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Biomedical subjects

Thomas E Van Dyke

Publications and source records attributed to Thomas E Van Dyke.

At least 19 recordsLinked to original sources
PubMed2006

Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice.

The role of polymorphonuclear neutrophils (PMN) in mediating diabetic tissue damage to the periodontium was investigated in a novel model of chronic hyperglycemia, the Akita mouse. Induction of acute peritoneal inflammation in wild-type (WT) and Akita mice resulted in exaggerated IL-6 response in Akita mice (2.9-fold increase over WT values) and a markedly increased chemokine response (KC, 2.6-fold; MCP-1, 2.6-fold; and MIP-1alpha, 4.4-fold increase over WT values). Chemotaxis to both fMLP and WKYMVm was significantly reduced in isolated Akita PMN compared with WT PMN as measured in a Boyden chamber. Superoxide release in contrast was significantly increased in Akita PMN as measured with cytochrome c reduction. Bone marrow-derived Akita PMN showed partial translocation of p47phox to the cell membrane without external stimulation, suggesting premature assembly of the superoxide-producing NADPH oxidase in hyperglycemia. In vivo studies revealed that ligature-induced periodontal bone loss is significantly greater in Akita mice compared with WT. Moreover, intravital microscopy of gingival vessels showed that leukocyte rolling and attachment to the vascular endothelium is enhanced in periodontal vessels of Akita mice. These results indicate that chronic hyperglycemia predisposes to exaggerated inflammatory response and primes leukocytes for marginalization and superoxide production but not for transmigration. Thus, leukocyte defects in hyperglycemia may contribute to periodontal tissue damage by impairing the innate immune response to periodontal pathogens as well as by increasing free radical load in the gingival microvasculature.

Acute Disease↗
PubMed2006

Activation of RAGE induces elevated O2- generation by mononuclear phagocytes in diabetes.

Oxidative stress has been found to play a role in the pathogenesis of diabetic complications. The aim of this study was to define the oxidative burst of diabetic monocytes to characterize the phenotype associated with poor diabetic control. Superoxide (O(2)(-)) is the first molecule generated during the respiratory burst of phagocytes by NADPH oxidase, and its generation by monocytes from 26 controls and 34 diabetic subjects was evaluated in this study. Under resting states or stimulation by PMA or opsonized zymosan, diabetic monocytes produce significantly more O(2)(-) than nondiabetic cells. The increased O(2)(-) generation was found to be correlated with glycemic control (glycated hemoglobin) of patients. To clarify the effects of hyperglycemia on O(2)(-) generation, normal human monocytes were treated with receptor for advanced glycation endproducts (RAGE) ligands (AGE protein and S100B) or high glucose media before stimulation. RAGE ligands and high glucose concentration increased O(2)(-) generation from human mononuclear phagocytes. RAGE ligands, specifically and potently, increased O(2)(-) generation from mononuclear phagocytes, and high-glucose effects were associated with correspondingly increased osmotic pressure. Differentiated THP-1 cells, from a human monocytic cell line, were used as a model of human monocytes to study the effects of S100B, the RAGE ligand. It was confirmed that RAGE is involved in the priming of O(2)(-) generation by S100B. This study demonstrates that RAGE ligands can contribute significantly to the hyper-responsive phenotype of diabetic monocytes, which might be reversible by blocking the RAGE or controlling the presence of RAGE ligands by controlling hyperglycemia.

Adult↗
PubMed2006

Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression.

During the resolution phase of inflammation, the 'corpses' of apoptotic leukocytes are gradually cleared by macrophages. Here we report that during the resolution of peritonitis, the CCR5 chemokine receptor ligands CCL3 and CCL5 persisted in CCR5-deficient mice. CCR5 expression on apoptotic neutrophils and activated apoptotic T cells sequestered and effectively cleared CCL3 and CCL5 from sites of inflammation. CCR5 expression on late apoptotic human polymorphonuclear cells was downregulated by proinflammatory stimuli, including tumor necrosis factor, and was upregulated by 'proresolution' lipid mediators, including lipoxin A4, resolvin E1 and protectin D1. Our results suggest that CCR5+ apoptotic leukocytes act as 'terminators' of chemokine signaling during the resolution of inflammation.

