Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031099 (periodontitis)
 12,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of bacteria in the initiation of periodontitis is well-documented and the end result, destruction of the alveolar bone and periodontal connective tissue, is readily observed; but the events occurring between these two points in time remain obscure and are the focus of this paper. Bacteria induce tissue destruction indirectly by activating host defense cells, which in turn produce and release mediators that stimulate the effectors of connective tissue breakdown. Components of microbial plaque have the capacity to induce the initial infiltrate of inflammatory cells including lymphocytes, macrophages, and PMNs. Microbial components, especially lipopolysaccharide (LPS), have the capacity to activate macrophages to synthesize and secrete a wide array of molecules including the cytokines interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-alpha), prostaglandins, especially PGE2, and hydrolytic enzymes. Likewise, bacterial substances activate T lymphocytes and they produce IL-1 and lymphotoxin (LT), a molecule having properties very similar to TNF-alpha. These cytokines manifest potent proinflammatory and catabolic activities, and play key roles in periodontal tissue breakdown. They induce fibroblasts and macrophages to produce neutral metalloproteinases such as procollagenase and prostromelysin, the serine proteinase urokinase-type plasminogen activator (u-PA), tissue inhibitor of metalloproteinase (TIMP), and prostaglandins, u-PA converts plasminogen into plasmin, which can activate neutral metalloproteinase proenzymes, and these enzymes degrade the extracellular matrix components. TIMP inactivates the active enzymes and thereby blocks further tissue degradation. Several amplification and suppression mechanisms are involved in the process. While LPS activates macrophages to produce IL-1, IL-1 is autostimulatory and can therefore amplify and perpetuate its own production. Interferon-gamma (INF-gamma) suppresses autostimulation, but it enhances LPS-induced IL-1 production. PGE2 exerts a control over the whole process by suppressing production of both IL-1 and TNF-alpha. Furthermore, the activated cells produce an IL-1 receptor antagonist that binds to the IL-1 receptor but does not induce the biologic consequences of IL-1 binding. Other cytokines such as transforming growth factor-beta (TGF-beta) suppress production of metalloproteinases and u-PA. Thus the progression and extent of tissue degradation is likely to be determined in major part by relative concentrations and half-life of IL-1, TNF-alpha, and related cytokines, competing molecules such as the IL-1 receptor antagonist, and suppressive molecules such as TGF-beta and PGE2. These molecules control levels of latent and active metalloproteinase and u-PA, and the availability and concentration of TIMP determines the extent and duration of degradative activity.
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PMID:The role of inflammatory mediators in the pathogenesis of periodontal disease. 167 30

Plasminogen activators, proteases associated with the fibrinolytic system, also play a major part in extravascular processes such as tissue remodelling, cell migration and activation of prohormones, growth factors and other proteases. It is likely that plasminogen activators participate in the pathophysiology of periodontal disease. Plasminogen activator has been identified in human gingival crevicular fluid in a concentration 100-fold greater than in plasma. The local activity of plasminogen activator in gingival tissues was examined and changes detected in its distribution in relation to the extent of disease. Frozen sections from human gingival biopsies were overlaid on fibrin-coated slides; tissue-type plasminogen activator activity was found in all samples. Focal activity was observed in healthy tissue, originating from the most superficial cells of the junctional epithelium. Biopsies of clinically healthy sites obtained 6 weeks after treatment for periodontitis also showed epithelial plasminogen activator activity localized to this area. In contrast, in diseased tissue the entire epithelium lining the periodontal pocket showed activity. This differential pattern of activity in health and disease is consistent with the hypothesis that plasminogen activator is a modulator of periodontal homeostasis.
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PMID:Plasminogen activator in human periodontal health and disease. 190 72

Plasminogen activator (PA) converts plasminogen to plasmin, and plasmin activates the kinin cascade and latent methalloproteases. It is known that the alteration of the PA-plasmin system affects the progression of periodontal disease. We have reported previously that LPS from Campylobacter rectus, which is associated with adult periodontitis, increased PA production in human gingival fibroblasts (hGF). The effects of in vitro- and in vivo-cellular ageing on PA production from human and rat gingival fibroblasts (rGF) were studied. In vitro cellular aged hGF were prepared by subcultivations of hGF, and in vivo aged rGF was cultured primarily from the gingival tissue of aged rats. The cells were challenged with LPS and PA released into the cultured medium was measured as PA activity. Both in vitro and in vivo cellular aged GFs produced a significantly higher PA activity by LPS compared with young GFs cell. In RT-PCR experiments, tissue type PA (tPA) mRNA levels in both aged hGF and rGF were higher than in young cells, whereas plasminogen activator inhibitor 1 (PAI-1) mRNA remained unchanged and urotype PA (uPA) mRNA was not detected. Since LPS-stimulated PA activity from gingival fibroblasts was stimulated in aged cells using both in vitro- and in vivo-experimental models, the ageing of gingival fibroblasts may have an effect on the severity of inflammation and degradation of the extracellular matrix of gingival tissues by producing a large amount of PA in response to LPS.
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PMID:Enhancement of LPS-stimulated plasminogen activator production in aged gingival fibroblasts. 1056 48

