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PubMed2005

Defense mechanisms in inflammatory bowel disease.

BACKGROUND: Although psychiatric disturbances and personality features are possibly involved in inflammatory bowel disease, little attention has been given to the potential role of defense mechanisms in the formation, course, or prognosis of the disease. The purpose of the present study was to determine whether certain defense styles and ego mechanisms of defense are associated with inflammatory bowel disease, including both ulcerative colitis and Crohn's disease. METHODS: Seventy-six consecutive unselected outpatients participated in the study. The sample consisted of 39 patients with Crohn's disease, 33 with ulcerative colitis, and 4 with an intermediate form of inflammatory bowel disease. The Symptom Distress Checklist (SCL-90-R), Defense Style Questionnaire (DSQ), and Hostility and Direction of Hostility Questionnaire (HDHQ) were used. RESULTS: Crohn's disease patients presented a more immature defensive profile than ulcerative colitis patients, using a "maladaptive action" style, as well as "consumption" and "pseudo-altruism" defense mechanisms more often. These differences were statistically significant and they were independent of age, sex, educational level, disease extension, and pharmacologic treatment. A significant positive correlation was also found between disease activity and defensive profiles in both ulcerative colitis and Crohn's disease patients. In contrast, there was no statistically significant difference between ulcerative colitis and Crohn's disease patients in terms of psychiatric symptoms. CONCLUSIONS: Crohn's disease patients presented a different and more immature defensive profile than patients with ulcerative colitis. In addition, the more psychologically mature inflammatory bowel disease patients had lower rates of relapses and surgical operations, providing evidence that these aspects of personality are likely to influence the patients' adaptation to the disease.

Adolescent↗
PubMed1997

Inflammation and Alzheimer's disease: mechanisms and therapeutic strategies.

Inflammatory mechanisms in the brain may contribute to the neurodegenerative process in Alzheimer's disease. The cerebral acute-phase response mediated by inflammatory cytokines, the complement cascade, and the accumulation of activated microglial cells are appropriate targets for anti-inflammatory intervention. Pilot studies showed that tolerable doses of prednisone suppress the peripheral acute-phase response in Alzheimer's disease, and a multicenter therapeutic trial of prednisone is in progress. Two other anti-inflammatory drugs, hydroxychloroquine and colchicine, are also under investigation.

Alzheimer Disease↗
PubMed1978

Neutral proteinases secreted by macrophages degrade basic protein: a possible mechanism of inflammatory demyelination.

In the inflammatory demyelinating diseases, such as multiple sclerosis, Landry-Guillain-Barré syndrome and experimental allergic encephalomyelitis, demyelination occurs in the vicinity of infiltrating mononuclear cells. Although the histopathology is characteristic of each disease, the general observation that myelin destruction in inflammatory lesions begins prior to phagocytosis suggests a common mechanism for myelinolysis in these diseases. Recent studies show that stimulated macrophages secrete several neutral proteinases, including plasminogen (Plg) activator. We have tested the possibility that these proteinases could, directly or indirectly, initiate myelin destruction. Isolated brain myelin was incubated with supernatant media from cultures of stimulated mouse peritoneal macrophages in the presence and absence of Plg. Cell supernatants alone caused some degradation of basic protein (BP) in myelin. The amount degraded was considerably enhanced in the presence of Plg. The other myelin proteins remained essentially intact. While the Plg-independent proteolytic activity in the supernatants was abolished by EDTA, known to inhibit the neutral proteinases, the Plg-dependent hydrolysis was inhibited by p-nitrophenylguanidinobenzoate, an inhibitor of Plg activator and plasmin. These results suggested that the Plg activator secreted by the macrophages generated plasmin, which selectively degraded BP. This interpretation was confirmed by the observation that urokinase, a Plg activator, plus Plg was effective in degrading BP in myelin. We propose that the action of neutral proteinases released by stimulated macrophages, and its amplification by the Plg-plasmin system, may play a significant role in several inflammatory demyelinating diseases; and that the relative specificity of these reactions for myelin lies in the extreme susceptibility of BP to proteolysis.

Animals↗
PubMed2005

HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways.

Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. HMG-CoA reductase inhibitors (statins) possess several anti-inflammatory mechanisms and may be beneficial in the treatment of inflammatory diseases. Our previous study has shown that statins can inhibit iNOS gene expression in murine RAW264.7 macrophages. In this study, we showed that lovastatin, fluvastatin, atorvastatin, simvastatin, mevastatin and pravastatin are able to upregulate the mRNA expression of HO-1 gene. This effect of lovastatin was attenuated by farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), a protein kinase G (PKG) inhibitor (KT5823), a soluble guanylyl cyclase inhibitor (ODQ), a p38 MAPK inhibitor (SB203580), and MEK inhibitors (U0126 and PD98059), but not by inhibitors of protein kinase C (PKC), protein kinase A (PKA), c-jun N-terminal kinase (JNK) and Rho kinase. Consistent with this notion, our previous study has reported the ability of statins to activate ERK and p38 MAPK in RAW264.7 macrophages. Here we further found the participation of cyclic guanosine monophosphate (cGMP)/PKG pathway for ERK activation in cells stimulated with statin and the ability of statin to induce AP-1 activity, which is an essential transcription factor in the regulation of HO-1 gene expression. In addition, a Ras inhibitor (manumycin A) treatment also caused a marked induction of HO-1 mRNA followed by a corresponding increase in HO-1 protein; instead, inhibition of Rho activity by toxin B only led to a transient and weak induction of HO-1. The involvement of signal pathways in manumycin A-induced HO-1 gene expression was associated with p38 MAPK, JNK and ERK activation. Taken together, these results demonstrate for the first time that statins might activate PKG to elicit activations of ERK and p38 MAPK pathways and finally induce HO-1 gene expression, which provides a novel anti-inflammatory mechanism in the therapeutic validity.

Animals↗
PubMed2000

Intraarticular glucocorticosteroid injection into the lateral atlantoaxial joint under fluoroscopic control. A retrospective comparative study in patients with mechanical and inflammatory disorders.

OBJECTIVES: To evaluate the overall efficacy in various disorders of glucocorticoid injection into the lateral atlantoaxial joints, performed via the posterior route under fluoroscopic control. METHODS: Retrospective study of 26 patients including 16 (19 injections) with mechanical disorders and ten (16 injections) with inflammatory disorders. RESULTS: The response rate was 69.3%, the mean pain scale score decrease was 52.3 +/- 40.1%, and the mean duration of pain relief was 8.1 +/- 11.8 months. All three parameters were significantly (P < 0.005) better in the subgroup with inflammatory disorders than in the subgroup with mechanical disorders (response rate, 100% vs 50%; pain scale score decrease, 80 +/- 27% vs 34.2 +/- 40%, and pain relief duration, 16.9 +/- 14.9 months vs 24.5 months). A single patient developed a side effect (moderately severe hypertension). CONCLUSION: Glucocorticoid injection into the lateral atlantoaxial joints is a valid treatment alternative in patients who fail to respond to conventional noninvasive therapy.

Aged↗
PubMed1993

[Therapeutic perspectives in primary glomerulonephritis from recent physiopathological data].

In this review the authors describe the physiopathological mechanisms responsible for inflammatory lesions in primary glomerulonephritis. Primary glomerular nephropathies can be reproduced experimentally: models have been set up for non-proliferative kidney diseases such as minimal change disease or membranous glomerulopathies, and for proliferative kidney diseases such as Berger's disease. Studies performed with these models have resulted in the identification of inflammatory mechanisms creating glomerular lesions which may be acute (proteinuria) or progressive (glomerular sclerosis). These mechanisms include activation of resident cells, notably mesangial cells, and recruitment of circulating cells such as neutrophils, monocytes/macrophages and platelets. These cells participate in the local inflammatory reaction by releasing soluble mediators including biologically active lipids, such as eicosanoids, reactive oxygen and nitrogen derivatives, proteases, cytokines and vasoactive polypeptides. The importance of these mediators has been deduced from the fact that they are produced locally in excess, their introduction produces lesions and, above all, their suppression by inhibitory or antagonistic pharmacological agents reduces the severity of the lesions. Several observations have shown that the development of all the lesions can be prevented simply by blocking the activity of only one of these mediators. It is therefore possible to consider replacing the conventional glucocorticoid treatment, which has multiple pharmacological actions, by a more specific treatment directed against a single mediator.

