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The article focuses on abnormal leukocyte motility in patients with early-onset periodontitis. Early-onset periodontitis is highly destructive to the tissues around the teeth is seen in some young children, teenagers and young adults. There are severe forms of periodontitis including perpubertal, juvenile and rapid progressive periodontitis. There is suppressed leukocyte chemotaxis in patients with early-onset periodontitis. It is suggested that suppressed neutrophil and monocyte functions such as chemotactic responsiveness may undergo a cyclic variation under normal circumstances that the observed abnormality of cells from periodontitis patients may be a significant alteration in the frequency or enhancement of the amplitude of this phenomenon rather than suppressed responsiveness.

In the present investigation an attempt was made to follow the sequence of events occurring in the gingival tissues of dogs reacting to the reaccumulation of microbial plaque. The experiment was performed on 5 young dogs which twice a day during a preparatory period of 5-6 months had been treated with a 2 % chlorhexidine mouthrinse. When the eruption of the permanent teeth was in a final phase a clinical examination (Plaque Index, Gingival Index, Gingival exudate measurements) was performed, biopsies sampled from predetermined tooth regions and the chlorhexidine regimen terminated. On days 1. 3, 5, 7, 14, and 28 the clinical examinations were repeated and biopsies of buccal gingival tissues taken from incisors, canines, and premolars. The gingival tissues were subjected to a stereologic analysis based on morphometric point counting procedures. On day zero small amounts of plaque were detected on most teeth. Following the termination of the chlorhexidine regimen plaque accumulation as well as gingival exudation increased. The morphometric data revealed that (1) all biopsies contained a small portion of ICT (infiltrated connective tissue) which did not increase in size with time (2) the cellular composition of ICT fluctuated but did not change its general pattern with time (3) immunoblasts were rarely seen but an unusual lymphoid cell (X-lymphocyte) was regularly present in ICT. The possibility was discussed that chlorhexidine not only interferes with plaque formation but also may suppress some aspects of the inflammatory and immunopathologie response of the gingiva. [ABSTRACT FROM AUTHOR]

The non-human primate Macaca nemestrina was evaluated for use as a potential model in periodontal research by study of 16 animals. Using one incisor, premolar, and molar per quadrant, we measured supragingival plaque. severity of gingival inflammation, and pocket depth, and analyzed the suhgingival flora. Serum IgG titers and avidities to antigens of Porphyromonas gingivalis (Pg) and Actinobacillus actinomycetemcomitans (Aa) were also assessed Ten animals were between 13 and 24 years old, and six were between 4 and 5 years old While mean gingival inflammation scores were significantly higher for older than for younger animals (2.2 vs 1.8, p<0.05), mean plaque index scores and mean probing depths did not differ significantly. The animals harbored a subgingival microflora considered to be pathogenic for humans including Aa, Pg, Bacteroides forsythus, Prevotella intermedia I and II. Campylobacter recta and Fusobacterium nucleatum. As, however, was found only in the younger animals. All of the animals had serum IgG antibodies reactive with antigens of Pg and Aa, and titers for Pg but not for Aa were significantly higher in the older relative to the younger animals (t test p<0.02). In contrast, antibody avidity did not significantly differ between the two groups. A combined clinical assessment index based on maximum probing depth, gingival index score, and tooth loss was used to assess the overall disease severity, Titers were positively associated with disease severity (Spearman's rank correlation 0.57, p=0.02). We conclude that M. nemestrina harbors a subgingival microflora considered to be pathogenic for humans, manifest serum IgG antibodies to antigens of Pg and Aa, and exhibits clinical features of periodontitis comparable to those seen in humans. This species appears, therefore, to be a useful model for investigating periodontal microbial-host interactions, including the immune response. [ABSTRACT FROM AUTHOR]