Animals↗
PubMed2006

Compliance as a prognostic indicator: retrospective study of 505 patients treated and maintained for 15 years.

BACKGROUND: The relationship of patient compliance to overall tooth prognosis remains controversial. There are little data, often conflicting, that pertain to tooth loss as a function of patient compliance. METHODS: This retrospective study evaluates the impact of compliance (complete versus erratic) on common periodontal clinical variables, such as probing depth, bleeding index, plaque index, and tooth loss for 505 patients in a long-term period of observation (15 to 23 years) and maintenance therapy (at least 10 years). Compliance was defined in two ways for all analyses. Under the definition for compliance 1, patients who missed <30% of all prescribed maintenance visits were classified as complete compliers. Under the definition for compliance 2, patients who never went 2 years without a maintenance visit were classified as complete compliers. Change in clinical variables was dichotomized into reduction in plaque index versus no reduction, reduction in bleeding on probing versus no reduction, reduction in the percentage of periodontal pockets>3 mm versus no reduction, no increase in decayed, missing, or filled teeth (DMFT) versus increase, and no tooth loss versus tooth loss. The effects of both definitions of compliance were then evaluated in a series of multiple logistic regression models with adjustment for potential confounders. RESULTS: The analysis of the dichotomous change in clinical parameters over time revealed that complete compliers tended to show reduction in bleeding on probing and reduction in plaque index compared to erratic compliers for both definitions of compliance. In contrast, complete compliers under compliance 2 were less likely to have a reduction in the percentage of periodontal pockets >3 mm compared to erratic compliers, whereas complete compliers under compliance 1 had about the same likelihood of demonstrating a reduction in periodontal pockets compared to erratic compliers under this classification scheme. Under both definitions for compliance, complete compliers were more likely to exhibit tooth loss than erratic compliers, with the greatest tooth loss exhibited by complete compliers under the definition for compliance 1. CONCLUSIONS: Based on these results, complete compliers under both definitions tended to show a reduction in plaque and bleeding on probing over time. However, change in periodontal pockets and DMFT over time varied according to the definition of compliance that was used. In addition, the results seem to indicate that the decision for tooth extraction made by dental health professionals at maintenance visits may result in greater tooth loss.

Adult↗
PubMed2005

Simultaneous measurements of cytoplasmic Ca2+ responses and intracellular pH in neutrophils of localized aggressive periodontitis (LAP) patients.

In view of the reports that polymorphonuclear leukocytes (PMN) of patients with localized aggressive periodontitis (LAP) exhibit hyper-responsiveness to stimulation, it has been suggested that such abnormalities could lead to PMN-mediated tissue damage during inflammation. To determine whether these abnormalities include signal transduction, we compared cytoplasmic calcium concentration (Delta[Ca2+](i)) and cytoplasmic pH (DeltapH(i)) changes, early stimulus responses to chemotactic agents, of LAP versus control (C)-PMN and explored whether these could be modulated by sensitizing cytokines or calcium channel-blocking agents. PMN responses of LAP patients were compared with age- and gender-matched controls. Delta[Ca2+](i) and DeltapH(i) were measured fluorimetrically using 1H-indole-6-carboxylic acid, 2-[4-[bis[2-[(acetyloxy)methoxy]-2-oxoethyl]amino]-3-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxoethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-1 and 2',7'-bis-(carboxyethyl)-5(6)-carboxyfluorescein as respective probes. Not only was the maximal calcium response to chemoattractants higher in LAP-PMN, but also their subsequent intracellular calcium redistribution was significantly slower. The slower calcium redistribution of LAP-PMN, but not their higher maximal calcium response, was successfully mimicked in C-PMN treated with Nifedipine or 1-[b-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole-HCl, both known to be inhibitors of membrane-associated calcium influx, but this redistribution was not affected when inhibitors of other calcium influx mechanisms, Diltiazem or Verapamil, were used. Taken together, our findings indicate that certain early stimulus responses are aberrant in LAP-PMN, that internal redistribution of cytoplasmic-free calcium is compromised, and, additionally, that a membrane-associated Ca2+ transport defect may be present.