Fusobacterium nucleatum subsp. nucleatum has been associated with a variety of oral and nonoral infections such as periodontitis, pericarditis, bone infections, and brain abscesses. Several studies have shown the role of plasmin, a plasma serine protease, in increasing the invasive capacity of microorganisms. In this study, we investigated the binding of human plasminogen to F. nucleatum subsp. nucleatum, and its subsequent activation into plasmin. Plasminogen-binding activity of bacterial cells was demonstrated by a solid-phase dot blot assay using an anti-plasminogen antibody. The binding activity was heat resistant and involved cell-surface lysine residues since it was abolished in the presence of the lysine analog epsilon-aminocaproic acid. Activation of plasminogen-coated bacteria occurred following incubation with either streptokinase, urokinase-type plasminogen activator (u-PA), or a Porphyromonas gingivalis culture supernatant. In the case of the P. gingivalis culture supernatant, a cysteine protease was likely involved in the activation. The plasmin activity generated on the cell surface of F. nucleatum subsp. nucleatum could be inhibited by aprotinin. Activation of plasminogen by u-PA was greatly enhanced when plasminogen was bound to bacteria rather than in a free soluble form. u-PA-activated plasminogen-coated F. nucleatum subsp. nucleatum was found to degrade fibronectin, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Tissue inhibitor of metalloproteinase-1 was also degraded by the plasmin activity generated on the bacterial cells. This study suggests a possible role for plasminogen, which is present in affected periodontal sites, in promoting tissue destruction and invasion by nonproteolytic bacteria such as F. nucleatum subsp. nucleatum.
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PMID:Acquisition of plasmin activity by Fusobacterium nucleatum subsp. nucleatum and potential contribution to tissue destruction during periodontitis. 1056 61

The plasminogen activating system plays an important role in tissue proteolysis in physiological as well as pathological processes. Earlier studies have shown high concentrations of the plasminogen activator t-PA as well as its inhibitor PAI-2 in gingival crevicular fluid (GCF). In addition, gingival inflammatory reactions have been related to increases in t-PA and PAI-2. In order to explore the potential role of the plasminogen activating system for the development of destructive periodontal disease, the aim of this study was to assess the balance of the activator t-PA to the inhibitor PAI-2 in GCF from patients, clinically defined to represent different periodontal conditions. The Progression Group consisted of 12 periodontitis patients with 1 or more sites having shown an increased pocket depth of > or = 3 mm during the last 2 years of maintenance care and with > or = 8 unchanged or improving sites during the period. The Non Progression Group consisted of patients who had shown a decreased or unchanged pocket depth of all sites during the last 3 years of maintenance care. Sampling of GCF was done with small disks of Millipore-filter, and t-PA and PAI-2 were analyzed with ELISAs. There was no difference in the t-PA/PAI-2 ratio between the two groups. However, an intra-individual comparison within the Progression Group showed a higher ratio at the deteriorating sites than at the stable sites. Even though no difference was found between the groups, the higher t-PA/PAI-2 ratio at the deteriorating sites in the Progression Group suggests an involvement of the plasminogen activating system in the proteolytic events leading to breakdown of the tooth supporting tissues.
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PMID:Plasminogen activating capacity in gingival fluid from deteriorating and stable periodontal pockets. 1184 39

The plasminogen activating system is important for extracellular proteolysis and plays a regulatory role in interactions with other tissue degrading systems. Studies on the plasminogen activating system in gingival crevicular fluid (GCF) as well as gingival tissue are reviewed. t-PA, u-PA, PAI-1 and PAI-2 have all been detected in GCF. Especially t-PA and PAI-2 are found in high concentrations. In tissue studies fibrinolytic activity has been found in the gingival pocket epithelium in humans and in animal studies. t-PA and PAI-2 have been detected there immunohistochemically. Local production of the PAs and PAls has been verified with in situ hybridization. In inflammation, a more intense and widespread immunohistochemical staining of t-PA and PAI-2 is seen. Higher concentrations of t-PA and PAI-2 are found in GCF but the balance between them seems to be constant. A systemically disturbed balance of the plasminogen activating system in GCF has been observed during pregnancy, with a possible protective function of PAI-2. In studies of periodontitis, the production of PAI-2 seemed to be locally lowered at impaired sites. In a study of children, a higher inflammatory response to bacterial plaque was accompanied by a higher fibrinolytic ativity in GCF samples. Bacterial LPS has been found to change the ratio of t-PA to PAI-2 in cultured gingival fibroblasts. Interactions between PAI-2 and a protease in the gingival epithelium has been verified through the immunohistochemical detection of relaxed PAI-2.
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PMID:The plasminogen activating system in periodontal health and disease. 1192 25