We have studied how collagen production is regulated in fibroblasts obtained from normal and phenytoin-induced hyperplastic human gingiva. Collagen production was determined as collagenase digestible radioactivity and degradation was examined by adding labelled procollagen to the cultures and by pulse-labelling in the presence of lysosomal inhibitors. Collagen mRNA levels were measured using a [35S]-UTP labelled proa[1] probe. The normal and phenytoin-induced fibroblasts did not degrade collagen extracellularly and lysosomal inhibition did not enhance collagen production in either culture. Collagen production by the cultures correlated with mRNA levels, and in 2 of 3 phenytoin-induced fibroblasts, which produced more collagen than other cells, collagen mRNA levels were higher. We conclude that collagen production in gingival fibroblasts is primarily regulated by the mRNA levels and that overproduction of collagen by cells from phenytoin-induced hyperplastic gingiva results from an increased steady state level of collagen mRNA and not decreased collagen degradation. [ABSTRACT FROM AUTHOR]

Prior studies have documented that a majority of patients with juvenile periodontitis have suppressed polymorphonuclear leukocyte (PMN) chemotaxis. However, in other forms of early-onset periodontitis, PMN migration has been studied only to a limited extent or not at all, and monocyte (MN) chemotaxis has not been extensively studied in patients with any of the forms of periodontitis. Accordingly, PMN and MN chemotaxis was studied in 7 patients with prepubertal, 37 with juvenile, and 35 with rapidly progressive periodontitis. In addition, PMN chemotaxis was studied in 8 patients with adult periodontitis. In the prepubertal group, 5 patients had abnormal PMN chemotaxis, 5 had depressed MN chemotaxis, and one had reduced serum chemotactic activity. All patients in this group had at least one form of leukocyte chemotaxis abnormality. In the juvenile periodontitis group, 17 patients had abnormal PMN responses, 16 of these were depressed while 1 was enhanced. MN chemotaxis was depressed in 4 of these patients and elevated in 2. Five patients had reduced serum chemotactic activity and one manifested a serum chemotactic inhibitor. In total, 65% of juvenile patients had some form of abnormality. In the rapidly progressive group, 15 had abnormal PMN chemotaxis, 7 had aberrant MN chemotaxis, 4 had reduced serum chemotactic activity, and 8 had a serum inhibitor of chemotaxis. No abnormalities were found in the PMNs or sera of patients with adult periodontitis. Overall, 66% of the early-onset patients manifested some form of cell or serum-related leukocyte chemotactic abnormality. Thus, abnormalities of leukocyte chemotaxis were present in all patients with prepubertal periodontitis and in a majority of those with juvenile and rapidly progressive disease, while no abnormalities were found in 8 patients with adult periodontitis. [ABSTRACT FROM AUTHOR]

Manifestations of inflammatory periodontal disease in a colony-maintained marmoset were studied. The disease was characterized clinically by an acute inflammatory response including redness, edema, exudation and spontaneous hemorrhage. Histopathologically, the cellular response observed was comprised of neutrophils and mononuclear cells, some of which could be definitively identified as macrophages. The lymphocyte-plasma cell infiltrate which comprises a major feature of the disease in man was not a prominent feature in the marmoset. Indeed only insignificant number of these cells were found even with electron microscopy. Thus the host tissue response in the marmoset appears to differ significantly from the seen in man, and reservation must be exercised in the use of the marmoset as a model of the human form of the disease. The observation that the important clinical and histopathologic manifestations of chronic peridontal disease can occur in this animal without the presence of an extensive lymphocyteplasma cell infiltrate suggest that contrary to current concepts the activity of these cells at the local site may not be essential to the induction and progress of periodontal disease. [ABSTRACT FROM AUTHOR]

The histologic features of the non-inflamed periodontium and the histopathologic manifestations of inflammatory gingival and periodontal disease were studied in fifteen wild-caught adult marmosets. The non-inflamed periodontium differs from that of humans in that keratinizing epithelium is more widely distributed, red bone marrow is found in the alveolar bone around most of the teeth, and there is a lamina propria-like zone immediately subjacent to the epithelial basement membrane. This zone is comprised predominantly of mononuclear phagocytic cells. The histopathologic manifestations of periodontal diesase in this animal include vascular proliferation, infiltration of polymorphonuclear neutrophilic leukocytes, proliferation and penetration by the epithelial rete ridges, and a marked increase in the population of mononuclear phagocytic cells, Notably, the plasma cell-lymphocyte infiltrate characteristically seen in man is not a prominent feature of the disease process in the marmoset. [ABSTRACT FROM AUTHOR]

Connective tissue alterations are the major cause of functional impairment of the periodontium and of tooth loss. The mechanisms and conditions favorable for reestablishing the connective tissue attachment to root surfaces are not clear. Fibroblasts are likely to play an important role in this process. The paper reports the preliminary results of attempts to isolate some of the fibroblast cell populations by using selective growth media supplemented with substances which are likely to be present in inflamed tissues.

