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PubMed2004

Effectiveness of a triclosan/copolymer dentifrice on microbiological and inflammatory parameters.

According to the US Surgeon General's report, "Oral Health in America," published in 2000, most adults in the United States show some degree of periodontal pathology, with severe periodontal diseases affecting about 14% of middle-aged adults. Periodontal diseases are polymicrobial-induced inflammatory diseases, and they vary from mild gingival inflammation to severe deterioration of the periodontium, ie, loss of periodontal supportive tissues and, ultimately, tooth loss. New evidence shows that periodontal diseases may impact systemic health. For this reason, the maintenance of a healthy mouth is becoming increasingly important for the overall health of the body. This article summarizes laboratory research conducted during the development of a novel, multibenefit, oral-care technology based on triclosan--a broad-spectrum antibacterial agent--and a polyvinylmethylether/maleic acid copolymer. This unique combination of agents is found in Colgate Total, a clinically proven efficacious dentifrice for control of dental plaque and gingivitis. Data are presented that demonstrate the unique antibacterial properties of this dentifrice: (1) a broad-spectrum antimicrobial profile; (2) the long-lasting retention of triclosan on hydroxyapatite and epithelial cells; and (3) molecular evidence of antibacterial activity against specific pathogens in clinical dental plaque. In addition, data are presented that demonstrate the anti-inflammatory effects of triclosan on specific cytokines, the interruption of inflammatory pathways, and the inhibition of bone resorption. Overall, these data support the multibenefit clinical effects of Colgate Total and suggest a plurality of mechanisms of action.

Actinomyces↗
PubMed2005

Common mechanisms in immune-mediated inflammatory disease.

Characterization of the K/BxN mouse model of spontaneous arthritis contributed to the rediscovery of immune complex-mediated inflammation in rheumatoid arthritis (RA). Serum from these animals can transfer joint-specific inflammation to normal mice. Fc receptors, interleukin 1, mast cells, and complement are all essential for the development of arthritis after serum transfer. In RA, additional amplifying factors have been identified, including cytokines and intracellular signaling molecules, such as mitogen-activated protein kinases and nuclear factor kappa B, that perpetuate inflammation. Understanding the autoimmune and inflammatory pathways implicated in disease has led to targeted drug development and improved clinical outcomes.

Animals↗
PubMed2005

Endothelin-1 induces CD40 but not IL-6 in human monocytes via the proinflammatory transcription factor NF-kappaB.

UNLABELLED: The vasoactive peptide endothelin-1 (ET-1) may contribute to the pathogenesis of atherosclerosis and its acute complications. Because inflammation of the vessel wall is a characteristic feature of atherosclerosis, this study investigated the effect of ET-1 on the proinflammatory transcription factor NF-kappaB in monocytes. Monocyte/macrophages are a major source of inflammatory mediators in atheroma and are located in rupture prone plaque areas. In human monocytes ET-1 caused NF-kappaB activation. Specificity of ET-1-induced NF-kappaB activation was ascertained by supershift and competition experiments. This ET-1 effect was blocked by the ET-A-receptor antagonist BQ-123 but not by the ET-B-receptor antagonist BQ-788. PI-1, a specific inhibitor of the IkappaB-alpha-degrading proteasome complex, also prevented NF-kappaB activation. ET-1 stimulated expression of the proinflammatory molecule CD40 but not of the cytokine IL-6 in a NF-kappaB-dependent manner. CONCLUSION: The data demonstrate the ability of ET-1 to activate inflammatory pathways in human monocytes differentially.

Antihypertensive Agents↗
PubMed1992

Elevation of interleukin-6 in response to a chronic inflammatory stimulus in mice: inhibition by indomethacin.

