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PubMed1999

Classification of herpes simplex virus keratitis and anterior uveitis.

PURPOSE: To review the classification of herpes simplex virus (HSV) keratitis and anterior uveitis using the available clinical, pathologic, and laboratory models of disease. METHODS: The literature was reviewed to establish prior classifications of herpes simplex keratitis and uveitis. The author introduces a classification attempting to encompass all patients with this disease process, taking into account the newer proposed mechanisms of disease. RESULTS: A classification of HSV keratitis and uveitis is introduced based on the literature and the experience of the author in treating patients with this condition. CONCLUSIONS: There are multiple mechanisms of disease after ocular HSV infection, including damage from live virus, from immune and inflammatory mechanisms, and from structural damage in the aftermath of HSV infection (metaherpetic disease). Clinical, pathologic, and etiologic descriptions of these disease manifestations are offered. This may allow better communication between clinicians and authors of research protocols by defining the different aspects of this complex disease process.

Cornea↗
PubMed1999

An overview of haemodialysis and oxidant stress.

Today's patient population is increasingly older. Patients with chronic renal failure therefore start extracorporeal substitutive treatment having congestive heart failure, chronic liver disease, diabetes and so forth. In these patients, however, long-term haemodialytic treatment may add further aggravation on their pre-existing pathological conditions. Oxidative stress and alterations in lipid metabolism are caused by haemodialysis mainly due to (1) bioincompatibility type of reactions such as production of reactive oxygen species by inflammatory cells due to complement-mediated or -independent pathways, and (2) the imbalance between oxidants and antioxidants due to the diffusive loss of hydrophilic vitamins such as ascorbic acid. The events related to the oxidant stress may sustain a state of chronic inflammation. Recent advances suggest that atherosclerosis and proliferation of the smooth muscle are initiated and sustained by inflammatory mechanisms. Therefore, attempts to counterbalance the prooxidant effect of haemodialysis and to reduce the chronic inflammatory state will be presented.

Cardiovascular Diseases↗
PubMed2004

HDL and inflammation in atherosclerosis.

Atherosclerotic vascular disease is among the most frequent causes of death worldwide. Current therapeutic strategies concentrate mainly on lowering of low-density lipoprotein (LDL) cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms are more and more recognized to play an important role in vascular disease as inflammatory markers correlate with prognosis in acute and chronic coronary artery disease. HDL cholesterol exerts anti-inflammatory effects on the vasculature. Moreover, HDL is an antioxidant, inhibits thrombogenesis, and has pro-fibrinolytic properties. Last but not least, HDL mediates reverse cholesterol transport. These pleiotropic effects make HDL an ideal therapeutic target for novel therapeutic strategies specifically aiming at HDL elevation for the prevention and treatment of atherosclerotic vascular disease.

Animals↗
PubMedDate not supplied

[The role of inflammatory reaction in Alzheimer's disease and neurodegenerative processes].

Recent studies state that specific inflammatory mechanisms contribute to neurodegeneration. The theory is based on laboratory evidence of local upregulation of inflammatory cytokines (ex. IL-1, IL-6), acute phase proteins (ex. alpha 1-antitrypsin), activation of the complement cascade and accumulation of microglia in damaged regions in AD. In addition epidemiologic studies suggest that anti-inflammatory treatment provides some protection from AD. The first trials with prednisone fail to show any positive influence in AD patients. The alternative therapies are now considered with nonsteroid anti-inflammatory drugs, colchicine, cyclophosphamide. The anti-inflammatory treatment gives hope for slowing progression of the disease and decline of AD incidence.

Acute-Phase Proteins↗
PubMed2005

Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis.