Periodontitis is a heterogenous condition, with at least four distinct subtypes adult (AP), juvenile (JP), rapidly progressive (RP) and prepubertal (PP). AP is a chronic generalized disease affecting patients approximately 35 years of age and older. RP begins beyond puberty usually in the 20 35 age range and produces acute inflammation and rapid bone destruction which can be either generalized or localized. PP starts prior to puberty often at about age 4 and affects the primary dentition. Both localized and generalized forms occur and the generalized disease progresses rapidly.

It is informed that the mongrel cat is one of the few laboratory animals susceptible to gingival enlargement subsequent to prolonged oral administration of the anticonvulsant drug phenytoin. Nine male and nine female colony-reared mongrel cats aged nine to 24 months were obtained from Mogul-Ed Laboratories located at Oskosh, Wisconsin, housed in stainless steel cages and given water and dry food and libitum. Twice each week, canned cat food was provided. At the beginning of the experiment and weekly thereafter, the animals were anaesthetized with a 30 mg/kg intramuscular injection of ketamine hydrochloride. Weights were recorded, physical and oral examinations were performed and photographs were taken of the anterior labial gingivae. During the course of the study, untoward drug reactions including lethargy and anorexia were noted in some animals, but in no case was the dosage was adjusted.

A significant recent development in periodontal research has been the convergence of basic and clinical research resulting in a logarithmic increase in the rate of progress. Scientific consensus has been reached in many areas. In most populations, moderate to severe periodontitis affects a relatively small segment of adults who are at high risk. The microbial etiology is accepted and the identity of the major pathogenic bacterial species is known. The mechanisms through which resistant individuals successfully fend off the microbial challenge are known, and the immuno-inflammatory pathways activated by bacteria that underlie destruction of the alveolar bone and the connective tissues of the periodontium are reasonably well understood. The evidence shows that these pathways are held in common by all forms of periodontitis. Therapeutic modulation of these pathways is now possible, and new treatments based on such modulation are now becoming available. Although bacteria are essential for disease to occur, they are insufficient; a susceptible host is also necessary. Host susceptibility, disease progression and response to treatment are determined predominantly by heredity and environmental and acquired risk factors. Some of these can be changed while others are immutable. Concepts and procedures for treatment are generally scientifically based and appropriately applied. Preventive measures are largely successful and widely practiced in industrialized countries. Clearly, control of these ancient chronic diseases is now within our reach. In spite of the tremendous progress, many unresolved issues remain. The purpose of this paper is to summarize some of the major accomplishments of periodontal research, and identify and discuss some of the more important critical issues that still need to be addressed.

Lipopolysaccharide from a variety of bacterial sources is known to inhibit gingival fibroblast proliferation and synthetic activity and has been implicated in the pathogenesis of periodontal inflammation. However, it may be involved not only in pathogenesis but also be responsible for delayed wound healing following periodontal therapy. The aim of this investigation was to determine whether the inhibitory effect of LPS on gingival fibroblast proliferation could be reversed by growth factors. Human gingival fibroblasts were cultured in the presence of varying concentrations of platelet-derived growth factor (PDGF) or Salmonella enteritidis LPS to determine the optimal concentrations for stimulation and inhibition of proliferation respectively. The effect of PDGF on LPS inhibition of fibroblast proliferation was studied by combining PDGF and LPS together at the outset of the experimental period or adding PDGF to cells which had been previously primed with LPS. Cell proliferation was monitored by incorporation of 3H-thymidine into precipitable DNA. The results indicated that maximal inhibition of fibroblast proliferation was obtained with 50 micrograms/ml LPS and maximal stimulation of proliferation with 5 ng/ml PDGF. PDGF was found to restore the proliferative activity of the cells exposed to LPS to approximately 60% of their control counterparts. A similar value was obtained for cultures exposed to PDGF after an extended priming period of LPS exposure. Subtle differences were noted in the time taken for cells to complete their cell cycle in the various culture conditions and this may reflect variations in subpopulations of cells in their response to various mitogenic stimuli. Overall the results indicate that PDGF has the capacity to significantly negate and reverse the inhibitory effects of LPS on human gingival fibroblast proliferation.

