Development Of Gingival Overgrowth Research Articles

Local and Systemic Effects of Cyclosporine A on the Severity of Gingival Overgrowth in Post-Transplant Renal Patients.

Background:Cyclosporine A (CsA) is a potent immunosuppressant widely used to prevent renal post transplantation rejection. Gingival overgrowth (GO) is among various side effects of the long-term administration of CsA. Up to 90% of the patients under CsA therapy has been reported to develop CsA-induced GO.Objectives:The aim of the present prospective pilot study is to determine the local and systemic effects of Cyclosporine A (CsA) on the severity of gingival overgrowth and its relationship with periodontal parameters in post-transplant renal patientsMethods:Twenty post-transplant renal patients, 12 females and 8 males, presenting gingival overgrowth were selected from Rizk Hospital’s clinic in Beirut. Patient’s CsA plaque levels were evaluated when CsA is administered by syrup and capsules mode. Periodontal parameters including gingival overgrowth, papillary bleeding, plaque and gingival indices were assessed for all patients.Results:Plaque concentration CsA levels, when administered in syrup mode, affected significantly the severity of gingival overgrowth as opposed to the administration by capsule mode. Significant correlations between severity of gingival overgrowth on one hand and plaque index, gingival index, and papillary bleeding index on the other hand were only observed in the Capsule group but not in the syrup group. A significant relationship was established between the severity of gingival overgrowth and all periodontal parameters (gingival, papillary and plaque).Conclusion:The present study underlines CsA dental plaque local effect, as a co-factor, in the development of gingival overgrowth. Cyclosporine plaque accumulation acts as a reservoir in the gingival inflammation and the periodontal indices seem to be the most accurate parameters associated with gingival overgrowth severity. Plaque CsA concentrations could be considered as a risk factor for inflammation and gingival overgrowth depending on CsA delivery mode in renal transplant patients.

The multifactorial aetiology of gingival overgrowth: a case report illustrating diagnosis and management

Gingival overgrowth is the enlargement of gingival tissues and has various underlying aetiological factors. This case report highlights the multifactorial aetiology of gingival overgrowth for a patient who was prescribed an immunosuppressive strategy following renal transplantation, had poor levels of oral hygiene and a diet deficient in fruit and vegetables. The report highlights the importance of a detailed assessment to identify all underlying factors and demonstrates how a referral to the specialist services for gingival overgrowth led to a diagnosis of vitamin C deficiency. It also illustrates how both patient engagement and a conservative cause-related therapy can achieve a satisfactory resolution without any surgical intervention. CPD/Clinical Relevance: This case report highlights the importance of a detailed assessment to diagnose all relevant underlying aetiological factors involved in the development of gingival overgrowth. It also illustrates how both patient engagement and a conservative cause-related therapy can achieve a satisfactory resolution of gingival overgrowth without any surgical intervention.

Relationship between periodontal inflammation and calcium channel blockers induced gingival overgrowth-a cross-sectional study in a Japanese population.

Periodontal inflammation is regarded as a risk factor for drug-induced gingival overgrowth (DIGO). In order to elucidate the involvement of periodontal inflammation in DIGO, the periodontal status of subjects who do not develop DIGO despite receiving causative drugs (non-responders) needs to be examined. Therefore, the aim of the present study which was a pilot study was to assess periodontal inflammatory variables in responders (calcium channel blocker induced-GO patients), non-responders, and patients who did not receive causative drugs (non-consumers). The following parameters were measured: (1) existence of gingival overgrowth, (2) number of teeth, (3) mean periodontal pocket depth (PPD), and (4) percentage of positive sites for bleeding on probing (BOP). The periodontal inflamed surface area (PISA) and periodontal epithelial surface area (PESA) and the PISA/PESA ratio which indicated the degree of periodontal inflammation in each patient were also used to evaluate periodontal inflammation. Thirteen responders, 32 non-responders, and 83 non-consumers were included in the analyses. The mean PPD, percentage of BOP, PESA, and PISA, and the PISA/PESA ratio were significantly higher in responders than in non-responders and non-consumers (p < 0.01). The BOP, PISA, and PISA/PESA ratio were significantly lower in non-responders than in non-consumers (p < 0.05). A positive correlation was found between PPD and age in non-consumers. On the other hand, a negative correlation was noted between PPD and age in non-responders. Periodontal inflammation may be associated with the initiation of DIGO. It could be speculated that periodontal therapy before the administration of calcium channel blockers may prevent the development of gingival overgrowth.