Animals↗
PubMed2004

3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity.

The purpose of this study was to develop a novel therapy for Parkinson's disease (PD). We recently reported that dextromethorphan (DM), an active ingredient in a variety of widely used anticough remedies, protected dopaminergic neurons in rat primary mesencephalic neuron-glia cultures against lipopolysaccharide (LPS)-mediated degeneration and provided potent protection for dopaminergic neurons in a MPTP mouse model. The underlying mechanism for the protective effect of DM was attributed to its anti-inflammatory activity through inhibition of microglia activation. In an effort to develop more potent compounds for the treatment of PD, we have screened a series of analogs of DM, and 3-hydroxymorphinan (3-HM) emerged as a promising candidate for this purpose. Our study using primary mesencephalic neuron-glia cultures showed that 3-HM provided more potent neuroprotection against LPS-induced dopaminergic neurotoxicity than its parent compound. The higher potency of 3-HM was attributed to its neurotrophic effect in addition to the anti-inflammatory effect shared by both DM and 3-HM. First, we showed that 3-HM exerted potent neuroprotective and neurotrophic effects on dopaminergic neurons in rat primary mesencephalic neuron-glia cultures treated with LPS. The neurotrophic effect of 3-HM was glia-dependent since 3-HM failed to show any protective effect in the neuron-enriched cultures. We subsequently demonstrated that it was the astroglia, not the microglia, that contributed to the neurotrophic effect of 3-HM. This conclusion was based on the reconstitution studies, in which we added different percentages of microglia (10-20%) or astroglia (40-50%) back to the neuron-enriched cultures and found that 3-HM was neurotrophic after the addition of astroglia, but not microglia. Furthermore, 3-HM-treated astroglia-derived conditioned media exerted a significant neurotrophic effect on dopaminergic neurons. It appeared likely that 3-HM caused the release of neurotrophic factor(s) from astroglia, which in turn was responsible for the neurotrophic effect. Second, the anti-inflammatory mechanism was also important for the neuroprotective activity of 3-HM because the more microglia were added back to the neuron-enriched cultures, the more significant neuroprotective effect was observed. The anti-inflammatory mechanism of 3-HM was attributed to its inhibition of LPS-induced production of an array of pro-inflammatory and neurotoxic factors, including nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2) and reactive oxygen species (ROS). In conclusion, this study showed that 3-HM exerted potent neuroprotection by acting on two different targets: a neurotrophic effect mediated by astroglia and an anti-inflammatory effect mediated by the inhibition of microglial activation. 3-HM thus possesses these two important features necessary for an effective neuroprotective agent. In view of the well-documented very low toxicity of DM and its analogs, this report may provide an important new direction for the development of therapeutic interventions for inflammation-related diseases such as PD.

Animals↗
PubMed2002

Possible pathogenic mechanisms in inflammatory myopathies.

The limitations associated with the different approaches into the pathogenesis of the IIM have resulted in incomplete knowledge of disease mechanisms in myositis. In most research, in which muscle tissue was used to study the different aspects of disease, biopsies with inflammatory infiltrates have been selected. Although inflammatory cell infiltrates are a characteristic feature of myositis, selecting patients with inflammatory cell infiltrates for investigations naturally introduces a selection bias. Only a few studies have been published on patients without inflammatory infiltrates but with muscle weakness, and few studies have included follow-up biopsies after different therapies. The heterogeneity of the population of patients with myositis is another limitation of the studies of pathogenic mechanisms. Although most studies classify patients according to the Bohan and Peter criteria [118, 119], some studies used histopathologic criteria [6], and only a few studies included characterization with myositis-specific autoantibodies. Because myositis-specific autoantibodies are often associated with certain clinical profiles, classification according to autoantibody profiles could be important to define differences in the pathogenesis of different phenotypes [3]. From available data on pathogenic mechanisms it is evident that cellular and humoral immune responses are involved in disease mechanisms of myositis, but whether there is a muscle-specific immune response cannot be answered by current studies. It is likely that other mechanisms are important for development of muscle weakness, including metabolic disturbances, and muscle weakness could be caused by different mechanisms in different IIM subsets or in patients in different phases of the disease. There could be early changes, which reversibly affect the metabolism, and later, irreversible changes, that could be dependent on muscle fiber damage and replacement of muscle tissue by connective tissue and fat. Current findings suggest that cytokines, which are produced in muscle tissue from different cell sources including inflammatory cells, endothelial cells, and muscle fibers, could affect muscle function. Careful follow-up studies, including the effect of therapies targeting different molecules on molecular expression in muscle tissue, are likely to increase our knowledge on disease mechanisms. A better understanding of which molecules and mechanisms affect muscle function is likely to lead to improved, less toxic therapies in patients with myositis. Many possible target molecules for blocking therapies, especially the proinflammatory cytokines IL-1 and TNF-alpha, have been identified and should be studied in appropriate clinical settings given the currently poor outcomes of many patients with IIM.