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.

A double-blind, placebo-controlled trial was conducted to determine the effects of the nonsteroidal anti-inflammatory drug Naprosyn (naproxen) on gingival inflammation. The enrollment of 114 patients provided 102 patients valid for efficacy evaluation, each having a mean gingival index (GI) score of 1.5 or greater at test-teeth sites. Patients were given oral Naprosyn 500 mg b.i.d. or placebo for 30 days. At 28 d, full-mouth prophylaxis was performed. Gingival index, modified sulcular bleeding index (SBI), and plaque index (PII) scores were taken at baseline, at 28 d, and at 30 d. When the 28-d index measurements were compared to baseline, the drug had no significant effect on plaque index scores or gingival inflammation. Statistically, Naprosyn enhanced the resolution of gingival inflammation following removal of microbial plaque. Thus, although this drug does not suppress the inflammation-inducing properties of plaque, Naprosyn may enhance recovery following plaque removal.

Tests based on the composition of gingival crevicular fluid (GCF) for detection of active periodontitis require a better understanding of sampling variables than currently exists. We have studied the effects of sample time and repetition on the presence and activity of aspartate aminotransferase (AST). Two 30-second samples of GCF were harvested within 10-minute intervals from 192 teeth with periodontitis. GCF sample size and AST activity were measured. GCF volume and AST activity of first samples were each approximately 10% greater than for second samples. The differences were significant. AST activity correlated positively with gingival index scores and probing pocket depth. Samples were also harvested from groups of 4 teeth during 5-, 10-, 20- and 30-s periods with 1-min intervals and varying sample order. For these samples, first samples contained the greatest amount of enzyme activity, regardless of sample time. When only first samples were considered, the 5- and 10-s samples showed more total activity than the 20- and 30-s samples, and differences were statistically significant. Flow rate for the 5-s sample was always higher than for all other samples, regardless of its position in the sampling sequence. Our observations are consistent with the existence of a reservoir of AST activity that is, in major part, depleted during the first 5 to 10 s of sampling, and that requires a time period of more than 10 min to reequilibrate. Five- to 10-s samples may distinguish active disease better than 20- or 30-s samples, since most of the activity is taken onto the strip in the first few seconds, and the activity is subsequently partly inactivated or diluted by the uptake of fluid less rich in enzyme activity.

Samples of gingival crevicular fluid (GCF) were harvested from sites manifesting features characteristic of active disease including inflammation, periodontal attachment loss, and radiographic signs of alveolar bone destruction in untreated patients with advanced periodontitis. The presence and concentrations of interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) were measured using ELISAs specific for these cytokine molecules. IL-1 alpha and/or IL-1 beta were identified in the GCF of 15 of 15 patients having untreated periodontitis. Ninety percent (71 of 79) of the sites tested contained measureable amounts of IL-1, with IL-1 beta as the more frequently occurring form. IL-1 alpha levels ranged from 0.23 nM to 13.9 nM in the GCFs. IL-1 beta levels were between 0.04 nM and 5.28 nM. Marked reductions of total IL-1 levels were observed following effective treatment. Both forms of IL-1 messenger RNA (mRNA) were detected in 17 of 17 gingival tissue samples from 6 patients. These results demonstrate that IL-1 is produced and released locally in periodontal disease at concentrations sufficient to mediate tissue inflammation and bone resorption. IL-1 may serve as a marker of periodontal tissue destruction.

Diploid fibroblasts obtained from explants of human gingiva and maintained in vitro undergo a several-fold decrease in protein and collagen synthesis as a function of increasing donor age. Using drug-induced gingival hyperplasia as a model, we performed experiments to learn whether fibroblasts derived from hyperplastic tissue behave in a similar manner. Fibroblast strains were established from explants of hyperplastic gingiva obtained from 10 patients chronically ingesting phenytoin and ranging in age from 9 to 45 years. Protein production and degradation were compared to previously reported data similarly obtained from periodontally normal donors ranging in age from 12 to 68 yr. The total quantity of protein and collagen produced by the phenytoin cells was significantly greater than previously reported for cells from normal gingiva. No donor age-related decrease in protein and collagen production nor in the proportion of cell synthetic activity committed to collagen production was observed for cultures of phenytoin cells. The gross pattern of proteins produced, as assessed by 2-dimensional gel electrophoresis, was unrelated to donor age in both normal and phenytoin cells, but three polypeptides ranging in size from about 20 kD to 40 kD that were not found in the cultures of normal cells were produced by five of seven phenytoin cells strains. The observations demonstrate that the phenytoin cells do not undergo the donor age-dependent decrease in synthesis observed for normal cells. This abnormality may account in part for the phenytoin-induced hyperplasia. The phenytoin cells appear to be a unique phenotype.