Intraperitoneal (i.p.) injection of a mineral oil such as pristane induces a chronic inflammatory response in mice. This is characterized by a large influx of macrophages and other inflammatory cells into the peritoneal cavity for months after injection of the oil. By using the B9 cell bioassay, it was found that injection of pristane caused a marked and prolonged elevation of interleukin-6 (IL-6) levels in the peritoneal cavities of the mice. IL-6 was undetectable (less than 15 U/mL) in the peritoneal fluids of unprimed mice and during the first week after injecting pristane. From 4 to 20 weeks, the concentration of IL-6 increased to an apparent plateau with concentrations ranging from 200 to 2,000 U/mL. Increasing the dose of pristane did not substantially increase the peritoneal levels of IL-6 established at 20 weeks after pristane treatment. At later times (by day 250), the level decreased to 263 +/- 217 U/mL. However, mice that developed plasma cell tumors around day 300 showed high levels of IL-6 in the ascites fluid (650 to 2,400 U/mL). Serum levels of IL-6 were also elevated in pristane-primed mice but were substantially lower than those found in the peritoneal cavity. Chronic administration of the nonsteroidal anti-inflammatory drug indomethacin decreased the levels of IL-6 by 75% to 80%. Experiments performed in vitro showed that pristane-elicited macrophages secreted low levels of IL-6 constitutively and high levels of IL-6 in the presence of lipopolysaccharide. Both IL-6 and prostaglandin E2 production were inhibited by addition of indomethacin to macrophage cultures in vitro. Treatment of mice with pristane may provide a model system for studying the inflammatory pathways that control IL-6 levels in vivo. The relevance of these results to elucidation of the role of IL-6 in plasma cell tumorigenesis is discussed.

Animals↗
PubMed2006

Could inflammation be a key component in the progression of benign prostatic hyperplasia?

PURPOSE OF REVIEW: This review covers recent developments in the role of chronic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). RECENT FINDINGS: A paper on the subanalysis of the Medical Therapy of Prostate Symptoms study highlighted the role of chronic inflammation in the progression of BPH as determined by the pathological tissue obtained in the 4.5-year study. It shows patients with inflammation had significantly larger prostates, higher serum prostate specific antigen and a greater risk of urinary retention. This follows several other in-situ studies which demonstrated that elevated expression of pro-inflammatory cytokines in BPH. IL-6, IL-8 and IL-17 may perpetuate chronic immune response in BPH and induce fibromuscular growth by an autocrine or paracrine loop or via induction of COX-2 expression. Immune reaction may be activated via Toll-like receptor signalling and mediated by macrophages and T cells. Conversely, anti-inflammatory factors such as macrophage inhibitory cytokine-1 decreased in symptomatic BPH tissues. Animal models provided evidence for the presence of unique T-cell subsets which may suppress autoimmunity in healthy Sprague-Dawley rats resistant to chronic nonbacterial prostatitis. SUMMARY: The pathogenesis of BPH is still unresolved, although chronic inflammation may play a significant role in disease progression. Further research is required to determine the putative (auto)antigen, the influence of infiltrating inflammatory cells on the stromal/epithelial cell crosstalk and a new classification of BPH quantifying local and systemic inflammatory/immune reactions in relation to clinical relevance. New treatments for BPH investigating these specific inflammatory pathways may arise as we learn more about the way they work.

Animals↗
PubMed2006

Antibiotic therapy for coronary heart disease: the myth and the reality.

Atherosclerosis is acknowledged as an active inflammatory and thrombotic disease, as opposed to simple degeneration. Infection with microorganisms may contribute to this inflammation and hence the atherosclerotic process. The "infective" hypothesis - first proposed more than a century ago by Virchow - has been revisited in recent years and has implicated numerous microorganisms as potential stimuli. The greatest body of evidence points to Chlamydia pneumoniae, a respiratory pathogen, as the "culprit" microorganism. Consistent finding of bacterial antigens, DNA and occasionally live "viable" organisms within human atherosclerotic plaque support the evidence for the concept linking C. pneumoniae to atherosclerosis. Although original seroepidemiological studies indicated an association, more recent prospective and larger studies suggest that there may be only a weak link between elevated antibodies and immune complexes to C. pneumoniae and coronary heart disease (CHD). Animal models have shown how atherogenesis can be induced by endovascular infection with C. pneumoniae; in vitro studies have explored various immunological and inflammatory pathways linking infection and atherothrombosis. On the basis of this, antibiotic trials have been explored to assess whether there is any role for antichlamydial agents in the treatment of cardiovascular events. Here, we focus on the main antibiotic studies and explores patient criteria and choice, duration of therapy, and whether effects on clinical events could be reduced.

Animals↗
PubMedDate not supplied

[Myocardial depression in the burn patient].