Aggressive Periodontitis↗
PubMed2005

Differentiation of HL-60 cells to granulocytes involves regulation of select diacylglycerol kinases (DGKs).

Diacylglycerol Kinases (DGKs) are a family of enzymes that regulate the levels of different pools of diacylglycerol (DAG), affecting DAG-mediated signal transduction. Since DAG is known to play several important regulatory roles in granulocyte physiology, we investigated the expression pattern of DGK isoforms throughout differentiation of HL-60 cells to granulocytes. HL-60 cells were incubated with 1.25% dimethyl-sulfoxide (DMSO) to initiate differentiation and total RNA isolated at different time points. DGK expression was assessed through Northern blot, end-point PCR, and real-time PCR. The non-selective inhibitors R59022 and R59949 were used to block DGK at different time points throughout differentiation. CD11b and GPI-80, reactive oxygen species (ROS) generation, changes in the cell cycle, and apoptosis were used as markers of differentiation. Of the nine isoforms of DGK evaluated (alpha, delta, epsilon, gamma, zeta, beta, theta;, iota, eta), only five (alpha, delta, epsilon, gamma, and zeta) were expressed in HL-60 cells. DGKalpha was virtually absent in non-differentiated cells, but was markedly upregulated throughout differentiation. The other isoforms (delta, epsilon, gamma, and zeta) were expressed in undifferentiated HL-60 cells but were substantially decreased throughout differentiation. Non-selective blocking of DGK with R59022 and R59949 led to acceleration of differentiation, reducing the time necessary to observe upregulation of CD11b, GPI-80 and generation of ROS by 50%. Likewise, the cell cycle was disrupted when DGK isoforms were inhibited. These results provide evidence that DGK levels are dynamically regulated throughout differentiation and that expression of DGKs play an important regulatory function during the differentiation of neutrophils.

Amidohydrolases↗
PubMed2005

CD38 cleavage in fMLP- and IL-8-induced chemotaxis is dependent on p38 MAP kinase but independent of p44/42 MAP kinase.

In this study, we examined the mechanism by which CD38 cleavage is regulated through the mitogen-activated protein (MAP) kinases after stimulation by fMLP and interleukin-8 (IL-8) in neutrophils. Both fMLP and IL-8 increased chemotaxis and decreased CD38 protein in neutrophils, but did not change CD38 mRNA levels. Both fMLP and IL-8 increased CD38 in supernatants, which was inhibitable with PMSF. fMLP stimulation resulted in phosphorylation of p38 MAP kinase and p42/44 MAP kinase (ERK). SB20358, a p38 MAP kinase inhibitor, down-regulated neutrophil chemotaxis. Conversely, PD98059, an ERK inhibitor, did not influence chemotaxis to either agonist. The addition of SB20358 blocked the decrease of CD38 on neutrophils and the increase in supernatants induced by fMLP or IL-8, whereas PD98059 did not. These findings suggest that CD38-mediated chemotaxis to fMLP or IL-8 is characterized by proteolytic cleavage of CD38 and signaling through p38 MAP kinase. Activation of the protease for cleavage appears to be a postreceptor event that is dependent on p38 MAP kinase signaling.

ADP-ribosyl Cyclase↗
PubMed2005

Gingipain-specific IgG in the sera of patients with periodontal disease is necessary for opsonophagocytosis of Porphyromonas gingivalis.