Systematic review of cyclosporin A-induced gingival overgrowth and genetic predisposition.

This systematic review aimed to investigate the influence of gene polymorphisms on the development of gingival overgrowth in renal transplant patients treated with cyclosporin A. Electronic and hand literature searches were conducted by two independent reviewers in MEDLINE-Pubmed, Cochrane Library, ISI Web of Science, and SCOPUS Elsevier for prospective (case-control studies, cohort studies), cross-sectional, and retrospective studies published up to June 2016 (first week) in any language. Data were reviewed and extracted in duplicate independently. Methodologic quality assessment of the included studies was performed during the data extraction process. Due to the estimated high risk of bias and the heterogeneity of the included studies in regards to the variety of medications administered to study patients, a systematic review of the literature and not a meta-analysis of the data was performed. Fourteen articles meeting study inclusion criteria were selected for data extraction that examined the association between various genetic polymorphisms and gingival overgrowth in kidney transplant patients receiving cyclosporin A. Interleukin-1A, interleukin-10, transforming growth factor-β1 and androgen receptor gene polymorphisms may have a significant effect on an individual susceptibility to cyclosporin A-induced gingival overgrowth in renal transplant patients. Genetic polymorphisms seem to affect the development of cyclosporin A-induced gingival overgrowth in renal transplant patients. Pharmacogenetics and pharmacogenomics have the potential to determine the clinical outcome of a medication, the drug efficacy, and adverse drug reactions such as gingival overgrowth.

Transglutaminase 2 May Be Associated with Peri-implant Gingival Overgrowth: Preliminary Assessments.

Tissue transglutaminase 2 (TG2) is ubiquitously expressed in normal tissues and plays an important role in the pathophysiology of wound healing. An increase in periodontal tissues has been previously reported in cyclosporine-induced gingival overgrowth. The aim of this study was to explore associations between TG2 expression and the vascularization and maturation processes of peri-implant soft tissues over time. Edentulous patients proposed for mandibular implant-retained overdentures were included in the study. Biopsies of the peri-implant mucosa were performed at the first surgical stage and at 4, 8, and 12 months after prosthetic load. A follow-up program was directed to record plaque indexes, bleeding on probing data, and pocket probing depth around implants. An evaluation of the vessels' density was carried out by digital virtual microscopy and using an immunohistochemistry approach (antibodies anti-CD31, anti-TG2). A robust multivariable regression model was implemented. According to model results, blood vessel count and probing (as a marker of gingival overgrowth in absence of plaque) significantly decrease over time and are associated with TG2, particularly for values above the median. The association of an increased TG2 expression in the extracellular matrix might have a significant impact in the development of gingival overgrowth around a loaded implant.

Effect of concomitant administration of nifedipine and tacrolimus on the development of gingival overgrowth in rats

Background/purposeIt is still controversial whether tacrolimus can induce gingival overgrowth. Calcium channel blockers of nifedipine are commonly used for lessening the side effect of high blood pressure induced by tacrolimus; however, nifedipine can also induce gingival overgrowth. This study was conducted to evaluate the effect of concomitant administration of nifedipine and tacrolimus on gingival overgrowth in rats. Materials and methodsThirty-six Sprague-Dawley rats were assigned into four groups, including a control group. In drug groups, either tacrolimus (1.5 mg/kg) or nifedipine (30 mg/kg), or both drugs together were administrated daily for 6 weeks. The gingival morphology was examined macroscopically on the mandibular central papilla from cast models biweekly, and analyzed by measuring the sulcular probing depth and the keratinized gingival width around the first mandibular molars immediately after sacrificing. By histology, changes of papillae, including the connective tissue, and the epithelial and total tissue areas, were measured at two different tissue levels. ResultsSignificant increases in papillary dimensions, including depth, width, and height, were observed across all groups after Week 1, with the control group showing less changes than experimental drug groups. Among drug groups, significantly increased papillary dimensions were noted in the nifedipine group when compared with groups treated with tacrolimus and both drugs. Changes in keratinized gingival width were found to be similar in the tacrolimus and combined-drug groups but greater in the nifedipine group. For probing depth, experimental groups showed greater changes than the control group, but no difference was observed among the experimental groups. Similar trends were presented for the total and connective tissue areas; however, the epithelial tissue areas did not show any difference among the four treatment groups. ConclusionGingival overgrowth could be induced either by nifedipine or by tacrolimus, although the extent of gingival overgrowth induced by tacrolimus would be less than that by nifedipine. However, a concomitant administration of nifedipine and tacrolimus did not aggravate the induced gingival overgrowth.