Multiple sclerosis lesion activity concurs with the extent of inflammation, demyelination and axonal suffering. Pro-inflammatory myeloid cells contribute to lesion development, but the self-limiting nature of lesions implies as yet unidentified anti-inflammatory mechanisms. We addressed the hypothesis that myelin ingestion by myeloid cells induces a foamy appearance and confers anti-inflammatory function. First, we show that myelin-containing foam cells in multiple sclerosis lesions consistently express a series of anti-inflammatory molecules while lacking pro-inflammatory cytokines. Second, unique location-dependent cytokine and membrane receptor expression profiles imply functional specialization allowing for differential responses to micro-environmental cues. A novel human in vitro model of foamy macrophages functionally confirmed that myelin ingestion induces an anti-inflammatory programme. Foamy macrophages are unable to respond to prototypical inflammatory stimuli but do express molecules involved in suppression of inflammation. These findings provide novel insights into the mechanisms of lesion control and may open new roads to intervention.

Biomarkers↗
PubMedDate not supplied

Inflammation and Alzheimer disease.

Inflammatory mechanisms are active in patients with Alzheimer disease. Serum elevations of acute phase proteins such as alpha 1-antichymotrypsin, along with deposition of inflammatory cytokines in the brain, suggest a "cerebral acute phase response" contributing to amyloid deposition and tissue destruction. Activated microglia possessing HLA-DR surface markers accumulate around amyloid plaques. The complement cascade leads to generation of the membrane attack complex, which may directly damage neuronal membranes. This growing body of evidence suggests that empirical trials of anti-inflammatory drugs are now appropriate to test the hypothesis that suppression of these mechanisms will slow the rate of progression of Alzheimer disease. Several drugs useful in the treatment of rheumatic diseases are candidates for study in Alzheimer disease, including glucocorticoids, antimalarial drugs, and colchicine. Pilot studies of the synthetic glucocorticoid prednisone indicate that treatment with a moderate dose is well tolerated in patients with Alzheimer disease, and suppresses serum levels of acute phase proteins. Based on this experience, a multicenter parallel-design placebo-controlled trial has been initiated with Alzheimer's Disease Cooperative Study to determine whether treatment with prednisone can slow the rate of progression of Alzheimer disease.

Acute-Phase Proteins↗
PubMed2001

Anti-inflammatory effects of macrolides in lung disease.

During the past five decades there has been increasing interest in the potential anti-inflammatory effects of macrolide antibiotics. Low-dose macrolide therapy has dramatically increased survival in patients with diffuse panbronchiolitis, a disease with many similarities to cystic fibrosis (CF). This has led to further investigation into the potential use of macrolides in chronic lung diseases with an inflammatory component. This review summarizes the proposed anti-inflammatory mechanisms for this group of antibiotics, and examines the effect of macrolides on modulation of the inflammatory pathways, neutrophil function, bronchoconstriction, Pseudomonas biofilm, mucus rheology, bacterial adherence, and multidrug-resistant protein. It discusses the current status of clinical studies in children with CF, bronchiectasis, and asthma. While there are much in vitro data for different proposed anti-inflammatory effects, randomized controlled clinical trials in children with CF, bronchiectasis, and asthma are still just beginning. The benefits and potential side effects need to be determined before routine use can be advised.

Anti-Bacterial Agents↗
PubMed2002

[Interleukin-10 and coronary disease].

Understanding of the pathophysiology of atherosclerosis has changed markedly over the past few decades. It is now widely accepted that inflammation plays a fundamental role in the genesis and development of atherosclerosis. Inflammatory mechanisms also appear to determine clinical presentation and disease outcome. Atherosclerotic lesions have high concentrations of inflammatory cells (T lymphocytes and activated macrophages) as well as an abundance of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-8, interferon-gamma, tumor necrosis factor-alpha, etc.] that modulate local inflammatory responses. These may also alter plaque stability and facilitate the development of acute cardiovascular events. The role of anti-inflammatory cytokines in this context remains to be studied. IL-10 is an anti-inflammatory cytokine synthesised by T-lymphocytes and macrophages and has other anti-inflammatory effects. IL-10 expression within human atherosclerotic plaques has been demonstrated and animal experiments have shown that low levels of IL-10 lead to the development of extensive and unstable atherosclerotic lesions. Currently available evidence suggests a potential protective role for IL-10 in atherosclerosis. This new perspective on coronary disease as a chronic inflammatory process may open new avenues for the management of ischemic heart disease.

