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Objectives This study analyzed the role of the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) pathway in dihydropyridine-induced gingival overgrowth (DIGO) fibroblasts. Materials and methods Tissue samples were obtained through surgical dissection from five DIGO patients and five healthy individuals. Cell cultures were conditioned with nifedipine (Nif) (0.34 M) and stimulated with IL-1 (10 ng/mL) to clarify whether IL-6 upregulates extracellular matrix overproduction or has a an impact on the cell proliferation rate of DIGO fibroblasts. STAT3 was knocked-down using short hairpin (sh)RNA to determine its role in collagen (Col) type-I alpha 1 (Colα1(I)) synthesis. Results Results showed that phosphorylated (p)STAT3 nuclear translocation was activated by a simulated autocrine concentration (50 ng/mL) of IL-6, and application of an anti-IL-6 antibody significantly decreased the pSTAT3/STAT3 ratio in DIGO fibroblasts. STAT3-knockdown significantly decreased STAT3 and Colα1(I) expressions in DIGO cells. DIGO tissues presented stronger proliferating cell nuclear antigen (PCNA) expression than did healthy individuals under the effect of IL-1β/Nif treatment. Conclusions Gingival inflammation (e.g., IL-1β) and taking dihydropyridine (e.g., Nif) may additively stimulate Col overproduction through the IL-6-STAT3-Colα1(I) cascade in DIGO cells. IL-6-STAT3 signaling may be considered a target for the control of DIGO.

Objective The purpose of this study was to evaluate the occurrence rate of drug-induced gingival overgrowth (DIGO) in patients treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) such as amlodipine, lercanidipine, and benidipine, as well as to assess the relationship of those mentioned above with medication variables and oral hygiene. Methods Sociodemographic details, DIGO, and clinical periodontal parameters were obtained from one hundred and thirty-one patients receiving ACE inhibitors, ARBs, and CCBs for a period of at least 2 years. Results The occurrence rate of DIGO was 19.6% in patients using CCB, 12.5% in the ARB group, and 7.5% in the ACE inhibitor group. In a subgroup analysis of CCBs, DIGO was found to be 31.8% in the amlodipine group, 13.3% in the lercanidipine group, and 7.1% in the benidipine group. While there was a significant relationship between amlodipine drug dosage and DIGO, no association was found between the duration of therapy and DIGO in all CCB subgroups. Conclusion There was no difference between the groups in terms of DIGO. Duration of therapy and drug dosage did not affect the severity of DIGO in both ACE inhibitors and ARB groups.

Myofibroblasts represent specific subpopulations of cells with important roles in tissue remodeling in both health and disease. They are not usually found in resting healthy tissues. However, they increase in number during the proliferative phase of wound healing. In these conditions, myofibroblasts secrete and organize different molecular components of the extracellular matrix that with time will reconstitute and hopefully regenerate the damaged tissue. Importantly, these cell populations must be eliminated after wound healing has been completed. However, deficiencies in their differentiation or the persistence of this cell population has been associated with the development of delayed wound healing and fibrosis, respectively. In the present review, we analyze the involvement of myofibroblasts in periodontal wound healing and their potential contribution to tissue homeostasis and disease.

Objective In this study, we investigated the role of phenytoin (PHT) in death receptor-induced apoptosis of gingival fibroblasts to clarify the mechanism of PHT-induced gingival overgrowth. Methods Human gingival fibroblasts were cultured to semiconfluence and treated with PHT (0.025, 0.1, 0.25, and 1.0 μM) for 48 h, and then, the apoptotic cell numbers were relatively determined by absorptiometry. After 24 h of 0.25 μM PHT treatment, caspase activity was measured by absorptiometry, apoptotic and cell cycle phase distribution was analyzed by flow cytometry, expression levels of apoptotic genes were quantified by real-time qPCR, and expression of apoptotic proteins was detected by Western blot analysis. After 48 h of 0.25 μM PHT treatment, appearance of apoptotic cells was detected by TUNEL assay. Results PHT treatment decreased the proportion of apoptotic cells in gingival fibroblasts compared to a serum-free control culture in response to the protein changes as follows: PHT upregulated c-FLIP and, in turn, downregulated FADD, caspase-8, and caspase-3; PHT upregulated c-IAP2 and downregulated TRAF2; PHT downregulated caspase-9 and caspase-3 via decreased RIPK1 activity and increased Bcl-2 activity. Conclusion PHT-induced gingival overgrowth may result from the above-mentioned mechanisms involving apoptosis inhibition in gingival fibroblasts.

