scholarly journals Drug-Induced Gingival Overgrowth: The Effect of Cyclosporin A and Mycophenolate Mophetil on Human Gingival Fibroblasts

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 221 ◽  
Author(s):  
Dorina Lauritano ◽  
Giulia Moreo ◽  
Luisa Limongelli ◽  
Annalisa Palmieri ◽  
Francesco Carinci
Keyword(s):  
Extracellular Matrix ◽  
Cell Viability ◽  
Cyclosporin A ◽  
Chronic Administration ◽  
Immunosuppressive Drugs ◽  
Matrix Metalloproteases ◽  
Human Gingival Fibroblasts ◽  
Gingival Fibroblasts ◽  
Drug Induced ◽  
Gingival Overgrowth

Drug-induced gingival overgrowth may occur after a chronic administration of three classes of systemic drugs: Anticonvulsants, immunosuppressants, and calcium channel blockers. This study aimed to investigate how cyclosporin A and mycophenolate mophetil (immunosuppressive drugs) could interfere with human gingival fibroblasts functions, leading to gingival enlargement. Human gingival fibroblasts derived from the tissue of a 60-year-old female were cultured in a DMEME medium. A stock solution with 1 mg/mL of mycophenolate and 1 mg/mL of cyclosporine were prepared and dissolved in a DMEM medium to prepare a serial dilution at the concentrations of 5000, 2000, 1000, 500, and 100 ng/mL, for both treatments. Cell viability was measured using the PrestoBlue™ Reagent Protocol. Quantitative real-time RT-PCR was performed in order to analyze the expression of 57 genes coding for gingival fibroblasts “Extracellular Matrix and Adhesion Molecules”. Mycophenolate and cyclosporine had no effect on fibroblast cell viability at 1000 ng/mL. Both the treatments showed similar effects on the expression profiling of treated cells: Downregulation of most extracellular matrix metalloproteases genes (MMP8, MMP11, MMP15, MMP16, MMP24) was assessed, while CDH1, ITGA2, ITGA7, LAMB3, MMP12, and MMP13 were recorded to be upregulated in fibroblasts treated with immunosuppressive drugs. It has been demonstrated that gingival overgrowth can be caused by the chronic administration of cyclosporin A and mycophenolate mophetil. However, given the contrasting data of literature, further investigations are needed, making clear the possible effects of immunosuppressive drugs on fibroblasts.

scholarly journals Drug-Induced Gingival Overgrowth: A Pilot Study on the Effect of Diphenylhydantoin and Gabapentin on Human Gingival Fibroblasts

2020 ◽  
Vol 17 (21) ◽  
pp. 8229
Author(s):  
Dorina Lauritano ◽  
Giulia Moreo ◽  
Luisa Limongelli ◽  
Elena Tregambi ◽  
Annalisa Palmieri ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Direct Action ◽  
Human Fibroblasts ◽  
Matrix Metalloproteases ◽  
Channel Blockers ◽  
Gingival Hyperplasia ◽  
Drug Induced ◽  
Gingival Overgrowth ◽  
Matrix Deposition ◽  
Extracellular Matrix Deposition

Introduction. The administration of several classes of drugs can lead to the onset of gingival overgrowth: anticonvulsants, immunosuppressants, and calcium channel blockers. Among the anticonvulsants, the main drug associated with gingival overgrowth is diphenylhydantoin. Materials and Methods. In this study, we compared the effects of diphenylhydantoin and gabapentin on 57 genes belonging to the “Extracellular Matrix and Adhesion Molecule” pathway, present in human fibroblasts of healthy volunteers. Results. Both molecules induce the same gene expression profile in fibroblasts as well as a significant upregulation of genes involved in extracellular matrix deposition like COL4A1, ITGA7, and LAMB3. The two treatments also induced a significant downregulation of genes involved in the expression of extracellular matrix metalloproteases like MMP11, MMP15, MMP16, MMP24, and transmembrane receptor ITGB4. Conclusions. Data recorded in our study confirmed the hypothesis of a direct action of these drugs at the periodontium level, inducing an increase in matrix production, a reduction in its degradation, and consequently resulting in gingival hyperplasia.

scholarly journals Mechanism of Drug-induced Gingival Overgrowth: Phenytoin Inhibits the Apoptosis of Human Gingival Fibroblasts

2021 ◽  
Vol 20 (2) ◽  
pp. 109-116
Author(s):  
Reiri Takeuchi ◽  
Hiroko Matsumoto ◽  
Chieko Taguchi ◽  
Yuichiro Okada ◽  
Masaru Mizuta ◽  
...  
Keyword(s):  
Human Gingival Fibroblasts ◽  
Gingival Fibroblasts ◽  
Drug Induced ◽  
Gingival Overgrowth

