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PubMed1996

The effect of 5-aminosalicylate and para-aminosalicylate on the synthesis of prostaglandin E2 and leukotriene B4 in isolated colonic mucosal cells.

The effect of 5-aminosalicylate (5-ASA) and para-aminosalicylate (PAS) on the synthesis of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) was studied in 24 healthy volunteers. Both drugs are successfully used in the treatment of chronic inflammatory bowel disease, but the biochemical pathway of their anti-inflammatory action is still unknown. Biopsies were taken from the descending colon and were isolated biochemically. 5-ASA, PAS and a control were added to the suspension of isolated colonic mucosal cells and incubated over 0-45 min. Both 5-ASA and PAS did not alter the PGE2 production but, compared with PAS and the control, 5-ASA decreased the LTB4 synthesis in a dose-related fashion. As a result, the LTB4/PGE2 ratio was significantly diminished by 10(-4) mol/l 5-ASA. These findings are consistent with those of other authors, indicating that 5-ASA, at least in part, modulates the colonic eicosanoid synthesis. In contrast, PAS did not influence the mucosal production of PGE2 and LTB4 and therefore must exert some other biochemical action in order to explain its therapeutic effects in the treatment of Crohn's disease or ulcerative colitis.

Adult↗

PubMed1992

[Physiopathology of asthma].

The author reviews some of the physiopathologic aspects of asthma. Airway obstruction is related to several factors which include airway contraction, sub-mucosal edema and mucus hypersecretion. Bronchial hyperresponsiveness is related to inflammatory factors which occur at the periphery of the airways. Inflammatory cells include mastocytes, macrophages, lymphocytes, eosinophils, neutrophils and platelets. These cells can release inflammatory mediators including metabolites of cyclooxygenase pathway, leukotrienes and PAF. Chronic inflammatory changes can occur and can be explained by the persisting release of inflammatory mediators and abnormalities of cellular activation. Cytokines might be involved in this process as shown by the author's recent findings.

Asthma↗

PubMed2007

Arachidonic acid metabolism as a potential mediator of cardiac fibrosis associated with inflammation.

An increase in left ventricular collagen (cardiac fibrosis) is a detrimental process that adversely affects heart function. Strong evidence implicates the infiltration of inflammatory cells as a critical part of the process resulting in cardiac fibrosis. Inflammatory cells are capable of releasing arachidonic acid, which may be further metabolized by cyclooxygenase, lipoxygenase, and cytochrome P450 monooxygenase enzymes to biologically active products, including PGs, leukotrienes, epoxyeicosatrienoic acids, and hydroxyeicosatetraenoic acids. Some of these products have profibrotic properties and may represent a pathway by which inflammatory cells initiate and mediate the development of cardiac fibrosis. In this study, we critically review the current literature on the potential link between this pathway and cardiac fibrosis.

Animals↗

PubMed2004

The discovery and role of ADAM33, a new candidate gene for asthma.

Asthma is a complex disorder in which major genetic and environmental factors interact to initiate the disease and propagate it as a chronic relapsing disorder. Until recently, genetic factors implicated in the disease pathogenesis have been restricted to variants in known molecules involved in the inflammatory or remodelling pathways. This review discusses evidence for a new susceptibility gene for asthma, ADAM33, which was identified by positional cloning and shown to be selectively expressed in mesenchymal but not immune or inflammatory cells. ADAM33 belongs to a family of membrane-anchored metalloproteinases that also have fusagenic, adhesion and intracellular signalling properties. ADAM33 might play a key role in predisposing to the reduced lung function characteristic of asthma, possibly by influencing airway wall remodelling.

ADAM Proteins↗

PubMed2006

Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor.

1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-kappaB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR-/- mice, the basal level of kappaB inhibitor (IkappaB) alpha protein was markedly decreased compared with VDR+/- MEFs; however, degradation of IkappaBalpha and its phosphorylation in response to TNF-alpha treatment or Salmonella infection were not altered in VDR-/- cells, neither were the levels of IkappaB kinase-alpha and IkappaB kinase-beta proteins. Consistent with IkappaBalpha reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR-/- cells. In addition, the physical interaction between VDR and p65 was absent in VDR-/- MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in nuclear p65 DNA binding and NF-kappaB transcriptional activity; consistently, induction of IL-6 by TNF-alpha or IL-1beta was much more robust in VDR-/- than in VDR+/- cells, indicating that VDR-/- cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more proinflammatory due to the intrinsic high NF-kappaB activity. The reduction of IkappaBalpha in VDR-/- MEFs may be partially explained by the lack of VDR-mediated stabilization of IkappaBalpha by 1,25(OH)2D3. This is supported by the observation that IkappaBalpha degradation induced by TNF-alpha was inhibited by 1,25(OH)2D3 in VDR+/- cells, but not in VDR-/- cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-kappaB activation.