BACKGROUND: Porphyromonas gingivalis is a primary etiologic agent of generalized aggressive periodontitis (GAgP), and gingipains, a group of cysteine proteinases, are critical virulence factors expressed by this organism. GAgP patients develop specific antibodies to gingipains; however, the function of these antibodies in the clearance of P. gingivalis infection is poorly understood. METHODS: In this study, we defined the levels of gingipain-specific antibodies in GAgP patient sera and examined the ability of gingipain-specific antibodies to facilitate opsonophagocytosis of P. gingivalis by human polymorphonuclear leukocytes (PMNs) using a fluorescent phagocytosis assay. RESULTS: GAgP patient sera possessed elevated levels of P. gingivalis-, arginine-gingipain (Rgp)A-, RgpB-, and lysine-gingipain (Kgp)-specific IgG (Kgp > RgpA > P. gingivalis > RgpB). Adsorption of GAgP sera with P. gingivalis whole organisms, RgpA, RgpB, and Kgp conjugated to sepharose beads reduced opsonophagocytosis of P. gingivalis by PMNs. CONCLUSIONS: Our studies demonstrate that GAgP patient sera possess elevated levels of P. gingivalis- and gingipain-specific IgG. Furthermore, we show that gingipain antibodies promote uptake of P. gingivalis by PMNs, and our data suggest that gingipain-specific antibodies may be important for the control of P. gingivalis infections.

Adhesins, Bacterial↗
PubMed2005

Resolution of inflammation in periodontitis.

Chronic inflammatory illnesses such as diabetes, arthritis, and heart disease are now seen as problems that might have impacts on the periodontium, and reciprocal effects of periodontal diseases are being considered as factors potentially affecting the progression of these diseases. Successful management of the inflammatory disorders in the human body depends on the identification of common pathways that would lead to a better understanding of the disease processes and development of novel treatment strategies. In this review, our objective is to identify the inflammatory basis of periodontal disease and common inflammatory mechanisms underlying several disorders elsewhere in the body, with an emphasis on how the potential extrinsic and intrinsic control methods could be used to prevent or treat the harmful effects linked to inflammation.

Animals↗
PubMed2005

CD38 expression in neutrophils from patients with localized aggressive periodontitis.

BACKGROUND: Localized aggressive periodontitis (LAgP) is associated with neutrophil dysfunction including decreased chemotaxis and reduced calcium entry. It has been suggested that CD38 is involved in chemotaxis. Little is known, however, about the relationship of CD38 and LAgP patients. In this study, we focused on the level of CD38 expression between LAgP and normal subjects and examined the involvement of CD38 in abnormal neutrophil chemotaxis of LAgP patients. METHODS: Neutrophils from 12 normal subjects and 12 LAgP patients were isolated from peripheral venous blood. Membrane associated proteins were extracted from cells with or without N-formylmethionine leucyl-phenylalanine (fMLP) stimulation. CD38 expression was measured using Western blotting. Band density was measured using an imaging densitometer. RESULTS: There was no statistical difference between normal subjects and LAgP patients in resting CD38 expression (basal level). However, the fMLP-stimulated neutrophils exhibited a significant decrease of CD38 expression in LAgP subjects compared to normal subjects. The decrease of CD38 was positively correlated with the defect in chemotactic migration to fMLP. CONCLUSION: These data suggest that the lower expression of CD38 in neutrophils may be related to altered neutrophil function in LAgP.

ADP-ribosyl Cyclase 1↗
PubMed2005

Effect of neutrophil apoptosis on monocytic cytokine response to Porphyromonas gingivalis lipopolysaccharide.