Data from several sources demonstrate that disease-active and disease-inactive periodontal pockets exist, and that disease progression occurs in bursts of activity. Currently used diagnostic procedures do not distinguish between disease-active and disease-inactive sites at any given point in time. We report the results of studies aimed at determining whether levels of the enzyme aspartate aminotransferase (AST) in gingival crevicular fluid (GCF) are associated with disease activity as assessed by the level of gingival inflammation and probing attachment loss. 25 previously treated periodontitis patients participating in a quarterly recall maintenance program, who had experienced recurrent periodontal deterioration, served as experimental subjects. Patients were evaluated at 3-month intervals for 2 years. Values for plaque index, gingival index, and probing attachment level were recorded, and 30-second samples of gingival fluid harvested from the mesiobuccal aspect of the 4 first molars and the distal of the 4 lateral incisors. GCF volume was measured using a Periotron 6000, and AST activity was measured by a standard method. Sites were ranked in a hierarchy based on the degree of certainty of attachment loss as well as the severity of gingival inflammation, and the relationship of the values to AST levels was determined. Three models were used to analyze the resulting data, and all led to the same conclusion. Maximum enzyme level was significantly elevated at sites with confirmed disease activity as assessed by attachment loss, with maximum AST levels 725 units higher at these sites, on average, than at other sites (p less than 0.0001). Our data support the idea that an objective diagnostic test, based on levels of AST in GCF, that distinguishes between disease-active and disease-inactive sites may be possible.

Data from several sources demonstrate that disease-active and disease-inactive periodontal pockets exist, but currently available diagnostic procedures do not permit identification of disease-active sites at any given point in time. Using the experimental gingivitis model, we have performed studies aimed at determining whether levels of the enzyme aspartate aminotransferase (AST) in gingival crevicular fluid correlate with the presence and extent of periodontal inflammation. Gingival inflammation was assessed using the Gingival Index and the Sulcular Bleeding Index, and enzyme activity was measured using a standard procedure. Our data reveal a statistically significant association between AST values and Gingival Index scores for spontaneously occurring lesions (p less than 0.02-0.04) and experimentally induced lesions (p less than 0.0001), as well as the extent of change in these values during developing experimental gingivitis (p less than 0.0001) and resolving experimental gingivitis (p less than 0.0001). The data demonstrate that AST levels can be used to assess the presence and extent of periodontal inflammation.

The pathologic alterations occurring in the gingival tissues of humans immediately following the beginning of plaque accumulation have not heen elucidated previously. Seven males, 22--31 years of age, free of clinical manifestations of dental and periodontal disease, and exhibiting a Plaque Index score of zero for the previous 28 days served as subjects. Plaque control measures were discontinued for 8 days and biopsies were taken from the buccal marginal gingiva of the first premolars on days 0, 2, 4, and 8. Paraffin- and Epon-embedded section, treated with a variety of histochemical stains were analyzed microscopically and cell counts were done on 1-micron Epon section. At 2 and 4 days following the beginning of plaque accumulation, the vessels subjacent to the juctional epithelium exhibited vasculitis and alterations in the perivascular collagen. There was a statistically significant increase in the number of neutrophils residing in the junctional epithelium. By the end of the 8-day period, the number of small mononuclear cells, mostly lymphocytes, in the connective tissues had increased by 3-fold and the area of collagen fiber alteration by 4-fold. In addition, the number of fibroblasts per unit area of connective tissue decreased significantly. Thus, within the period of 8 days following the beginning of plaque accumulation, an early lesion exhibiting many features characteristic of delayed hypersensitivity develops.