A number of idiopathic, pathological and pharmacological reactions may result in an overgrowth of the gingiva. This review concentrates on those overgrowths associated with various pharmacological agents. The pharmaco-kinetics and side effects of each drug associated with gingival overgrowth are discussed along with the clinical and histological features and treatment. By examining the possible pathogeneses for these overgrowths we propose a unifying hypothesis for the causation based around inhibition of apoptosis and decreased collagenase activity modulated by cytoplasmic calcium.

The present study was planned to analyze the effects of a 12-month non-surgical periodontal treatment on histologic and immunohistochemical features of cyclosporin A (CsA)-induced gingival overgrowth (GO).Gingival samples were collected from 21 liver transplant subjects exhibiting CsA-induced GO prior to, and 12 months after non-surgical periodontal therapy including oral hygiene instructions, scaling and 2-month recall appointments, and also from 18 healthy control subjects. Gingival biopsy specimens were stained with hematoxylin-eosin and monoclonal antibodies for vimentin, CD3 (T-lymphocytes), CD20 (B-lymphocytes), CD34 (endothelium) and Ki-67 (fibroblasts proliferation rate), using a streptavidin-biotin-peroxidase complex method.Total inflammatory cells, gingival vessels and fibroblast proliferation rate demonstrated significant reduction after non-surgical periodontal treatment (P0.0001) in overgrown gingiva, while B- and T-lymphocytes remained nearly unchanged (P = 0.61 and 0.33, respectively). At the 12-month evaluation no significant differences were found when comparing the gingival biopsies from CsA-treated patients and those from healthy controls (P0.05).Control of clinical inflammation by means of non-surgical periodontal treatment results both in lowering of inflammatory infiltrate and in changes in connective tissue composition. Thus, plaque-induced inflammation would seem to modulate the drug-gingival tissue interaction.A strict plaque control program play a pivotal role in the management of transplant patients exhibiting cyclosporin A-GO.

Department of Head and Neck Surgery, Heliopolis Hospital, Sa˜o Paulo,BrazilOBJECTIVE: The aim of this study was to determine theoral status of renal transplant recipients receivingcyclosporin A (CsA) or tacrolimus (FK-506) as immuno-suppressant.SUBJECTS AND METHODS: A total of 88 renal trans-plant recipients receiving CsA (63 men and 25 women,mean age 51.4 years) and 67 receiving FK-506 (57 menand 10 women, mean age 33.5 years) were included in thestudy. Donor type, histocompatibility, cold ischemia timeand prior delayed graft function were similar between thetwo groups. Demographics and pharmacological datawere recorded for all subjects.RESULTS: The results demonstrated that CsA caused agreater number of oral diseases. A greater number ofgingival overgrowth was present in patients treated withCsA. However, the combined use with calcium channelblockers increased the gingival overgrowth number. Theoccurrence of candida in saliva was observed in 80 renalrecipients treated with CsA and 20 treated with FK-506.The presence of squamous oral carcinoma (n ¼ 3) andherpes simplex (n ¼ 10) was observed in patients treatedwith CsA. These alterations were not observed in renalrecipients treated with FK-506.CONCLUSIONS: Renal recipients constitute a high-riskgroup for oral diseases, as they are immunocompro-mised. However, the FK-506 regime appears to ameli-orate this effect, compared with CsA. Adequate pre- andpost-transplant oral health care is recommended forthese subjects, irrespective of the time interval for whichthe drug is administered.Oral Diseases (2006) 12, 309–314Keywords: oral health; renal transplant; cyclosporin; tacrolimus

Objective: To investigate possible associations between platelet-derived growth factor (PDGF), PDGF receptor expression and macrophages in drug-induced and hereditary gingival overgrowth. Materials and Methods: Tissues from patients with drug-induced gingival overgrowth (DIGO) (n = 10) and hereditary gingival fibrosis (n = 10) were studied and compared with ‘control’ gingiva (n = 10). Expression of PDGF and its α and β receptors was investigated immunohistochemically and by RT-PCR. Macrophages were identified by immunostaining for CD68. Results: PDGF isoforms and receptors were detected in most cells within all specimens. There were no differences in the numbers of macrophages, or fibroblasts expressing PDGF or receptors, between groups. The level of PDGF expression by fibroblasts, determined by absorbance measurements, was similar between groups for PDGF A. Significantly lower levels of total PDGF and the receptors were detected in drug-induced overgrowth compared to those in hereditary fibrosis (P