Curcumin Inhibits Thrombin‐Stimulated Connective Tissue Growth Factor (CTGF/CCN2) Production Through c‐Jun NH2‐Terminal Kinase Suppression in Human Gingival Fibroblasts

Connective tissue growth factor (CTGF/CCN2), associated with multiple human fibrotic diseases, is overexpressed in the tissue of gingival overgrowth. Although surgical excision is the current treatment modality for gingival overgrowth, the recurrent rate is high despite proper recall programs. Thrombin plays a key role in wound repair, remodeling, and fibrosis after injury and exerts profibrotic effects by activating protease-activated receptors (PARs). Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a natural plant phenolic compound that possesses both anti-inflammatory and antioxidant properties. This study investigates the signaling pathway of thrombin-induced CCN2 expression and inhibition of CCN2 expression by curcumin. The signaling pathway of thrombin-induced CCN2 expression in human gingival fibroblasts (HGFs) was studied using Western blot analysis. The CCN2 mRNA level was determined by quantitative reverse transcription-polymerase chain reaction. Thrombin induced CCN2 expression in HGFs by activating PAR1. Pretreatment with antioxidant N-acetyl-l-cysteine, apoptosis signal-regulating kinase 1 (ASK1) inhibitor thioredoxin, and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) significantly reduced thrombin-induced CCN2 expression in HGFs. Curcumin dose dependently inhibited thrombin-induced CCN2 expression through JNK suppression in HGFs. The results of this study suggest that thrombin-induced CCN2 expression may occur through PAR1, reactive oxygen species, ASK1, and JNK signaling in HGFs. Curcumin could effectively inhibit CCN2 expression through JNK suppression. These signaling events are important for wound healing and fibrosis. Additional research, including animal studies, is required to confirm the inhibiting role of curcumin in the development of gingival overgrowth.

Analysis of changes in gingival contour from three‐dimensional co‐ordinate data in subjects with drug‐induced gingival overgrowth

This aim of this study was to develop and assess a technique that could be used to assess accurately the gingival volume changes seen in drug-induced gingival overgrowth by the analysis of data obtained from an entire gingival surface by means of three-dimensional imaging. Stone dental models of patients before and after gingivectomy procedures were digitized with a laser scanner and then regenerated as computer models constructed from the acquired three-dimensional co-ordinate data. A comparison of superposed "before" and "after" surfaces was undertaken to assess and accurately quantify changes in gingival contour. The mean vertical tissue reduction varied from 1.58 to 2.56 mm in the four study subjects and individual differences are shown. The maximum thickness of removed buccal gingival overgrowth was found to range between 1.20 and 3.40 mm. The volume of tissue removed from each inter-dental papilla ranged from 4.2 to 46.1 mm3 and the mean volume of the papilla removed from each subject+/-SD values was 24.8+/-13.1 mm3. This method will measure changes in gingival tissues to within 60 microm in one plane, making it ideal for the assessment of longitudinal changes in gingival contour as seen in the development of gingival overgrowth, its recurrence after surgery or the changes in volume brought about by surgery.

Cyclosporin A Specifically Affects Nuclear PLCβ1 in Immunodepressed Heart Transplant Patients with Gingival Overgrowth

One of the most commonly observed adverse effects of cyclosporin A (CsA) is the development of gingival overgrowth (GO). Fibroblasts are involved in GO, but the question why only a percentage of patients undergoing CsA treatment shows this side-effect remains unanswered. In a previous study, CsA has been demonstrated to induce over-expression of phospholipase C (PLC) beta(1) in fibroblasts of patients with clinical GO, in cells from both enlarged and clinically healthy gingival sites. In this work, we assessed the expression of PLCbeta isoforms to investigate whether the exaggerated fibroblast response to CsA related to increased PLCbeta(1) expression could also be detected in CsA-treated patients without clinical signs of GO. Our results support the hypothesis of a multi-factorial origin of gingival overgrowth, including specific changes within the gingival tissues orchestrating fibroblastic hyper-responsiveness as a consequence of a long-term in vivo exposure to cyclosporin A.

