VAS 7 Scale 3: severe pain: 7<VAS 1 (Thongprasom 1992).4- Sample collection: Venous blood samples (5ml) were collected from the antecubital fossa from all subjects. The whole blood samples collected were transferred to tubes, without using anticoagulants,and sent to the laboratory of the Department of Clinical athology, aculty of Medicine, Alexandra University. Blood samples ware left for 3 minutes to clot, and then the blood was centrifuged at 2, rpm for 15 minutes. The yellow serum layer was pipetted off without disturbing the white buffy layer. Serum was then stored in -8 C till analyzed. Determination of IL-8 and TN-α assay : Concentrations of serum TN-α and IL-8 will be determined using the Human TN-α ELISA Kit and

3 Maha M Mahmoud, 215 Advances in Natural and Applied Sciences, 9(23) July 215, ages: 28-34 Human IL-8 ELISA Kit respectively (Hotamisligil 1998). The assay will be performed according to the manufacturer's instructions. Results: The results of the present study showed a statistically significant increase in the mean value of stress, anxiety and depression between all the studied groups (<1) table I. According to the VAS scores, results showed a statistically significant increase in VAS scores in relation to group A(high stress values group) when compared to group B(moderate stress values group) and group C (as a normal stress values group) respectively and statistically significant increase in relation to group B when compared to group C (1>4, <1) table II. According to the lesion size, there was a statistically significant increase in the lesion size in group A when compared to both group B and C, and in group B when compared to group C.( p 1 =18, <1) table III. According to the serum level of proinflammatory cytokines IL-8 and TN-α, ther was a statistically significant increase in both group A and group B when compared to group C and in group B when compared to group C. (<1) Table IV and V. Discussion: Lichen planus is a common multifactorial disease. Immunological mechanisms are fundamental in the initiation and perpetetuation of L (Scully 28, Zhou 21). Although the etiology and pathogenesis of OL are not fully understood, oral lichen planus has been associated with multiple disease processes and agents, such as viral, bacterial infections, autoimmune diseases, medications and vaccinations (Rubaci 212, Ertugrul 213, Tavassol 28). Lately, it is generally agreed that OL is associated with various psychogenic factors, the most frequent psychogenic conditions which may lead to it are depression, anxiety and stress (Sreedhar 24). The present study results showed statistically significant increase in the clinical features represented by lesion size and VAS scores in relation to the high stress values group A when compared to group B and group C respectively. ig. 1: lichen planus lesion size measurement. ig. 2: sterile graduated periodontal probe and ruler used for lesion measurement. Table I: The mean values of anxiety and depression scale of the three groups. Group A Group B HDA Scale Anxiety Min Max Mean ± SD Median Sig.bet.Groups Depression Min.- Max. Meab±SD Median 14.-18. 16.2±1.32 16. 11.-16. 13.1±1.52 13. 9.-1 9.5±.53 9.5 1 >1*,p2>1*,p3>1* 8.-1 8.5±.71 8. Sig.bet.Groups 11>1*,p2>1*,p3>1* : test (ANOVA) 1: value for ost Hoc Test (LSD) for comparing between Group A and Group B. 2: value for ost Hoc Test (LSD) for comparing between Group A and Group C. 3: value for ost Hoc Test (LSD) for comparing between Group B and Group C. *: Statistically significant at p 5 **: Sig. bet. Grps: significant between groups. Group C 6.-7. 6.8±.42 7. 4.-7. 5.5±.85 5.5 321.3* >1* 124.25* >1*