Objectives: We investigated the relationship between phenytoin-induced gingival overgrowth (GO) and the harboring of periodontal bacteria. Materials and methods: Periodontal conditions and subgingival bacterial profiles were examined in 450 sites of 75 subjects. A polymerase chain reaction method was used to detect six bacterial species; Porphyromonas gingivalis (Pg), Actinobacillus actinomycetemcomitans (Aa), Tannerella forsythia, Treponema denticola (Td), Prevotella intermedia (Pi), and Prevotella nigrescens (Pn). Genetic variations of the Pg fimA gene were also examined. Bacterial occurrence was compared with the severity of GO, and alterations in the bacterial occurrence rate and quantities were monitored following periodontal treatment. Results: The occurrences of Aa, Td, Pi, Pn, and Pg with type II fimA (type II Pg) were significantly associated with the severity of GO. Td occurrence was reduced in association with gingival improvement following ultrasonic scaling, however, no such relationship was observed with Aa, Pi, Pn, and Pg. In addition, Pg and Pi markedly persisted after treatment. Clinical improvement of the sites, following an Er:YAG laser treatment, significantly associated with quantitative reduction of Pg in improved sites, however, not that of Pi. Conclusion: Type II Pg and Td were each found to have a significant relationship with the development and deterioration of GO.

Drug-induced gingival overgrowth (DIGO) is a disfiguring side effect of anti-convulsants, calcineurin inhibitors, and calcium channel blocking agents. A unifying hypothesis has been constructed which begins with cation flux inhibition induced by all three of these drug categories. Decreased cation influx of folic acid active transport within gingival fibroblasts leads to decreased cellular folate uptake, which in turn leads to changes in matrix metalloproteinases metabolism and the failure to activate collagenase. Decreased availability of activated collagenase results in decreased degradation of accumulated connective tissue which presents as DIGO. Studies supporting this hypothesis are discussed.

The incidence of gingival overgrowth among renal transplant patients treated with cyclosporine A ranges from 13% to 84.6%, and the overgrowth is not only esthetic but also a medical problem. We studied the determination of association between TGF-β1 (TGFB1) gene polymorphism and gingival overgrowth in kidney transplant patients medicated with cyclosporin A.Eighty-four kidney transplant patients with gingival overgrowth and 140 control transplant patients without overgrowth were enrolled into the case control study. TGFB1 polymorphism was determined using the PCR-RFLP assay for +869TC in codon 10 and +915GC in codon 25 as well as TaqMan real-time PCR assays for promoter -800GA and -509CT SNPs.In kidney transplant patients suffering from gingival overgrowth, mean score of gingival overgrowth was 1.38 ± 0.60, whereas in control subjects it was 0.0. The patients with gingival overgrowth were characterized by similar distribution of TGFB1 genotypes and allele in comparison to subjects without gingival overgrowth. Among 16 potentially possible haplotypes of TGFB1 gene, only four were observed in the studied sample of kidney transplant patients: G_C_T_G, G_T_C_G, G_C_C_C, and A_C_T_G, with similar frequency in patients with and without gingival overgrowth.No association between the TGFB1 gene polymorphism and gingival overgrowth was revealed in kidney transplant patients administered cyclosporine A.

Tacrolimus, an immunosuppressive drug used in organ transplantation, has been reported not to induce gingival overgrowth. However, prevalence studies are limited, and the methods used for assessing gingival overgrowth varies among studies.The purpose of this study was to evaluate the effects of up to 240 days of tacrolimus therapy on gingival tissues of rats.Rats were treated for 60, 120, 180 and 240 days with daily subcutaneous injections of 1 mg/kg body weight of tacrolimus. After histological processing, the oral and connective tissue, volume densities of fibroblasts (Vf), collagen fibers (Vcf) and other structures (Vo) were assessed in the region of the lower first molar.After 60 and 120 days of treatment with tacrolimus, gingival overgrowth was not observed. The gingival epithelium, connective tissue, as well as the values for Vf, Vcf, and Vo were similar to those of the control rats (P0.05). After 180 and 240 days of the treatment, gingival overgrowth was associated with a significant increase in the gingival epithelium and connective tissue as well as an increase in the Vf and Vcf (P0.05).Within the limits of the experimental study, it may be concluded that the deleterious side effects of tacrolimus on the gingival tissues of rats may be time-related.