Myocardial depression and heart failure are frequent complications in critically ill burn patients. The physiopathology is complex and involves the activation of inflammatory pathways, ischemia-reperfusion, oxidative stress and endothelial lesion. Diagnosis should be made early by means of hemodynamic monitoring. Treatment is accomplished by inotropics that act on different pathways of the contractile function and immune response associated with antioxidants and allopurinol.

Adult↗
PubMed1991

[Bronchial hyperreactivity].

Bronchial hyperreactivity, the abnormal reaction of the airways on non-allergic stimuli, is a feature of patients with chronic nonspecific lung disease. Several underlying mechanisms such as the neurogenic pathways, inflammatory cells and mediators, increased vascular leakage, epithelial damage and pathological changes in airway smooth muscle seem to play a role of importance in bronchial hyperreactivity. Recent developments in these research fields produce more clarity in the mutual connection of these factors in relation to the phenomenon of bronchial hyperreactivity.

Adrenergic Fibers↗
PubMed1990

Actinobacillus pleuropneumoniae: molecular aspects of virulence and pulmonary injury.

Contributions made by several laboratories in the area of Actinobacillus pleuropneumoniae virulence and its relationship to pulmonary disease will be reviewed briefly. Lung injury and subsequent disease, after infection with A. pleuropneumoniae, can be related to various bacterial toxins and host factors. Similar to other gram-negative bacteria. A. pleuropneumoniae has cell wall lipopolysaccharides which have been incriminated in a wide variety of toxic and tissue damaging processes. Virulent isolates of A. pleuropneumoniae have been shown to have a thick capsule whereas some avirulent isolates have a thin and easily removed capsule. The capsule of A. pleuropneumoniae is a linear unbranched polysaccharide composed of repeating dissaccharide subunits that bestow antiphagocytic properties to the bacterium but are also immunogenic. In addition, A. pleuropneumoniae has several chemically defined exotoxins. These toxins have generally been shown to be proteinaceous molecules that are hemolytic, cytotoxic, or edemogenic. Some of these toxins are proteolytic and others have the putative activity of being lytic for secretory IgA. Several of these molecules are capable of inducing lesions that are similar to those observed in natural infections and disease. Endogenous host factors have also been implicated in the development of lung lesions after infection by A. pleuropneumoniae Coagulation and inflammatory pathways have been demonstrated to be pivotal in the early phases of lesion development. In addition, the immune status of the animal is clearly related to the severity and ultimate outcome of A. pleuropneumoniae infection. To adequately treat and prevent this disease, we must understand the distinguishable interactions that occur between the host and the various molecular virulence attributes of A. pleuropneumoniae.

Actinobacillus↗
PubMed1990

[Immunohistology of polyps of the nose and paranasal sinuses. Physiopathologic value].

The pathophysiology of nasal polyposis is yet unclear, but chronic disturbances of the inflammatory pathways may be suspected. Immunological investigations were performed in 3 series of patients: 37 with nasal polyps, 22 with chronic sinusitis, and 15 controls with healthy nasal and sinusal mucosa. Patients with nasal polyps had up to ten times more eosinophil density than patients with sinusitis or healthy mucosa. The average of mast cells and IgE or IgA, M, G plasma cells were not different in the various group. Deposited immune complexes were always absent. These results gave us the opportunity to discuss recent pathogenic theories.

Adolescent↗
PubMed1989

Molecular mechanisms involved in human autoimmune diseases: relevance of chronic antigen presentation. Class II expression and cytokine production.

The observation that the local site of autoimmune responses over-expressed HLA class II led to the formulation that tissue antigen-presenting capacity contributes significantly to the mechanism of autoimmune disease perpetuation, by continually reactivating auto-antigen-reactive T lymphocytes. These in turn produce mediator molecules which maintain HLA class II expression (and hence antigen-presenting capacity) in the target tissues; and also initiate the immune and inflammatory pathways. The importance of this concept is that it provides a readily testable hypothesis that has been investigated extensively. For the thyroid diseases compelling data to support it have accumulated; in other diseases such as rheumatoid arthritis the evidence is increasing. The concept also relates the human autoimmune diseases to the normal mechanisms of immune induction and immunoregulation. This highlights the areas that we do not yet understand, namely the interplay of genetic susceptibility, extrinsic agents or disorders of immune regulation which permit the autoimmune process to become sufficiently pronounced as to engender a clinical autoimmune disease. Even with our limited understanding of the disease process, it is apparent that there are many opportunities for newer approaches at therapy, based on interfering with the immune cells or their mediators.