Autoimmunity↗
PubMed2005

Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration.

BACKGROUND: Inflammation-activated glia are seen in many CNS pathologies and may kill neurons through the release of cytotoxic mediators, such as nitric oxide from inducible NO synthase (iNOS), and possibly superoxide from NADPH oxidase (NOX). We set out to determine the relative role of these species in inducing neuronal death, and to test the dual-key hypothesis that the production of both species simultaneously is required for significant neuronal death. METHODS: Primary co-cultures of cerebellar granule neurons and glia from rats were used to investigate the effect of NO (from iNOS, following lipopolysaccharide (LPS) and/or cytokine addition) or superoxide/hydrogen peroxide (from NOX, following phorbol 12-myristate 13-acetate (PMA), ATP analogue (BzATP), interleukin-1beta (IL-1beta) or arachidonic acid (AA) addition) on neuronal survival. RESULTS: Induction of glial iNOS caused little neuronal death. Similarly, activation of NOX alone resulted in little or no neuronal death. However, if NOX was activated (by PMA or BzATP) in the presence of iNOS (induced by LPS and interferon-gamma) then substantial delayed neuronal death occurred over 48 hours, which was prevented by inhibitors of iNOS (1400W), NOX (apocynin) or a peroxynitrite decomposer (FeTPPS). Neurons and glia were also found to stain positive for nitrotyrosine (a putative marker of peroxynitrite) only when both iNOS and NOX were simultaneously active. If NOX was activated by weak stimulators (IL-1beta, AA or the fibrillogenic prion peptide PrP106-126) in the presence of iNOS, it caused microglial proliferation and delayed neurodegeneration, which was prevented by iNOS or NOX inhibitors, a peroxynitrite decomposer or a NMDA-receptor antagonist (MK-801). CONCLUSION: These results suggest a dual-key mechanism, whereby glial iNOS or microglial NOX activation alone is relatively benign, but if activated simultaneously are synergistic in killing neurons, through generating peroxynitrite. This mechanism may mediate inflammatory neurodegeneration in response to cytokines, bacteria, ATP, arachidonate and pathological prions, in which case neurons may be protected by iNOS or NOX inhibitors, or scavengers of NO, superoxide or peroxynitrite.

Journal Article↗
PubMedDate not supplied

Type 4 phosphodiesterase-dependent pathways: role in inflammatory processes.

Type 4 phosphodiesterases (PDE4) belong to a superfamily of at least 11 isozymes catalyzing the hydrolysis of cyclic AMP (cAMP) and/or cyclic GMP (cGMP). PDE4 regulate intracellular levels of cAMP and are the predominant PDE expressed in inflammatory cells. Elevation of cAMP produces the inhibition of different inflammatory processes, such as cellular trafficking, cytokine release or reactive oxygen species production. But recent papers showed that the involvement of PDE4 in inflammatory mechanisms cannot be completely attributed to a cAMP-dependent pathway. The wide range of inflammatory mechanisms controlled by PDE4 designated these enzymes as a good target for anti-inflammatory compounds. PDE4 inhibitors have been demonstrated to be very potent in the treatment of chronic inflammatory diseases like asthma or chronic obstructive pulmonary disease (COPD) but their therapeutic window has yet to be improved.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Inflammatory mediators and modulation of blood-brain barrier permeability.