BACKGROUND: Neutrophil apoptosis may play a critical role in the resolution of inflammation by stimulating anti-inflammatory cytokine generation from monocytes. In this study, we investigated the effect of apoptotic neutrophils on interleukin (IL)-10 and IL-1beta production from monocytes in response to Porphyromonas gingivalis lipopolysaccharide. METHODS: Peripheral blood neutrophils from healthy individuals were isolated by sodium diatrizoate density gradient centrifugation. In order to induce apoptosis, neutrophils were cultured for 24 hours in modified Dulbecco's medium supplemented with 10% autologous serum. Cell apoptosis was quantified by Annexin V positivity and loss of CD16 expression on the cell surface. Peripheral blood mononuclear cells were isolated from the same subjects; monocytes were purified by magnetic cell sorting and cultured with or without apoptotic or fresh neutrophils. Lipopolysaccharide from Porphyromonas gingivalis was used for cell stimulation. IL-1beta and IL-10 levels in supernatants were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: IL-10 generation was significantly increased in monocytes cultured with apoptotic neutrophils compared to monocytes alone or cocultured with fresh neutrophils (P <0.05). IL-1beta was suppressed both in resting and lipopolysaccharide-stimulated monocytes in the presence of apoptotic neutrophils compared to monocytes alone or monocytes cultured with fresh neutrophils at all time points (P <0.05). CONCLUSION: Neutrophil apoptosis provides a signal to monocytes, changing the phenotype of the monocyte resulting in the production of anti-inflammatory cytokines and suppression of proinflammatory cytokines in response to lipopolysaccharide.

Adult↗
PubMed2005

Effect of topical cimetidine rinse on gingival crevicular neutrophil leukocyte function.

BACKGROUND: Three coordinated mechanism-of-action clinical studies were conducted to examine the effects of topical cimetidine rinse on neutrophil function in the gingival crevice. METHODS: The first study was a randomized, double-blind, placebo-controlled, 28-day experimental gingivitis study involving 21 healthy adults, in which subjects rinsed twice a day with placebo or 0.5% cimetidine rinses. At baseline and days 14, 21, and 28, neutrophils were harvested from prespecified gingival sulcular sites, purified, stained, and examined by trifluorochrome phagocytosis and killing microassay. The second and third studies were placebo-controlled, 9-week, three-period (each of 3 weeks' duration), longitudinal studies involving seven and nine adults with moderate periodontitis, respectively. Subjects rinsed twice a day during periods 1 and 3 with placebo and during period 2 with 0.5% cimetidine. At baseline and weekly intervals, neutrophils were harvested from prespecified periodontal pockets, purified, stained, and examined by trifluorochrome phagocytosis and killing microassay in the second study. In the third study, neutrophils were examined spectrophotometrically for superoxide production and in a luminol-enhanced chemiluminescence assay. RESULTS: In the first study, the mean number of phagocytosing neutrophils was statistically significantly increased (P = 0.016) in the cimetidine group (31.1 cells/subject) versus the placebo group (13.7 cells/subject) at day 28. In addition, a statistically significant increase (P = 0.036) in bacterial killing was observed in the cimetidine rinse group; in the cimetidine group, 63.4% of bacteria in the neutrophils were killed compared to 46.2% in the placebo group. Additional data from the other two studies support these findings. CONCLUSION: Collectively, these studies provide evidence that topical 0.5% cimetidine oral rinse enhances the antibacterial function of crevicular neutrophils.

Adjuvants, Immunologic↗
PubMed2005

Risk factors for periodontitis.

In recent years, it has become apparent that the pathogenesis of periodontal diseases is more complex than the presence of virulent microorganisms. In fact, it is now widely accepted that susceptibility to periodontitis varies greatly between individuals who harbor the same pathogenic microflora. To date, the bulk of evidence points to the host response to bacterial challenge as a major determinant of susceptibility. In this review, we will assess the data implicating various inherited and acquired risk factors for susceptibility to periodontal diseases.

Age Factors↗
PubMed2005

The clinical significance of new therapies for the management of periodontal disease.