Animals↗

PubMed1996

Filamin translocation is an early endothelial cell inflammatory response to bradykinin: regulation by calcium, protein kinases, and protein phosphatases.

Endothelial cell (EC) cytoskeletal proteins are one of the earliest primary targets of second messenger cascades generated in response to inflammatory agonists. Actin binding proteins, by modulating actin gelation-solation state and membrane-cytoskeleton interactions, in part regulate cell motility and cell-cell apposition. This in turn can also modulate interendothelial junctional diameter and permeability. Nonmuscle filamin (ABP-280), a dimeric actin-crosslinking protein, promotes orthogonal branching of F-actin and links microfilaments to membrane glycoproteins. In the present study, immunoblot analysis demonstrates that filamin protein levels are low in sparse EC cultures, increase once cell-cell contact is initiated and then decrease slightly at post-confluency. Both bradykinin and ionomycin cause filamin redistribution from the peripheral cell border to the cytosol of confluent EC. Forskolin, an activator of adenylate cyclase, blocks filamin translocation. Bradykinin activation of EC is not accompanied by significant proteolytic cleavage of filamin. Instead, intact filamin is recycled back to the membrane within 5-10 min of bradykinin stimulation. Inhibitors of calcium/calmodulin dependent protein kinase (KT-5926 and KN-62) attenuate bradykinin-induced filamin translocation. H-89, an inhibitor of cAMP-dependent protein kinase, causes translocation of filamin in unstimulated cells. Calyculin A, an inhibitor of protein phosphatases, also causes translocation of filamin in the absence of an inflammatory agent. ML-7, an inhibitor of myosin light chain kinase and phorbol myristate acetate, an activator of protein kinase C, do not cause filamin movement into the cytosol, indicating that these pathways do not modulate the translocation. Pharmacological data suggest that filamin translocation is initiated by the calcium/calmodulin-dependent protein kinase whereas the cAMP-dependent protein kinase pathway prevents translocation. Inflammatory agents therefore may increase vascular junctional permeability by increasing cytoplasmic calcium, which disassembles the microfilament dense peripheral band by releasing filamin from F-actin.

Animals↗

PubMed2001

Induction of apoptosis in colon cancer cells by cyclooxygenase-2 inhibitor NS398 through a cytochrome c-dependent pathway.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown cancer preventive activity in patients who took them frequently. These drugs can induce tumor cells to undergo apoptosis in vitro. NS398, a cyclooxygenase-2 (COX-2)-selective inhibitor, has been reported to cause apoptosis in cancer cell lines. Therefore, we examined its effect on 15 human colon cancer cell lines and investigated its mechanism of action. NS398 decreased cell viability in all of the cell lines. Tumor cells that expressed COX-2 were shown to be more sensitive to NS398 treatment. In three selected colon cancer cell lines, NS398-induced apoptosis was mediated by the release of cytochrome c from mitochondria and, consequently, by the activation of caspase-9 and caspase-3 and by the cleavage of poly(ADP-ribose) polymerase. In contrast, caspase-8 was not involved in NS398-induced apoptosis, which suggested that the cytochrome c pathway may play an important role in NS398-induced apoptosis in colon cancer cell lines. Therefore, the combination of NS398 with apoptosis-inducing drugs through cytochrome c-independent pathways may be warranted.

Apoptosis↗

PubMed1999

Animal models of neuroimmune interactions in inflammatory diseases.

Animal models have been used successfully to study various aspects of neural-immune interactions. Although different approaches carry certain advantages and disadvantages, current high sensitivity screening and manipulation methods coupled with molecular and genetic approaches can be successfully used to tease out the neural pathways that regulate inflammatory disease and the effects of immune molecules, such as interleukins, on neuronal function and pathology. Newer methodologies that measure gene expression of thousands of genes will in the future add to the ability to evaluate complex systems interactions in whole animal models. This review addresses the advantages and disadvantages of some of these approaches in the context of application to neural-immune interactions.

Animals↗

PubMed2004

Ethanol selectively modulates inflammatory activation signaling of brain microglia.