31 Maha M Mahmoud, 215 Advances in Natural and Applied Sciences, 9(23) July 215, ages: 28-34 Table II: The mean pain scores in the three groups. Group A Group B Group C VAS No. % No. % No. % VAS No pain() Mild(1) 6 4 Moderate (2) 6 4 6 6 Severe (3) 1 4 1 4 Sig.between. Groups Min.- Max. Meab±SD Median 3.-3. 3±1. 3. 1 >1*,p2>1*,p3>27* 2.-3. 2.4±.52 2. Sig.between. 1>4*,p2>1*,p3>6* Groups χ 2 Chi square Monte carlo test sig. between groups. KW χ 2 : Chi equare for Kruskal Wallis test, sig. between groups using Mann Whitney test. 1: value for comparing between Group A and Group B. 2: value for comparing between Group A and Group C. 3: value for comparing between Group B and Group C. *: Statistically significant p 5 **: Sig. bet. Grps: significant between groups. 1.-2. 1.6±.52 2. Test of significance χ 2 24.237* KW χ 2 = 2.337* MC >1* >1* Table III: The mean lesion size score of the three groups. Lesion Size (cm 2 Group A Group B Group C Lesion Size (cm 2 ) Min.-Max. 4.-5. 3.-5. 2.-4. Mean±SD 4.7±.48 4.±.67 2.6±.7 Median 5. 4. 2.5 Sig. bet. Groups p 1=18 *, p 2=1 *, p 3<1 * : test (ANOVA) p 1: p value for post Hoc Test (LSD) for comparing between Group A and Group B. p 2: p value for post Hoc Test (LSD) for comparing between Group A and Group C. p 3: p value for post Hoc Test (LSD) for comparing between Group B and Group C. *: Statistically significant at p 5. **: Sig. bet. Groups: significant between groups. Table 1V: Comparison between three studied groups according to Interleukin-8. High stress Moderate stress Interleukin-8 Mild stress Min. Max. 43.2 75.5 2.4 42.4 2.9 13.1 Mean ± SD. 56.17 ± 1.92 31.6 ± 7.18 7.61 ± 3.88 Median 52.1 31.1 6.65 Sig. bet. Groups p 1<1 *, p 2 <1 *, p 3 <1 * : test (ANOVA) p 1: p value for ost Hoc Test (LSD) for comparing between High stress and Moderate stress p 2: p value for ost Hoc Test (LSD) for comparing between High stress and Mild stress p 3: p value for ost Hoc Test (LSD) for comparing between Moderate stress and Mild stress *: Statistically significant at p 5 Table V: Comparison between three studied groups according to TN- α. High stress Moderate stress TN- α Mild stress Min. Max. 19. 3.2 9.7 17. 1.9 9. Mean ± SD. 25.95 ± 3.74 12.54 ± 2.34 4.61 ± 2.58 Median 26.54 12.65 3.95 Sig. bet. groups p 1<1 *, p 2 <1 *, p 3 <1 * : test (ANOVA) p 1: p value for ost Hoc Test (LSD) for comparing between High stress and Moderate stress p 2: p value for ost Hoc Test (LSD) for comparing between High stress and Mild stress p 3: p value for ost Hoc Test (LSD) for comparing between Moderate stress and Mild stress *: Statistically significant at p 5 29.4* <1* 95.185 * <1 * 133.625 * <1 * The is in line with several investigators who found a positive correlation between stress scores, and clinical features and manifestations of OL giving an evidence that stress could aggravate the signs and symptoms of EOL as visual analogue scale(vas)and lesions size scoring (Shetty 21, Girardi 211 ). Additionally, Evidences showed that stressful life events and psychological agents could

32 Maha M Mahmoud, 215 Advances in Natural and Applied Sciences, 9(23) July 215, ages: 28-34 play a role in development and exacerbation of skin 1995)demonstrated that L develops in relation to stress, emotional events and stressful life events that could exacerbate both skin and oral lesions with more severe symptoms and eruption of new lesion (Girardi 211, Lami 25). The results of the present study showed also a statistically significant increase in the serum level of pro-inflammatory mediators IL-8 and TN-α, in relation to high stress values group A and moderate stress values group B when compared to normal stress values group C. These results are in accordance with Chiappelli et al.,1992,1994 in their study where they found a significant positive correlation between the psychological status and the ratios of lymphocytes in patients with L. This finding is parallel with the associations between stress and immune response observed in OL and provides support that OL also involves psycho-physiological and immune changes that can be of significance for its onset and course. The results of present study could be explained by previous studies that found a close correlation between central nervous system (CNS) and immune system. The immune system cells are found to express some receptors for many molecules such as neurotransmitters, neuropeptides and steroid hormones, that are modulated by nervous system, thus they could play an important role in health maintenance or disease development. In OL the stressful situation may cause the HA-axis to release corticosteroids; simultaneously there are psychoneuro-immunologic interactions that ultimately stimulate lymphocytes to release various cytokines important in OLbdevelopment ( Lundqvist 26), Valter 213). Neuro-endocrine hormones triggered during stress may lead to immune dysregulation or altered or amplified cytokine production, resulting in autoimmune diseases (Miller 1995). Corticosteroids used in management of immune mediated diseases is mainly due to the effects of cortisol on immune system inhibiting the inflammatory response through suppressing synthesis and decreases the release of a number of inflammatory mediators and they decrease leukocyte emigration into inflamed sites,also decreases differentiation and proliferation of local mast cells, while suppress immune response by decreasing the number of circulating T4 lymphocytes and by decreasing the production of interleukins (IL) and & - interferon that are critical mediators of immune response. Although cortisol also decreases recruitment and activation of B lymphocytes, its main effects are exhibited on cell-mediated immunity (Herold MJ 26, Holsboer 1997, Miller 1995). Moreover, a randomized clinical trial studied the effect of using psychological drug therapy for 6 months in OL patients comparing them with control group and at end of study,they found significant decrease in the size of the lesions. Hence the authors recommended the combination of psychiatric drug therapy and routine treatment of OL (Delavaian et al. 21). Based on these results several investigators recommended the use of psychotherapy in adjunct to OL treatment for reducing pain and the lesion size (Schiavone 212, Mollaoglu 2, Seoane 24). The effect of stress on immune system is mediated by a complex network of signals that function in a bidirectional manner in the nervous, endocrine, and immune systems. The mediators of these interactions are mainly neurotransmitters, neuropeptides, hormones, and cytokines. Neuroendocrine hormones triggered during stress may lead to immune dysregulation or altered or amplified cytokine production, resulting in autoimmune diseases(elten 1994). 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