Animals↗
PubMed1998

[Systemic changes of the immune system in patients with Alzheimer's dementia].

OBJECTIVE: The etiology of Alzheimer's disease (AD) is still unknown. Recent investigations have shown that immune and inflammatory mechanisms could be of importance in the pathophysiology of AD. In this study 10 different immune parameters were measured to further investigate immunological changes in AD. PATIENTS AND METHODS: In 30 randomized patients with AD (20 females and ten males aged 74.5 +/- 6.5 years) as well as 13 controls aged 70.7 +/- 8.4 years, mostly relatives of the patients, all free of acute infection, serum concentrations of IgA, IgG, IgM, C3, C4, circulating immune complexes, sCD23, cardiolipin and the soluble cytokine receptors interleukin 2-receptor (sIL2-R) and tumor necrosis factor-receptor (sTNF-R) were measured. Diagnosis of AD was made according to NINCDS/ ADRDA criteria. The degree of dementia was determined by Mini-Mental-State-Examination (MMSE). RESULTS: Compared to the control group, patients with AD had significantly increased IgA (369,3 +/- 160,9 mg/dl vs 253.5 +/- 101.8 mg/dl [P = 0.02]), sCD23 [207.4 +/- 217.7 I. U./ml vs 80.6 +/- 35.5 I. U./ml [P = 0.004]), sIL2-R (829.6 +/- 742.1 I. U./ml vs 299.7 +/- 168.5 I. U./ml [P = 0.001]) and sTNF-R (4.6 +/- 2.0 I. U./ml vs 2.9 +/- 1.1 I. U./ml [P = 0.001]) levels. A negative correlation was seen between MMSE and sTNF-R (r = -0.34; P < 0.05). CONCLUSION: These findings indicate a chronic state of immune activation in AD and support the hypothesis of immune mediated mechanisms as part of the pathogenesis of AD. Prospective studies of the effect of anti-inflammatory drugs on the progression of AD will be needed.

Aged↗
PubMed2005

[Cytokines in the pathogeny of celiac disease].

Celiac disease is manifested by an enteropathy caused by intolerance to gluten, a family of proteins found in wheat and other cereals. Following intestinal T-cell activation in predisposed individuals, different inflammatory mechanisms are triggered under the control of the cytokine balance including those with a pro-inflammatory Th1 pattern such as IFNgamma, TNFalpha, IL-15 and IL-18; and regulatory cytokines such as TGFbeta and IL-10. These cytokines, besides increasing the intensity of the activation and the number of immune cells within the intestinal mucosa, regulate the activity of epithelial growth factors and metalloproteinases, a group of molecules involved in the maintenance and turnover of the intestinal mucosa structure; in inflammatory conditions, they also induce the intestinal lesion responsible for malabsorption syndrome.

Celiac Disease↗
PubMed2004

Cardiovascular disease and periodontal diseases: commonality and causation.

Periodontal diseases have long been recognized as a public health problem. Awareness of the destructive nature of periodontal diseases and the importance of a tight control of bacterial plaque are basic concepts of periodontal treatment. In the past decade, there has been a conceptual shift from periodontal diseases as an oral problem to periodontitis having an impact on systemic health. Recent evidence suggests a strong relationship between periodontal inflammatory disease and systemic diseases, such as cardiovascular disease. It is now generally accepted that inflammation plays an important role in atherosclerosis, and factors that systemically amplify inflammation are under close investigation. This article reviews some of the emerging concepts for the inflammatory mechanisms of periodontal diseases and atherosclerosis and examines the potential role of local inflammation in systemic inflammatory disease.

Animals↗
PubMed1998

Genetic variations in cytokine expression: a risk factor for severity of adult periodontitis.