In spite of well-known deleterious effects of alcohol on the nervous system in general, its specific effect on the brain immune system remains poorly understood. In order to better understand the effect of alcohol consumption on the innate immunity and inflammatory responses in the central nervous system (CNS), we sought to determine how ethanol influences inflammatory activation of microglia that function as the resident immune defense system of the brain. After treatment of BV-2 mouse microglial cells or rat primary microglia cultures with various stimuli, nitric oxide (NO) production was measured as an indicator of microglial activation. Pretreatment of the cells with ethanol (10-100 mM) for 1 h resulted in a significant decrease in lipopolysaccharide (LPS)-induced, but not interferon-gamma (IFNgamma)-induced, NO production, indicating that ethanol specifically inhibits LPS-induced inflammatory activation of microglia. This was further supported by the ethanol inhibition of LPS-induced IL-1beta expression. In addition, ethanol pretreatment selectively regulated LPS-induced NF-kappaB signaling pathway without affecting IFNgamma-induced signal transducer and activator of transcription 1 (STAT1) phosphorylation, interferon regulatory factor-1 (IRF-1) induction or IFNgamma-inducible IP-10 expression. The modulation of LPS-induced NF-kappaB by ethanol was due to the inhibition of coactivator p300. Altogether, these results suggest that acute ethanol exposure may selectively modulate signal transduction pathways associated with inflammatory activation of microglia, which may lead to derangement of CNS immune and inflammatory responses.

Animals↗

PubMed2006

Cellular inflammatory response and clinical outcome in cardiac surgery.

PURPOSE: This review briefly summarizes recent advances in the understanding of the pathophysiology of the inflammatory response to cardiac surgery and its ties to clinical outcomes. Links between specific inflammatory mediators and vulnerable organs will be emphasized, along with genetic risk factors that render specific patients susceptible to these complications. RECENT FINDINGS: Circulation of blood on the cardiopulmonary bypass circuit and the operative procedure itself provoke activation of circulating hematopoietic cells and vascular endothelial cells. These activated cells subsequently secrete mediators that amplify this inflammatory response and activated phagocytes undergo changes that facilitate their exit from the circulation into tissue, where they exacerbate organ complications of the procedure. Cardiac, renal and pulmonary dysfunction are among the most common complications of cardiac surgery and progress has been made in recent years demonstrating how the cellular inflammatory response is related to adverse outcomes in these organs. Accordingly, this review will focus on these three systems and the pathophysiology of their cardiac surgical complications. SUMMARY: Advances in our understanding of the pathways by which inflammatory mediators contribute to host injury offers the promise of interventions that are tailored to specific risks and the possibility of preoperatively identifying those patients most likely to benefit.

Cardiac Surgical Procedures↗

PubMed2001

Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling.

Psoriasis is recognized as the most common T cell-mediated inflammatory disease in humans. Genetic linkage to as many as six distinct disease loci has been established but the molecular etiology and genetics remain unknown. To begin to identify psoriasis disease-related genes and construct in vivo pathways of the inflammatory process, a genome-wide expression screen of multiple psoriasis patients was undertaken. A comprehensive list of 159 genes that define psoriasis in molecular terms was generated; numerous genes in this set mapped to six different disease-associated loci. To further interpret the functional role of this gene set in the disease process, a longitudinal pharmacogenomic study was initiated to understand how expression levels of these transcripts are altered following patient treatment with therapeutic agents that antagonize calcineurin or NF-KB pathways. Transcript levels for a subset of these 159 genes changed significantly in those patients who responded to therapy and many of the changes preceded clinical improvement. The disease-related gene map provides new insights into the pathogenesis of psoriasis, wound healing and cellular-immune reactions occurring in human skin as well as other T cell-mediated autoimmune diseases. In addition, it provides a set of candidate genes that may serve as novel therapeutic intervention points as well as surrogate and predictive markers of treatment outcome.

Adult↗

PubMed2005

Acetylcholinesterase biogenesis is impaired in lung cancer tissues.