Periodontal diseases belong to the most common chronic disorders affecting mankind. Smoking and impaired plasminogen activation with hypercoagulation and fibrinolysis inhibition have been proposed as having a role in predisposition to these diseases. We investigated relationships among adult periodontitis, smoking, and a variation in the deletion/insertion (4G/5G) promoter polymorphism of the plasminogen-activator-inhibitor-1 (PAI-1) gene in 304 Caucasian subjects. An association was detected between the deletion (4G) allele (and 4G/4G genotype) and periodontitis (P = 0.0022, P(corr) < 0.01; P = 0.014, P(corr) < 0.05). A stronger association occurred in non-smokers (P = 0.00021, P(corr) < 0.01; P = 0.0024, P(corr) < 0.05) where the presence of the PAI-1 gene 4G allele appears to be one of the risk factors for periodontitis.
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PMID:Plasminogen-activator-inhibitor-1 promoter polymorphism as a risk factor for adult periodontitis in non-smokers. 1214 Jul 48

Elastin peptides were previously reported to increase MMP expression in several cell types. We found binding of these peptides to their receptors led to enhanced MMP-3 and MMP-1 expression, but not activation, in human gingival fibroblasts cultured on plastic dishes. We hypothesized that these peptides, in a more physiological environment, might additionally trigger an MMP-3/MMP-1 activation cascade, leading to matrix lysis, as occurs in periodontitis. To test this hypothesis, we used contracted and attached lattices as gingival lamina propria equivalents. In such 3D models, supplementation of elastin peptides and plasminogen triggered an MMP-3/MMP-1 activation cascade and significant down-regulation of TIMPs production, further leading to intense collagen degradation. We propose that elastolysis, as occurs in periodontitis, potentiates collagenolysis, thus promoting disease progression.
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PMID:Elastolysis induces collagenolysis in a gingival lamina propria model. 1686 Dec 93

Tobacco smoking is an important risk factor for the development of severe periodontitis. Recently, we showed that nicotine affected mineralized nodule formation, and that nicotine and lipopolysaccharide stimulated the formation of osteoclast-like cells by increasing production of macrophage colony-stimulating factor (M-CSF) and prostaglandin E2 (PGE2) by human osteoblastic Saos-2 cells. In the present study, we examined the effects of nicotine on the expression of matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), the plasminogen activation system including the component of tissue-type plasminogen activator (tPA), urokinase-type PA (uPA), and PA inhibitor type 1 (PAI-1), alpha7 nicotine receptor, and c-fos. We also examined the effect of the nicotine antagonist D-tubocurarine on nicotine-induced expression of MMP-1. Gene expression was examined using real-time polymerase chain reaction (PCR) to estimate mRNA levels. In addition, expression of the MMP, TIMP, uPA, tPA, and PAI-1 proteins was determined by Western blotting analysis. Nicotine treatment caused expression of MMP-1, 2, 3, and 13, but not MMP-14, to increase significantly after 5 or 10 d of culture; MMP-14 expression did not change through day 14. Enhancement of MMP-1 expression by nicotine treatment was eliminated by simultaneous treatment with D-tubocurarine. In the presence of nicotine, expression of uPA, PAI-1, or TIMP-1, 2, 3, or 4 did not change over 14 d of culture, whereas expression of tPA increased significantly by day 7. Nicotine also increased expression of the alpha7 nicotine receptor and c-fos genes. These results suggest that nicotine stimulates bone matrix turnover by increasing production of tPA and MMP-1, 2, 3, and 13, thereby tipping the balance between bone matrix formation and resorption toward the latter process.
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PMID:Nicotine treatment induces expression of matrix metalloproteinases in human osteoblastic Saos-2 cells. 1715 81

Ligneous periodontitis (LP) is a rare periodontal disease in which plasminogen deficiency and fibrin deposition both play a part, resulting in characteristic gingival enlargement and periodontal breakdown. Recent data suggest that oxidant/antioxidant changes are significant in the pathology of oral diseases. This study examines the gingival histopathology in 2 cases with LP. To examine the antioxidant (AO) status, the activity of the major AOs glutathione (GSH), catalase (CAT), and glutathione S-transferase (GST) and the malondialdehyde (MDA) levels, a product of lipid peroxidation, were measured and compared with healthy control subjects. The histopathologic examination of the gingiva revealed subepithelial fibrin accumulation and irregular extensive downward proliferation of the epithelium. Biochemical analysis showed that the CAT, GST, and MDA levels were higher in LP patients than in the control subjects, and the GSH level was lower. Our preliminary findings show that in LP, the AO capacity of the gingiva changes or decreases and lipid peroxidation increases, which suggests that oxidative stress is involved in the pathology of the periodontal breakdown observed in this disease.
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PMID:Ligneous periodontitis and gingival antioxidant status: report of two cases. 1750 67


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