Antigen-Presenting Cells↗
PubMed1987

Urokinase: a chemotactic factor for polymorphonuclear leukocytes in vivo.

The effects of injecting urokinase into subdermal air sacs on the back of mice was studied. Urokinase was leukotactic in the concentration range of 2 X 10(-13) to 2 X 10(-15) M. This response was absolutely dependent on the enzyme activity of the serine esterase, but was found to be independent of generation of the chemotactic complement split product C5a. At high doses of urokinase (greater than 2 X 10(-12) M), no cellular infiltration was observed. Injection of 2 X 10(-10) M urokinase i.p. led to the systemic desensitization of mice when challenged in the skin with a lower dose (2 X 10(-14) M) of urokinase. Urokinase desensitization did not alter the ability of mice to respond to the chemical chemotactic factor f-met-leu-phe or to respond to C5a-dependent chemotactic stimuli. Urokinase desensitized mice failed to demonstrate a chemotactic response to nerve growth factor, thrombin, plasmin, or factor X activating enzyme, all of which were chemotactic in non-urokinase pre-treated animals. The results of these studies indicate the presence of three physiologically independent inflammatory pathways in mice: independent of C5 and not influenced by pretreatment with urokinase, independent of C5 and inhibited by pretreatment with urokinase, and dependent on C5 and not influenced by pretreatment with urokinase.

Animals↗
PubMed1985

The immunopathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) may represent a T cell dependent immune response to a restricted antigen(s) within the joint, with inflammatory pathways reflecting secondary recruitment. The nature of the inciting antigen is unknown--the stimulus could be an infectious agent or a host constituent. In patients with RA, the centrality of antiself reactivities and immunogenetic influences is apparent. Further clarification of these mechanisms would result in a potential for antigen-specific immunosuppressive therapy.

Antigens↗
PubMed1984

Cytokines and the chronic inflammation of rheumatic disease. I. The presence of interleukin-1 in synovial fluids.

Synovial fluids from patients with rheumatoid arthritis (13 cases), ankylosing spondylitis (six), psoriatic arthritis (two), osteoarthritis (three) and rubella arthritis (four) contain interleukin-1 (Il-1) activity as measured in the CH3/He mouse thymocyte assay. That this activity is Il-1 was shown by: (i) the time course of thymocyte stimulation; (ii) failure of PHA blast cells to absorb out the activity; (iii) molecular weight of 15,000-20,000 daltons, and (iv) ability to stimulate prostaglandin E2 production from synovial cells. These results indicate that IL-1 is an important mediator in the inflammatory pathway of different types of joint disease.

Animals↗
PubMed1994

Role of endothelin and tumour necrosis factor in the renal response to sepsis.

A rapidly increasing body of evidence is implicating endothelin and TNF in the pathogenesis of septic acute renal failure. TNF causes renal damage by recruiting leukocytes, accelerating fibrin accumulation, promoting cell lysis, stimulating the release of vasoconstrictor substances, and other mechanisms. ET-1 causes renal dysfunction in sepsis and endotoxaemia primarily by evoking severe reductions in RBF and GFR. While these are only two of the many agents that mediate renal dysfunction during sepsis, they stand out by virtue of their combined ability to modulate numerous inflammatory pathways and to elicit marked alterations in renal function. Clearly the development of specific TNF and endothelin antagonists holds out promise for the treatment and prevention of septic acute renal failure.

Acute Kidney Injury↗
PubMed1993

Haemostatic derangements associated with arenavirus infection in the guinea-pig: radioimmunoassay of fibrinopeptide A to assess thrombin action in infected animals.