Studies cited by Cowan et al. [J. Appl. Toxicol. 23, 177 (2003)] indicate existence of inflammatory and cholinergic pathways in both nerve agents and sulfur mustard (HD) injury. Increase in AChE synthesis and neurite extension was noted after exposure to HD [K.W. Lanks et al., Exp. Cell Res. 355 (1975)]. Moreover, anti-inflammatory drugs reduce the dermal, respiratory and ocular damage caused by exposure to HD. On the other hand, recent studies have noted the involvement of neuro-inflammatory processes during exposure to the nerve agents sarin or soman [Cowan et al., 2003]. The use of various anti-inflammatory drugs in addition to the classical antidotal drugs (e.g. atropine and oximes) caused decrease in certain toxic symptoms and inflammation-induced brain damage. Our new bifunctional drugs (Scheme 1) are based on CNS-permeable molecular combination of pseudo-reversible AChE inhibitor (pyridostigmine, PYR) coupled via a hydrophobic spacer (octyl or decyl hydrocarbon chain) to a non-steroidal anti-inflammatory drug (NSAID) such as Ibuprofen or Diclofenac (Scheme 1). This study evaluates the efficacy of certain bifunctional compounds against HD and soman poisoning in mice in vivo.

Acetylcholinesterase↗

PubMed2005

Bifunctional compounds eliciting anti-inflammatory and anti-cholinesterase activity as potential treatment of nerve and blister chemical agents poisoning.

Animals↗

PubMed2005

Soybean saponins suppress the release of proinflammatory mediators by LPS-stimulated peritoneal macrophages.

Proinflammatory mediators such as prostaglandins (PGs), nitric oxide (NO), certain inflammatory cytokines and chemokines play a pivotal role in tumor development. The anti-inflammatory properties of naturally occurring phytochemicals are associated with significant reduction in the risk of certain cancers in vitro and in vivo. In the present study, we investigated the effects of soybean saponins on the production of proinflammatory mediators in LPS-stimulated peritoneal macrophages. Soybean saponins significantly inhibited the release of PGE(2), NO, TNFalpha and monocyte chemotactic protein-1 (MCP-1) in a dose-dependent manner. Soybean saponins also down-regulated the expression of COX-2 and iNOS at mRNA/protein levels. Moreover, soybean saponins suppressed NF-kappaB activation by blocking IkappaB-alpha degradation. Our data indicate that soybean saponins exhibit anti-inflammatory properties by suppressing the transcription of inflammatory cytokine genes through the NF-kappaB signaling pathway. The anti-inflammatory properties of soybean saponins may be useful for ameliorating inflammatory diseases as well as suppressing tumor progression.

Animals↗

PubMed2006

Inhibition of classical PKC isoenzymes downregulates STAT1 activation and iNOS expression in LPS-treated murine J774 macrophages.

Proinflammatory cytokines and bacterial products trigger inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in inflammatory and tissue cells. In inflammation, NO acts as an important mediator having both proinflammatory and destructive effects. Protein kinase C (PKC) is a family of serine-threonine protein kinase isoenzymes involved in signal transduction pathways related to inflammatory responses. The aim of the present study was to investigate the role of classical PKC (cPKC) isoenzymes in the regulation of iNOS expression and NO production in murine J774 macrophages and the mechanisms involved. RO318220 (inhibits PKCbeta, PKCgamma and PKCvarepsilon), GO6976 (inhibits cPKC isoenzymes PKCalpha and PKCbeta) and LY333531 (inhibits PKCbeta) reduced lipopolysaccharide (LPS)-induced NO production and iNOS expression in a dose-dependent manner as did 6 h pretreatment with 1 microM phorbol 12-myristate 13-acetate (PMA) (which was shown to downregulate PKC expression). PKC inhibitors also reduced LPS-induced iNOS mRNA levels, but they did not affect the half-life of iNOS mRNA. PKC inhibitors did not alter LPS-induced activation of NF-kappaB as measured by electrophoretic mobility shift assay. All PKC inhibitors used and pretreatment with 1 microM PMA inhibited signal transducer and activator of transcription 1 (STAT1) activation as measured by the translocation of STAT1alpha from the cytosol to the nucleus by Western blot. In addition, inhibition of STAT1 activation by AG-490, an inhibitor of JAK-2, also reduced NO production. These results suggest that cPKC isoenzymes, especially PKCbeta, mediate the upregulation of iNOS expression and NO production in activated macrophages in an NF-kappaB-independent manner, possibly through the activation of transcription factor STAT1.

Animals↗

PubMed2004

New strategies to control the inflammatory response in cardiac surgery.