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.

Animals↗
PubMed2006

Decreased risk for myocardial infarction and lower tumor necrosis factor-alpha levels in carriers of variants of the PDCD1 gene.

Increasing interest has been directed toward the inflammatory mechanisms involved in the pathogenesis of myocardial infarction (MI). In the search for genetic mechanisms underlying these inflammatory components, we studied variants of programmed cell death-1 (PDCD1), an immunoinhibitory receptor that inhibits lymphocyte activation and cytokine production, previously shown to be associated with several autoimmune disorders. The PD1.1, PD1.3, and PD1.6 polymorphisms of the PDCD1 gene were typed in the Stockholm Heart Epidemiology Program, a population-based clinical material consisting of 1179 first-time MI case patients and 1528 unaffected control subjects. Individual alleles and haplotypes were studied for association with levels of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6, and C-reactive protein and risk for MI. We observed a weak protective effect of PD1.3A allele for MI (odds ratio: 0.78, 95% confidence interval: 0.61-0.98). We also observed decreased levels of TNF-alpha in carriers of the PD1.1A/PD1.3G/PD1.6A haplotype, which is consistent with our previous observation that this haplotype may be protective from autoimmune conditions. Carriers of variants of the PDCD1 gene exhibit a decreased risk for nonfatal myocardial infarction, and PDCD1 mediates variation in TNF-alpha levels.

Aged↗
PubMed1998

Differential myocardial abundance of collagen type I and type III mRNA in dilated cardiomyopathy: effects of myocardial inflammation.

OBJECTIVE: The collagen subtypes I (Col I) and III (Col III) are essential components of the cardiac extracellular matrix (ECM) maintaining the functional integrity of the heart. Histological, immunohistological, and biochemical studies, however, demonstrate characteristical changes of the ECM in dilated cardiomyopathy, myocarditis, ischemic cardiomyopathy, and hypertensive heart disease. METHODS: In order to investigate possible effects of inflammatory processes on mRNA abundance of Col I and Col III, we examined 24 patients with the presumptive clinical diagnosis of dilated cardiomyopathy (EF = 30 +/- 11%). 12 Patients were classified as idiopathic dilated cardiomyopathy without any evidence of myocardial inflammation; the remaining 12 patients were classified as inflammatory cardiomyopathy due to the immunohistologically documented inflammatory myocardial process. RESULTS: Quantification of reverse transcription polymerase chain reaction (RT-PCR) products revealed significant differences as to the mRNA abundance ratio Col III/Col I between subgroups of patients with inflammatory cardiomyopathy (1.16 +/- 0.18) and idiopathic dilated cardiomyopathy (2.77 +/- 0.65) regardless of left ventricular dysfunction (p < or = 0.05). CONCLUSION: It is not yet known, whether different Col III/Col I ratios differentially influence diastolic compliance. Our data suggest that inflammatory mechanisms seen in inflammatory cardiomyopathy influence the mRNA abundance of collagen subtypes I and III.

Adult↗
PubMed1980

Giant papillary conjunctivitis--a closer look.

Giant papillary conjunctivitis is a clinical entity which is thought to be caused by a combination of mechanical, immunological and inflammatory mechanisms. This paper reviews the laboratory research data associated with giant papillary conjunctivitis.

Conjunctivitis↗
PubMed2004

Blood and endothelium in immune complex-mediated tissue injury.

Antigen-antibody complexes can be formed both intravascularly and perivascularly and damage tissues by inducing inflammatory mechanisms. Recent studies have characterized a definite sequence of steps involved in these inflammatory mechanisms, and identified the predominance of particular chemical mediator(s) in each step. The lesions associated with this type of inflammation are characterized by the early development of plasma leakage, followed by the recruitment of polymorphonuclear leukocytes mediated by chemokines generated by FcgammaR-dependent mechanisms. The development of these lesions is modulated by endothelial cell-derived paracrine mediators, and activation of the coagulation system can ensue. The activation of platelets and coagulation, if not properly counterbalanced by fibrinolysis, might be a major factor for the late development of fibrotic changes and organ remodeling.