Análise quantitativa dos tecidos gengivais de ratos tratados com fenitoína e ciclosporina

Os aumentos gengivais podem ser decorrentes de reações teciduais a estímulos idiopáticos, patológicos e farmacológicos. O objetivo desse trabalho foi avaliar morfometricamente e estereologicamente a ação da fenitoína (Fen) e ciclosporina (CsA) sobre os tecidos gengivais de ratos. Dez ratos receberam, por via intraperitonial, Fen na dose inicial de 2 mg/kg de peso corporal/dia, aumentando 2 mg a cada duas semanas, durante 60 dias. Em outros 10 ratos, administraram-se, por via subcutânea, 10mg/kg de peso corporal/dia de CsA, durante o mesmo período do grupo anterior. Os valores morfométricos e estereométricos dos tecidos gengivais dos ratos tratados com CsA foram significativamente maiores quando comparado com os valores dos tecidos gengivais do grupo tratado com Fen. Esses resultados sugerem que a CsA na dose utilizada é mais eficaz no desenvolvimento do aumento gengival em ratos, podendo estar atuando na proliferação de fibroblastos e no desequilíbrio fisiológico da síntese de fibras colágenas.

Regulation of gingival fibroblast interleukin-6 secretion by cyclosporine A.

Cyclosporine A (CsA) is a widely used immunosuppressant, with clinical applications ranging from organ transplants to chronic inflammatory diseases. One of the side effects associated with CsA treatment is the development of gingival overgrowth. Exuberant growth of connective tissue within the periodontium can result from hyperactivity of resident fibroblasts. Fibroblasts are capable of secreting interleukin-6 (IL-6), which has been shown to enhance proliferation as well as collagen and glycosaminoglycan synthesis by these cells. We tested the hypothesis that one of the pathogenetic mechanisms underlying CsA-induced fibrosis is an enhanced IL-6 secretion by gingival fibroblasts (GF) in response to this drug. The ability of CsA to upregulate GF IL-6 secretion alone or in combination with bacterial challenge or other inflammatory cytokines was tested in an in vitro system. Fibroblast cultures were established from systemically healthy gingival tissue donors and were challenged with CsA in the absence or presence of bacteria, IL-1beta, or tumor necrosis factor (TNF) alpha as co-stimulants. Nifedipine and phenytoin were also tested to further support findings with CsA. After 72 hours of incubation, culture supernatants were collected and analyzed for IL-6 content by ELISA. We have shown that GF respond to CsA with an increase in IL-6 secretion. The magnitude of this response varies among cultures derived from different tissue donors. We have also demonstrated that GF IL-6 responses to bacterial challenge or TNFalpha are downregulated by CsA. However, CsA synergizes with IL-1beta to further upregulate IL-6 secretion, and this effect is shared by phenytoin and nifedipine. We conclude that one of the pathogenetic mechanisms underlying drug-induced gingival overgrowth may be enhanced secretion of IL-6 by GF in response to these medications. This is the first report on direct and indirect effects of gingival overgrowth-related medications on GF IL-6 metabolism. This work will lay the foundation for future studies directed towards the development of prevention or treatment modalities for gingival overgrowth based on blocking the fibrogenic activities of IL-6 at the cellular level.

The clinical effects of nifedipine on periodontal status.

The present study was conducted to determine the clinical effects of nifedipine on the gingiva of 97 patients. Patients were examined for changes in periodontal status and divided into subgroups, based on their age, gender, duration of drug intake, presence/absence of plaque and gingival inflammation, and according to the presence and severity of gingival overgrowth. Gingival overgrowth was noticed in 29% of the patients. Among the recorded parameters, duration of drug intake, presence/severity of gingival inflammation, and gender seemed to have the greatest effect on the development of gingival overgrowth. Patients with higher gingival inflammation scores, those on nifedipine medication for more than 4 years, and males were likely to have an increased tendency for higher incidence and severity of gingival overgrowth. The findings of the present study suggest that nifedipine medication induces gingival overgrowth and that certain local factors are involved in the pathogenesis of drug-induced gingival overgrowth. However, individual ability and sensitivity to metabolize the drug and its metabolites also seem to be important etiological factors.