Pichinde virus infection of inbred guinea-pigs is a model for arenaviral infections in humans. Infected animals experience reduced levels of multiple coagulation factors caused by either consumption coagulopathy or impaired factor synthesis. A radioimmunoassay (RIA) of guinea-pig fibrinopeptide A (gFPA) has been developed to measure the degree of thrombin action in vivo. gFPA was synthesized via the solid-phase method and conjugated to bovine serum albumin (BSA). A double antibody RIA was established employing goat anti-rabbit IgG to precipitate the primary complex composed of either 125I-5-Tyr-gFPA or 125I-12-Tyr-gFPA and rabbit anti-gFPA-BSA. The cross-reaching material was removed by mixing the plasma with 3 vol of ethanol. The supernatant was filtered through a hollow fibre apparatus by centrifugation. Plasma gFPA immunoreactivities of outbred guinea-pigs averaged 6.56 ng/ml. The gFPA-RIA was validated by determining the quantity of gFPA released from thrombin-degraded fibrinogen. A transient elevation of gFPA levels was detected in Pichinde-infected animals by the gFPA-RIA using 125I-12-Tyr-gFPA as a tracer. The pathogenic mechanism by which the increased gFPA levels may lead to the lethality of Pichinde virus infection remains to be elucidated. It is possible that the coagulopathy triggers changes in immune and inflammatory pathways that induces high cytokine concentrations, with deleterious effects on organs such as the heart and lungs.

Amino Acid Sequence↗
PubMed1993

Human Hageman factor (factor XII) and high molecular weight kininogen compete for the same binding site on human umbilical vein endothelial cells.

Factor XII (FXII, plasma concentration 375 nM) is a critical member of the plasma contact activation system and is the zymogen form of FXIIa, a serine protease involved in intrinsic coagulation, complement activation, activation of factor VII, and generation of the vasoactive peptide bradykinin. As such its interaction with cells involved in inflammatory pathways can be of physiologic and pathologic significance. We have studied the binding of FXII to cultured human umbilical vein endothelial cells (HUVEC). HUVEC were incubated with 125I-FXII, and cell-bound factor FXII was measured. FXII bound to HUVEC saturably in a zinc-dependent manner. The optimal zinc concentration was 50-60 microM. Binding of labeled FXII was drastically reduced when a 200-fold molar excess of unlabeled FXII was included in the incubation mixture at time zero or when added at 60 min during a 150-min time course experiment. Quantitative binding experiments indicated a dissociation constant of 144 nM with 10-12 million binding sites/endothelial cell. Unlabeled high molecular weight kininogen (HK) inhibited the binding of labeled FXII with a Ki of 98 nM, whereas unlabeled FXII inhibited the binding of labeled HK to HUVEC with a Ki of 152 nM. SDS-polyacrylamide gel electrophoresis and autoradiography of cell-bound 125I-FXII showed that factor XII underwent limited proteolysis and the molecular weights of the fragments were similar in size to activated FXII. The cell-bound activated factor XII was also able to activate prekallikrein. These data suggest that (i) FXII binds to HUVEC specifically, saturably, and reversibly in a zinc-dependent manner, (ii) HK and FXII may compete with each other for the same cell-surface receptor/s, and (iii) cell-bound FXII is capable of undergoing activation to FXIIa.

Binding Sites↗
PubMed1996

Selective decrease of M. leprae-specific IgG1 and IgG3 antibodies in leprosy patients associated with ENL.

Erythema nodosum leprosum (ENL) is a serious complication of lepromatous leprosy. Because of the similarities with the Arthus-type reaction, ENL is presumed to be due to immune complex formation and their deposition in tissues. The aim of this study was to dissect the antibody response at the IgG subclass level to ascertain differences in IgG subclasses in nonreactional lepromatous/borderline lepromatous (LL/BL) patients and reactional (ENL) lepromatous patients. The ENL group showed significantly lower serum antibody levels for the four subclasses compared to the LL/BL group of patients using the Mann-Whitney U test (IgG1, p = 0.0001; IgG2, p = 0.0009; IgG3, p = 0.0001; IgG4, p = 0.03). Since the majority of ENL patients (54 of 67) had received leprosy chemotherapy for varying durations of time, LL/BL patients were also compared with 19 ENL patients who had received < or = 2 weeks of chemotherapy. In this group only IgG1 (p = 0.048) and IgG2 (p = 0.001) antibodies showed significantly lower concentrations. Immunoblotting analysis demonstrated that in ENL patients IgG1 showed a selective disappearance of several antigenic bands recognized by the LL/BL serum pool; while most of the antigens recognized by IgG3 antibodies in the LL/BL serum pool were not detected in the ENL serum pool or in the sera of pretreated individual ENL patients. These results suggest that IgG1 and IgG3 may be the most pathogenic IgG subclass antibodies during ENL, and their deposition in tissues could initiate the complement-mediated inflammatory pathway resulting in the clinical disease associated with ENL.

Antigens, Bacterial↗