With the approval of interventions or treatments for periodontal disease based on results of large clinical trials, it is often difficult for the clinician to determine whether the statistical results obtained from these studies are clinically significant and whether these interventions or treatments will thus be effective in their individual patients. In this article, a series of measures of clinical significance are derived from the literature, and a 2-step approach is suggested for determining clinical significance. First, the reliability of the data as a function of the reliability of the measurement tool(s) is calculated, and then clinical significance is put into the context of effect size. By using these estimators, clinicians can determine, for example, whether administration of an experimental local medication plus scaling and root planing provides a clinically significant outcome, which can assist them in deciding which interventions are most effective for their patients.

Clinical Trials as Topic↗
PubMed2004

A stable aspirin-triggered lipoxin A4 analog blocks phosphorylation of leukocyte-specific protein 1 in human neutrophils.

Lipoxins and their aspirin-triggered 15-epimers are endogenous anti-inflammatory agents that block neutrophil chemotaxis in vitro and inhibit neutrophil influx in several models of acute inflammation. In this study, we examined the effects of 15-epi-16-(p-fluoro)-phenoxy-lipoxin A(4) methyl ester, an aspirin-triggered lipoxin A(4)-stable analog (ATLa), on the protein phosphorylation pattern of human neutrophils. Neutrophils stimulated with the chemoattractant fMLP were found to exhibit intense phosphorylation of a 55-kDa protein that was blocked by ATLa (10-50 nM). This 55-kDa protein was identified as leukocyte-specific protein 1, a downstream component of the p38-MAPK cascade in neutrophils, by mass spectrometry, Western blotting, and immunoprecipitation experiments. ATLa (50 nM) also reduced phosphorylation/activation of several components of the p38-MAPK pathway in these cells (MAPK kinase 3/MAPK kinase 6, p38-MAPK, MAPK-activated protein kinase-2). These results indicate that ATLa exerts its anti-inflammatory effects, at least in part, by blocking activation of the p38-MAPK cascade in neutrophils, which is known to promote chemotaxis and other proinflammatory responses by these cells.

Amino Acid Sequence↗
PubMed2004

A molecular defect in intracellular lipid signaling in human neutrophils in localized aggressive periodontal tissue damage.

Host defense mechanisms are impaired in patients with congenital neutrophil (polymorphonuclear neutrophils (PMN)) defects. Impaired PMN chemotaxis is observed in localized aggressive periodontitis (LAP), a familial disorder characterized by destruction of the supporting structures of dentition. In the present studies, we sought evidence for molecular events underlying this aberrant human PMN phenotype. To this end, PMN transendothelial migration and superoxide anion generation were assessed with LAP patients and asymptomatic family members, as well as patients with other chronic mucosal inflammation. PMN from LAP patients showed decreased transmigration across vascular endothelial monolayers (18 +/- 12% of control, n = 4) and increased superoxide anion generation (358 +/- 37%, p = 0.003). Gene expression was analyzed using oligonucleotide microarrays and fluorescence-based kinetic PCR. cDNA microarray and kinetic-PCR analysis revealed diminished RNA expression of leukocyte-type diacylglycerol (DAG) kinase alpha in PMN from LAP patients (4.6 +/- 1.7 relative units, n = 6, p = 0.007) compared with asymptomatic individuals (51 +/- 27 relative units, n = 7). DAG kinase activity was monitored by DAG phosphorylation and individual DAG molecular species were quantified using liquid chromatography and tandem mass spectrometry-based lipidomics. DAG kinase activity was also significantly decreased (73 +/- 2%, p = 0.007) and correlated with increased accumulation of 1,2-diacyl-sn-3-glycerol substrates (p = 0.01). These results implicate defects in both PMN transendothelial migration and PMN DAG kinase alpha signaling as disordered functions in LAP. Moreover, they identify a potential molecular lesion in PMN signal transduction that may account for their aberrant responses and tissue destruction in this disease.

Adolescent↗