Periodontitis is a collection of chronic inflammatory diseases that are caused by specific bacteria. The bacteria activate inflammatory mechanisms in the periodontal tissues that destroy collagen and bone that support the teeth. Although bacteria are essential for the initiation of periodontitis, the quantity and types of bacteria have not been sufficient to explain the differences in disease severity. In recent years, it has become evident that for many common chronic diseases, there are modifying factors that do not cause the disease but rather amplify some disease mechanisms to make the clinical condition more severe. There are now data to suggest that a few factors which amplify the inflammatory process make people susceptible to an increased severity of periodontitis. Studies of untreated disease in Sri Lanka identified 3 patterns of disease progression. Studies in twins suggested that part of the clinical characteristics of periodontitis may be explained by genetic factors, but previous attempts to identify genetic markers for periodontitis have been unsuccessful Some genetic variations (polymorphisms) are commonly found in our population and represent a mechanism by which individuals may exhibit variations within the range of what is considered biologically normal. Since certain cytokines are key regulators of the inflammatory response and are important in periodontitis, we investigated the relationship between genetic variations associated with cytokine production and periodontitis severity. There are several polymorphisms in the cluster of genes that influence IL-1 biological activity. In recent clinical trials, two of these polymorphisms, when found together, have been associated with a significant increase in the risk for severe generalized periodontitis. Genetic association with periodontitis was evident only when smokers were excluded from the analysis, confirming the importance of smoking, and suggesting that both smoking and the IL- I genotype are independent factors in severe periodontitis. It is notable that 1 polymorphism associated with severe periodontitis in our study is also known to correlate with a 2- to 4-fold increase in IL-1 beta production. These findings are consistent with the current model of how genetic factors influence common chronic diseases. If we apply this model to periodontitis, it would involve the following: 1) a disease-initiating factor that would undoubtedly be specific bacteria such as Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans. and Bacteroides forsythus: and 2) modifiers of disease mechanisms that account for the clinical severity, including smoking, the IL-I genotype, certain systemic diseases, and psychosocial stress. The association of the IL-I genotype with severe periodontitis is consistent with several lines of periodontal research. Several studies have suggested there is a substantial genetic influence in periodontal disease. Although specific genetic markers have been identified in the uncommon juvenile forms of periodontitis, previous studies of specific genetic markers in adults with periodontitis have not been encouraging. Many investigators have, however, demonstrated a role for IL-1 in the initiation and progression of periodontitis. For example, IL-1 activates the degradation of the extracellular matrix and bone of the periodontal tissues, and elevated tissue or gingival fluid levels of IL-1 beta have been repeatedly associated with periodontitis. In addition, IL-1 is a strong enhancer of tissue levels of PGE2 and TNF-alpha. The association of severe periodontitis with smoking and the IL-1 genotype suggest a role for these factors in the pathogenesis of periodontitis. The finding that host modifying factors are associated with severe periodontitis suggest a biological mechanism by which some individuals, if challenged by bacterial accumulations, may have a more vigorous immunoinflammatory response, leading to more severe clinical disease. (ABSTRACT

Adult↗
PubMed1996

Inflammatory mediators and parturition.

A role for inflammatory mechanisms in ovulation and parturition has been proposed on many occasions. In addition, many agents directly implicated in parturition, such as cytokines and prostaglandins, can be pro-inflammatory. The cervix can be softened and labour induced in women by mechanical trauma (sweeping the membranes), prostaglandins, antiprogestins or chemokines such as interleukin 8 (IL-8). This review presents evidence that invading cells, such as neutrophils, may be involved in the softening of the cervix and the onset of birth, and describes pathways in which this action can be controlled by cytokines and vasodilatory agents such as prostaglandins. Such mechanisms may, in turn, be controlled by steroids. The role of progesterone is enigmatic since progesterone concentrations do not fall in the peripheral circulation of women at the time of birth and yet antiprogestins soften the cervix in a manner indistinguishable from that seen during parturition. Prostaglandin E (PGE) can be both pro-inflammatory and anti-inflammatory, the former action probably occurs at the level of the blood vessel, whereas the latter is associated with the change in cytokine profile induced by PGE. This latter effect may contribute to pregnancy maintenance by maintaining a favourable cytokine profile in decidua. In contrast, the pro-inflammatory action of PGE may be involved in a synergistic action with chemokines such as IL-8 and play a role in parturition. In early pregnancy decidua, this pro-inflammatory action is likely to be controlled by progesterone-dependent prostaglandin dehydrogenase associated with the small blood vessels in decidua.