Drug-Induced Gingival Overgrowth - A Review

1970 ◽  
pp. 26-29
Author(s):  
Mst Fatema Akhter ◽  
Shaheen Lipika Quayum ◽  
Afrin Bintal Ali ◽  
Zia Mamoon
Keyword(s):  
Extracellular Matrix ◽  
Collagen Synthesis ◽  
Immunosuppressive Agents ◽  
Channel Blockers ◽  
Gingival Fibroblasts ◽  
Connective Tissues ◽  
Drug Induced ◽  
Gingival Overgrowth ◽  
Collagen Phagocytosis ◽  
Synthesis And Degradation

Drug-induced gingival overgrowth is a side effect associated with 3 types of drugs: anticonvulsants (phenytoin), immunosuppressive agents (cyclosporine A), and various calcium channel blockers for cardiovascular diseases. Gingival overgrowth is characterized by the accumulation of extracellular matrix in gingival connective tissues, particularly collagenous components with various degrees of inflammation. Although the mechanisms of these disorders have not been elucidated, recent studies suggest that these disorders seem to be induced by the disruption of homeostasis of collagen synthesis and degradation in gingival connective tissue, predominantly through the inhibition of collagen phagocytosis of gingival fibroblasts. In this review, we focus on collagen metabolism in drug-induced gingival overgrowth, focusing on the regulation of collagen phagocytosis in fibroblasts. DOI: 10.3329/bjpp.v25i1.5743Bangladesh J Physiol Pharmacol 2009; 25(1&2) : 26-29

scholarly journals Cyclosporin A and Phenytoin Modulate Inflammatory Responses

2009 ◽  
Vol 88 (12) ◽  
pp. 1131-1136 ◽  
Author(s):  
A.M.M. Suzuki ◽  
A. Yoshimura ◽  
Y. Ozaki ◽  
T. Kaneko ◽  
Y. Hara
Keyword(s):  
Cyclosporin A ◽  
Inflammatory Responses ◽  
Chinese Hamster ◽  
Human Gingival Fibroblasts ◽  
Common Side Effect ◽  
Gingival Fibroblasts ◽  
Toll Like Receptor ◽  
Gingival Overgrowth ◽  
Anti Epileptic Drug ◽  
Tlr4 Ligand

Gingival overgrowth is a common side-effect of administration of the immunosuppressant cyclosporin A and the anti-epileptic drug phenytoin. While cyclosporin-induced gingival overgrowth is often accompanied by gingival inflammation, phenytoin-induced gingival overgrowth usually forms fibrotic lesions. To determine whether these drugs alter the inflammatory responses of gingival fibroblasts, we investigated the effects of cyclosporin and phenytoin on Toll-like receptor (TLR)-mediated responses to microbial components. In Chinese hamster ovary reporter cell lines, cyclosporin alone triggered signaling, whereas phenytoin down-regulated signaling induced by the TLR2 or TLR4 ligand. In human gingival fibroblasts, cyclosporin alone did not induce evident inflammatory responses, but augmented the expression of CD54 and the production of interleukin (IL)-6 and IL-8 induced by TLR ligands, whereas phenytoin attenuated those responses. Cyclosporin also augmented CD54 expression in gingiva of mice injected with lipopolysaccharide. These results indicated that cyclosporin positively and phenytoin negatively modulated inflammatory responses of human gingival fibroblasts.

Cyclosporin A Affects Signaling Events Differentially in Human Gingival Fibroblasts

2005 ◽  
Vol 84 (6) ◽  
pp. 532-536 ◽  
Author(s):  
A. Bostrom ◽  
H. Bharath ◽  
A. Saulewicz ◽  
A.S. Narayanan
Keyword(s):  
Transcription Factors ◽  
Cyclosporin A ◽  
Map Kinases ◽  
Cell Types ◽  
Binding Activity ◽  
Human Gingival Fibroblasts ◽  
Common Side Effect ◽  
Gingival Fibroblasts ◽  
Calcium Blockers ◽  
Gingival Overgrowth

Gingival overgrowth is a common side-effect of the administration of cyclosporin A (CSA), phenytoin, and calcium blockers. To identify the signaling mechanisms possibly involved in the overgrowth, we examined how CSA affects the activities of MAP kinases and transcription factors in human gingival fibroblasts (HGF). The HGF were treated with CSA and TNF-α or PDGF. DNA-binding activity of NFAT, NFκB, and AP-1 transcription factors was determined by gel shift assay, and JNK, p38, and ERK1 and ERK2 activation was assessed by Western blot analysis of immunoprecipitates. The CSA inhibited NFAT, NFκB, and p38 and JNK activities; however, ERK1 and ERK2 were not affected significantly. AP-1 activity increased ~ 4.5-fold. Our results indicate that CSA affects signaling molecules in HGF differently from other cell types, and that a CSA-induced increase in AP-1 activity may affect the expression of fibrogenic molecules in gingiva and promote gingival overgrowth.

scholarly journals Drug-induced gingival hyperplasia: An in vitro study using amlodipine and human gingival fibroblasts