Determination of nifedipine in gingival crevicular fluid: a capillary gas chromatographic method for nifedipine in microlitre volumes of biological fluid

This paper describes a sensitive capillary gas chromatographic (GC) method for the determination of nifedipine in sub-microliter samples of gingival crevicular fluid (GCF) in order to assess if nifedipine is present in the GCF and if so, whether the local tissue concentrations of this drug are an important determinant in the development of gingival overgrowth. Liquid—liquid and solid-phase extraction were combined to give adequate sample clean-up and concentration for measurement by automated capillary GC with electron capture detection. Nifedipine and its principal metabolite, M-I, were analysed in both plasma and GCF in 9 adult male patients who had been taking nifedipine for over six months. M-I could not be measured in GCF. Plasma nifedipine and M-I levels were nomal, but the nifedipine levels found in the GCF of 7 patients (including all those with overgrowth) were remarkably elevated, 15 to 316-fold greater. This massive concentration of nifedipine into the GCF is therefore linked with gingival overgrowth. This is the first time that a GC method has been developed which permits determination of GCF pharmacokinetics of a drug which causes gingival overgrowth, and further investigation will lead to a better understanding of the tissue mechanisms involved.

Influence of phenytoin on cytoplasmic free Ca2+level in human gingival fibroblasts

Influence of 5,5-diphenylhydantoin (phenytoin; PHT) on the cytoplasmic free Ca2+ concentration, [Ca2+]i, was studied in fura 2 loaded adherent monolayers of human gingival fibroblasts derived from three patients before and after 9 months of PHT therapy. In the patient where gingival overgrowth developed during PHT medication (responder), addition of PHT to gingival fibroblasts derived before PHT medication induced a transient extracellular Ca2+ dependent increase in [Ca2+]i. In a non-responder patient, where gingival overgrowth did not develop during the same period of PHT therapy, addition of PHT to gingival fibroblasts derived before the start of medication did not significantly affect [Ca2+]i. Under extracellular Ca2+ deficient conditions, addition of PHT to serum-starved fibroblasts derived from the two categories of patients before the medication resulted in an increase in [Ca2+]i. In fibroblasts derived from the responder patient during PHT medication, in contrast to those from the non-responders (n = 2), the basal level of [Ca2+]i was significantly decreased. The results indicate that, in the cases studied, there is a relationship between PHT induced alterations in [Ca2+]i in gingival fibroblasts and the clinical development of gingival overgrowth.

Cyclosporine-induced gingival overgrowth in beagle dogs.

Development of gingival overgrowth during daily long-term cyclosporine A treatment was studied in 2-yr-old beagles. Gingival enlargement developed in five of 12 dogs (42%), primarily in the mandibular anterior area. The earliest gingival changes occurred by 3 wk as an increase in the size of the interdental papillae. The lesions progressively became more severe, in some cases obscuring portions of teeth by wk 6. The redundant tissue exhibited an increase in connective tissue components and an inflammatory infiltrate primarily of plasma cells. Severity of the overgrowth varied in responding animals; both incidence and severity were related to the CSA concentration in blood. The mean CSA blood levels of responders were significantly greater than nonresponders at wk 3, 6 and 10. Since beagles develop gingival overgrowth similar to humans, they provide an excellent model to investigate the roles of local and systemic factors in the induction of gingival overgrowth.

Phenytoin induces interleukin-1 production in vitro

Human adherent mononuclear cells and subcloned cell lines established from the human histiocytic cell line U-937 were cultured with phenytoin (PHT) and/or lipopolysaccharide (LPS) purified from Bacteroides fragilis . After the cultivation period, the cell-free supernatants were tested for interleukin-1 (Il-1) activity. The results showed that PHT induces Il-1 activity and potentiates LPS-induced Il-1 production. In the monocytic cell line U-937, the induced Il-1 production was found to be clonally distributed indicating that the response to PHT may be exerted by a subpopulation of monocytes. The PHT-induced Il-1 activity may be of importance in the development of gingival overgrowth. The induced Il-1 could also contribute to other known side effects such as dermatologic reactions accompanied by transient fever seen in patients medicating the drug.