PURPOSE OF REVIEW: To present and interpret data from recent clinical studies (July 2002-August 2003) of strategies to control the inflammatory response after cardiac surgery. RECENT FINDINGS: Off-pump coronary artery bypass techniques, which avoid the need for extracorporeal circulation, attenuate the inflammatory response and appear to confer clinical benefit. Concerns regarding the quality of the revascularization after off-pump coronary artery bypass appear to have been allayed. At present, ventricular assist devices do not enhance the efficacy of off-pump coronary artery bypass. In patients undergoing cardiopulmonary bypass, heparin-coated circuits, hypothermic pulmonary perfusion, normoxic reperfusion after aortic unclamping, and modified ultrafiltration hold promise. Strategies to maintain perioperative haemodynamic stability, such as enoximone therapy, may be beneficial, particularly in elderly patients. Aprotinin may have important beneficial anti-inflammatory actions in higher-risk adult and paediatric patients. The therapeutic potential of corticosteroids, particularly when administered in multiple dosages is increasingly clear. Direct anti-mediator therapies that focus upon key effector molecules and pathways of the inflammatory response offer future therapeutic options. SUMMARY: The potential for strategies that inhibit the inflammatory response to improve outcome after cardiac surgery is clear. Large-scale multicentre trials investigating the most promising strategies, including off-pump coronary artery bypass, heparin-coated circuits, and perioperative corticosteroid and aprotinin therapy, are urgently needed. These trials need to be restricted to the high-risk patient groups most likely to experience benefit. In the interim, the optimal strategy to minimize the inflammatory response to cardiac surgery will remain elusive.

Journal Article↗

PubMed2003

High dietary fructose induces a hepatic stress response resulting in cholesterol and lipid dysregulation.

High-fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity with alterations of hepatic pyruvate dehydrogenase and hepatic very low-density lipoprotein secretion. Inflammatory cytokines also induce dramatic changes in lipid metabolism, particularly in serum triglycerides via increased hepatic secretion and/or delayed clearance of very low-density lipoprotein. The aim of this study was to determine whether the mechanism of lipid dysregulation in the high-fructose diet is induced by stress response pathways. Animals were fed a high-fructose diet for 14 d to establish hypertriglyceridemia and then were treated with lipoxygenase inhibitors for 4 d concurrent with the diet. At the end of drug treatment, the animals were divided into two groups and treated with lipopolysaccharide or a vehicle. Serum samples were taken pretreatment and posttreatment, and liver tissue was harvested at the end of study. Serum samples were tested for metabolic parameters, and the tissue samples were tested for metabolic and stress pathway responses. Our results show that fructose-fed rats have changes in the c-Jun N-terminal kinase pathway with correspondingly elevated activator protein-1 activity, consistent with an inflammatory response. Treatment with lipoxygenase inhibitors reversed the hypertriglyceridemia and also reduced activator protein-1 activation, suggesting that the basis for lipid dysregulation in this model is due to activation of inflammatory pathways in the liver.

Acute-Phase Reaction↗

PubMed2004

Cytokine-induced cell death in human oligodendroglial cell lines. II: Alterations in gene expression induced by interferon-gamma and tumor necrosis factor-alpha.

Cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), can initiate dual effects resulting in either cell growth or cell death. In this study, the human oligodendroglial cell lines HOG and MO3.13 were used as a model to study the molecular mechanisms of cytokine-induced cell death in human oligodendrocytes. We have previously shown that TNF-alpha and IFN-gamma induce apoptosis in both oligodendroglial cell lines within 72 hr. In the present study, the cell death pathways operating within these cells were further investigated at the gene expression level. Both cell lines express a broad repertoire of caspases and apoptosis-related genes. Some of these genes are specifically up-regulated by cytokine treatment; e.g., caspase-1 is up-regulated by IFN-gamma. In addition to direct cytotoxic effects, IFN-gamma and TNF-alpha also enhance the expression of Fas, TNFR1, and MHC class I molecules in both cell lines. This suggests that cytokines can make oligodendrocytes more vulnerable to different cell death pathways in an inflammatory environment. cDNA microarray analysis of the HOG cell line revealed that TNF-alpha induces genes that regulate apoptosis, survival, inflammation, cell metabolism, and cell signaling. The data suggest that oligodendroglial cells activate both death and survival pathways upon cytokine challenges. However, the survival pathways seem to be unable to compete with the death signal after more than 24 hr of cytokine treatment. These results may contribute to the development of therapeutic strategies aimed at interfering with cytokine-induced cell death of oligodendrocytes in patients with multiple sclerosis.

Adaptor Proteins, Signal Transducing↗