Animals↗
PubMed1987

Description, mechanisms and control of reactions to treatment in the human filariases.

Since diethylcarbamazine at the dosages used to treat filarial infections has little direct toxicity, most of the post-treatment reactions (termed Mazzotti reactions in onchocerciasis) result from the immunological inflammatory mechanisms activated in the process of clearing and killing the skin-swelling or blood-borne microfilariae. These reactions may be either localized to the skin, eyes or lymphatics or generalized systemically (e.g. headache, fever, adenopathy, arthralgia, tachypnoea, tachycardia, hypotension and even death). The occurrence and intensity of such reactions can be shown to be related to the intensity of infection. It had previously been speculated that the best candidates for triggering these post-treatment reactions were activation of complement, immediate hypersensitivity responses mediated by immunoglobulin E, and degranulation of eosinophils with resultant inflammatory reactivity. Recent detailed studies have given little support to the primacy of either complement or immediate hypersensitivity responses in triggering such reactions, but eosinophil degranulation with the release of inflammatory mediators into the tissues and peripheral blood is extremely prominent in all patients undergoing post-treatment reactions and develops with a time course generally consistent with what would be required of an initiator of such reactions. Other inflammatory mediators and pathways may be involved (e.g. kinins, prostaglandins, immune complexes, leukotrienes, platelets and parasite-derived inflammatory molecules), but there is currently no evidence to implicate any of these mechanisms as initiators of the response. Symptomatic treatment of these post-treatment reactions with analgesics, antipyretics, antihypotensive agents etc. has been successful, but their prevention has been achieved only with the broadly anti-inflammatory corticosteroids.

Animals↗
PubMed2006

Biochemical effects of two different hyaluronic acid products in a co-culture model of osteoarthritis.

OBJECTIVES: To compare the effects of two hyaluronic acid (HA) formulations on mediators of matrix turnover and inflammation in an IL-1-treated cartilage-synovium co-culture model with the aim of elucidating mechanisms by which viscosupplementation exerts beneficial effects in osteoarthritic joints. DESIGN: A co-culture model (100 ng/ml interleukin-1beta (IL-1beta) added to canine synovial and cartilage explants) was used to investigate the effects of HA on cartilage-synovium interactions. Three concentrations (1x, 0.5x, and 0.1x) of two commercial sources of HA (A: Synvisc [hylan G-F 20]; B: Hyalgan [sodium hyaluronate]) were used. Co-cultures without IL-1beta (negative) or with IL-1beta (positive) but neither HA product served as controls. The liquid media were collected every 3 days and explants of cartilage and synovium were collected on days 3, 6, and 20. Media and explants were analyzed histologically, biochemically, and immunohistochemically. RESULTS: Glycosaminoglycan (GAG) content was measured in cartilage explants. GAG content in explants was higher in both HA groups at the beginning and the conclusion of the study compared to the IL-1beta-treated group. GAG content of the media was significantly (P<0.05) lower in the Synvisc group than all other groups early. The Hyalgan group demonstrated progressively less GAG release later in the study. The addition of Synvisc did not decrease the matrix metalloproteinase (MMP)-3 concentrations at any point. MMP-3 concentrations were significantly (P<0.05) lower among the 1x and 0.5x Hyalgan groups on day 20 compared to the IL-1beta-treated group. On day 3, prostaglandin E(2) concentrations were significantly (P<0.05) higher in the IL-1beta-treated group compared to other groups. Both HA groups had less nitric oxide production than the control groups throughout the study. CONCLUSIONS: This study supports two potential mechanisms for viscosupplementation: a biosynthetic-chondroprotective mechanism, with a possible delay in onset depending on the form of HA; and an anti-inflammatory mechanism.