Animals↗
PubMed2003

Staphylococcal enterotoxin B-induced acute inflammation is inhibited by dexamethasone: important role of CXC chemokines KC and macrophage inflammatory protein 2.

This study was conducted to examine the anti-inflammatory mechanisms of dexamethasone during leukocyte recruitment and expression of the CXC chemokines macrophage inflammatory protein 2 (MIP-2) (CXCL2) and cytokine-induced neutrophil chemoattractant (KC) (CXCL1) in staphylococcal enterotoxin B (SEB)-induced acute inflammation. To do this, SEB was injected into murine air pouches with or without dexamethasone pretreatment for 2 h. SEB induced infiltration of leukocytes in a dose- and time-dependent manner, with the maximal response observed after 4 h of treatment with 10 microg of SEB. The recruited leukocytes comprised more than 77% neutrophils. Moreover, SEB challenge (10 microg) provoked time-dependent secretion of CXC chemokines, which peaked after 1 h. Local administration of antibodies against MIP-2 and KC significantly reduced SEB-triggered neutrophil accumulation by 38 and 59%, respectively. Dexamethasone (10 mg kg(-1)) significantly decreased neutrophil recruitment by 82% and reduced secretion of MIP-2 and KC by 89 and 85%, respectively, in response to SEB challenge. Our data demonstrate that dexamethasone potently inhibits neutrophil recruitment in SEB-induced inflammation. Moreover, we provide evidence that MIP-2 and KC are key mediators in the neutrophil response to SEB. Furthermore, our findings demonstrate that dexamethasone attenuates SEB-induced expression of MIP-2 and KC. Thus, this study elucidates important signaling pathways of SEB-induced neutrophil recruitment and anti-inflammatory mechanisms of action of dexamethasone.

Acute Disease↗
PubMed2000

[Non-steroidal anti-inflammatory drugs with selectivity for cyclooxygenase-2 in Alzheimer's disease. Rationale and perspectives].

POSSIBLE INFLAMMATORY MECHANISMS: Alzheimer's disease (AD) is a degenerative disease of the brain including possibly inflammatory mechanisms, as illustrated by the presence of activated microglial cells in the periphery of senile plaques and neurofibrillary tangles and the subsequent release of proinflammatory mediators with neurotoxic potency. RATIONALE FOR NSAID USE: Although not firmly demonstrated, the rationale for the prescription of non steroidal anti-inflammatory drugs (NSAIDS) as neuroprotective agents in AD lies on epidemiological data having shown a reduced risk of developing AD in patients on long-term therapy with NSAIDs (non selective cyclo-oxygenase [COX] inhibitors). RATIONALE FOR THE USE OF SELECTIVE COX-2 INHIBITORS: The rationale for the prescription of selective COX-2 inhibitors as neuroprotective drugs in AD lies on: Epidemiological data having shown a reduced risk of developing AD in patients treated with anti-inflammatory doses of classical NSAIDs (inhibition of COX-1 and COX-2) but not with antithrombotic doses of aspirin (selective inhibition of COX-1), Cellular experiments, Demonstration of a better gastro-intestinal (GI) safety profile with selective COX-2 inhibitors than with classical NSAIDs in short-term studies, allowing a possible long-term use in AD. BEFORE PRESCRIBING: COX-2 may have an ambivalent functionality in the brain since the basal production of prostaglandins through COX-2 may participate in neuronal homeostasis whereas the expression of COX-2 is associated with brain development. Classical NSAIDs are ineffective in reducing the formation of senile plaque and neurofibrillary tangles in AD, which is consistent with an ability to reduce inflammation associated with activation of microglia but illustrates their failure to suppress the degenerative process. Prophylactic use of selective COX-2 NSAIDs can be considered on the basis of their good GI safety after 6 months of marketing in United States but need to be confirmed for a longer time. CURRENT TRIALS: Clinical studies focusing on both the prevention and the slowing down of early AD are under way with two recently launched selective COX-2 inhibitors, celecoxib and rofecoxib.

Adult↗