2019 ◽  
Vol 33 ◽  
pp. 205873841982774 ◽  
Author(s):  
Dorina Lauritano ◽  
Marcella Martinelli ◽  
Alessandro Baj ◽  
Giada Beltramini ◽  
Valentina Candotto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Human Gingival Fibroblasts ◽  
Gingival Tissue ◽  
Gingival Fibroblast ◽  
Gingival Hyperplasia ◽  
Gingival Fibroblasts ◽  
Drug Induced ◽  
Gingival Overgrowth

Gingival overgrowth is a serious side effect that accompanies the use of amlodipine. Several conflicting theories have been proposed to explain the fibroblast’s function in gingival overgrowth. To determine whether amlodipine alters the inflammatory responses, we investigated its effects on gingival fibroblast gene expression as compared with untreated cells. Fragments of gingival tissue of healthy volunteers (11 years old boy, 68 years old woman, and 20 years old men) were collected during operation. Gene expression of 29 genes was investigated in gingival fibroblast cell culture treated with amlodipine, compared with untreated cells. Among the studied genes, only 15 ( CCL1, CCL2D, CCL5, CCL8, CXCL5, CXCL10, CCR1, CCR10, IL1A, IL1B, IL5, IL7, IL8, SPP1, and TNFSF10) were significantly deregulated. In particular, the most evident overexpressed genes in treated cells were CCR10 and IL1A. These results seem to indicate a possible role of amlodipine in the inflammatory response of treated human gingival fibroblasts.

scholarly journals Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts

2020 ◽  
Vol 21 (2) ◽  
pp. 595 ◽  
Author(s):  
Dorina Lauritano ◽  
Annalisa Palmieri ◽  
Alberta Lucchese ◽  
Dario Di Stasio ◽  
Giulia Moreo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Cyclosporine A ◽  
Matrix Metalloproteases ◽  
Gingival Hyperplasia ◽  
Gingival Fibroblasts ◽  
Down Regulation ◽  
Gingival Overgrowth ◽  
Expression Levels

Background: Gingival hyperplasia could occur after the administration of cyclosporine A. Up to 90% of the patients submitted to immunosuppressant drugs have been reported to suffer from this side effect. The role of fibroblasts in gingival hyperplasia has been widely discussed by literature, showing contrasting results. In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the gene expression profile of human fibroblasts after cyclosporine A administration. Materials and methods: Primary gingival fibroblasts were stimulated with 1000 ng/mL cyclosporine A solution for 16 h. Gene expression levels of 57 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway were analyzed using real-time PCR in treated cells, compared to untreated cells used as control. Results: Expression levels of different genes were significantly de-regulated. The gene CDH1, which codes for the cell adhesion protein E-cadherin, showed up-regulation. Almost all the extracellular matrix metalloproteases showed down-regulation (MMP8, MMP11, MMP15, MMP16, MMP24, MMP26). The administration of cyclosporine A was followed by down-regulation of other genes: COL7A1, the transmembrane receptors ITGB2 and ITGB4, and the basement membrane constituents LAMA2 and LAMB1. Conclusion: Data collected demonstrate that cyclosporine inhibits the secretion of matrix proteases, contributing to the accumulation of extracellular matrix components in the gingival connective tissue, causing gingival overgrowth. Patients affected by gingival overgrowth caused by cyclosporine A need to be further investigated in order to determine the role of this drug on fibroblasts.

scholarly journals Connective Tissue Metabolism and Gingival Overgrowth

2004 ◽  
Vol 15 (3) ◽  
pp. 165-175 ◽  
Author(s):  
P. C. Trackman ◽  
A. Kantarci
Keyword(s):  
Extracellular Matrix ◽  
Connective Tissue ◽  
Oral Hygiene ◽  
Tissue Specificity ◽  
Gingival Fibroblast ◽  
Drug Induced ◽  
Gingival Overgrowth ◽  
Connective Tissue Metabolism ◽  
Matrix Metabolism ◽  
Systemic Health

Gingival overgrowth occurs mainly as a result of certain anti-seizure, immunosuppressive, or antihypertensive drug therapies. Excess gingival tissues impede oral function and are disfiguring. Effective oral hygiene is compromised in the presence of gingival overgrowth, and it is now recognized that this may have negative implications for the systemic health of affected patients. Recent studies indicate that cytokine balances are abnormal in drug-induced forms of gingival overgrowth. Data supporting molecular and cellular characteristics that distinguish different forms of gingival overgrowth are summarized, and aspects of gingival fibroblast extracellular matrix metabolism that are unique to gingival tissues and cells are reviewed. Abnormal cytokine balances derived principally from lymphocytes and macrophages, and unique aspects of gingival extracellular matrix metabolism, are elements of a working model presented to facilitate our gaining a better understanding of mechanisms and of the tissue specificity of gingival overgrowth.

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