Animals↗
PubMed2004

Anti-inflammatory treatment with acetylsalicylate or rofecoxib is not neuroprotective in Huntington's disease transgenic mice.

Inflammatory mechanisms have been implicated in the pathogenesis of Huntington's disease (HD). Possible benefits of anti-inflammatory treatments include improved folding of mutant huntingtin mediated through chaperones, reduction of destructive cellular and humoral inflammatory pathways, and reduction of proapoptotic signaling mediated by NF-kappaB or other transcription factors. This study was performed to investigate the therapeutic potential of anti-inflammatory drugs as treatments for Huntington's disease by examining whether two compounds in widespread human use can ameliorate the phenotype of HD transgenic mouse models. We examined the effectiveness of acetylsalicylate and rofecoxib as treatments for the R6/2 and N171-82Q transgenic mouse models of Huntington's disease. Both drugs were administered from weaning. To monitor the effectiveness of the treatment, we analyzed the mice for weight loss, behavioral changes, and gross cerebral and striatal atrophy. The studies showed that neither drug benefited the animals at doses comparable to those tolerated by humans.

Acoustic Stimulation↗
PubMed2005

PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression.

Phosphodiesterase 4 (PDE4) is a major cyclic AMP-hydrolyzing enzyme in inflammatory and immunomodulatory cells. The wide range of inflammatory mechanisms under control by PDE4 points to this isoenzyme as an attractive target for new anti-inflammatory drugs. Selective inhibitors of PDE4 have demonstrated a broad spectrum of anti-inflammatory activities including the inhibition of cellular trafficking and microvascular leakage, cytokine and chemokine release from inflammatory cells, reactive oxygen species production, and cell adhesion molecule expression in a variety of in vitro and in vivo experimental models. The initially detected side effects, mainly nausea and emesis, appear at least partially overcome by the 'second generation' PDE4 inhibitors, some of which like roflumilast and cilomilast are in the later stages of clinical development for treatment of chronic obstructive pulmonary disease. These new drugs may also offer opportunities for treatment of other inflammatory diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

Uremia-associated immune defect: the IL-10-CRP axis.

Unstable atherosclerotic disease is related to systemic inflammation. While this inflammation remains at a subclinical level in otherwise healthy individuals, chronic elevation of pro-inflammatory cytokines is a common feature in patients with end-stage renal disease (ESRD). Current hypotheses on the pathogenetic links between inflammation and atherosclerosis emphasize that cytokine-producing monocytes/macrophages can actively infiltrate atherosclerotic plaques. A high activation level of this cell type may contribute to plaque growth. In the healthy, some 15% to 20% of circulating monocytes may be activated for cytokine production. This percentage is much higher in dialysis patients (50%), which may contribute to the rapid progression of atherosclerosis. Anti-inflammatory mechanisms such as interleukin-10 (IL-10) limit the production of a broad range of pro-inflammatory factors. Animal models, as well as clinical findings, suggest an involvement of this cytokine in the pathogenesis of vascular lesions. In hemodialysis (HD) patients, a protective role of IL-10 against systemic inflammation could be proven. A high interindividual variability in IL-10 production leads to distinct patient groups who can or cannot effectively limit the uremia- and dialysis-induced inflammation. Single nucleotide polymorphisms (SNPs) in the promotor of the IL-10 gene may genetically explain this heterogeneity. The IL-10 genotype strongly influences the range of variation of C-reactive protein (CRP), the most widely used marker of inflammation in dialysis patients. By limiting the inflammatory activation in ESRD patients, the IL-10 genotype is predictive for the risk of cardiovascular disease, meaning that the IL-10 "high-producer" genotype is associated with a lower event rate, and even mortality, than the IL-10 "low-producer" genotype.

C-Reactive Protein↗