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PubMed1999

Arachidonic acid in platelet microparticles up-regulates cyclooxygenase-2-dependent prostaglandin formation via a protein kinase C/mitogen-activated protein kinase-dependent pathway.

Activation of platelets results in shedding of membrane microparticles (MP) with potentially bioactive properties. Platelet MP modulate platelet, monocyte, and vascular endothelial cell function, both by direct effects of MP arachidonic acid (AA) and by its metabolism to bioactive prostanoids. We have previously reported that platelet MP induce expression of cyclooxygenase (COX)-2 and prostacyclin production in monocytes and endothelial cells. To elucidate further the molecular mechanisms that underlie MP-induced up-regulation of COX-2 expression, we investigated the response of a human monocytoid (U-937) cell line to platelet MP stimulation. In U-937 cells, MP-induced COX-2 expression and eicosanoid formation is prevented by pharmacological inhibitors of protein kinase C (PKC), PI 3-kinase, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase, and p38 kinase. Treatment with the PI 3-kinase inhibitors wortmannin and LY294002 also blocked MP-induced p42/p44 MAPK, p38, and JNK1 phosphorylation. Conversely, platelet MP stimulation of U-937 cells results in direct activation of PKC, p42/p44 MAPK, p38 kinase, and c-Jun N-terminal kinase (JNK) as well as activation of the transcription factors c-Jun and Elk-1. However, MP failed to activate the cAMP response element. Activation of U-937 cells by MP induces translocation of classical (PKCbeta), novel (PKCdelta) and atypical (PKCzeta and PKClambda) isozymes of PKC from the cytosol to the membrane, with concomitant activation of downstream MAPK. While MP-induced activation of p42/p44 MAPK and p38 kinase is transient, a sustained activation of JNK1 was observed. Although PKC activation is required for MP-induced p42/p44 MAPK, activation of the stress kinases p38 and JNK1 was PKC-independent. The fatty acid fraction of the MP accounted for these effects, which were mimicked by MP AA. Rather than acting directly via nuclear receptors, MP AA activates COX-2-dependent prostaglandin production by a PKC/p42/p44 MAPK/p38 kinase-sensitive pathway in which PI 3-kinase plays a significant role. MP AA also stimulates transcriptional activation of COX-2 as well as c-Jun and Elk-1.

Arachidonic Acid↗

PubMed2004

Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis.

OBJECTIVE: Monosodium urate monohydrate (MSU) crystals promote gouty inflammation that is critically mediated by neutrophil recruitment and activation. Interleukin-8 (IL-8) and closely related chemokines are major neutrophil chemotaxins in experimental gout. But MSU crystals also activate the classical and alternative pathways of complement, and MSU crystals directly cleave C5 on the crystal surface. Unlike IL-8, the roles in acute gout of individual complement-derived peptides and of the terminal C5b-9 complement components that comprise the membrane attack complex (MAC) are unclear. Hence, we studied rabbits deficient in the MAC component C6 to determine if MAC mediated urate crystal-induced arthritis. METHODS: We injected C6-deficient and C6-sufficient rabbit knee joints with 10 mg of pyrogen-free urate crystals and analyzed IL-8 levels, leukocyte influx, and joint inflammation 24 hours later. RESULTS: There was a significant decrease (>60%) in swelling in MSU crystal-injected knees of C6-deficient animals as compared with C6-sufficient animals (P < 0.05). An attenuated rise in MSU crystal-induced joint effusion levels of IL-8 also was observed, which was concordant with diminished numbers of neutrophils (P < 0.05) but not monocytes in MSU crystal-induced knee synovial fluid from C6-deficient animals. Synovial tissue analysis confirmed mononuclear leukocyte infiltration in response to MSU crystal injection in all animals, but substantial neutrophil infiltration only in C6-sufficient animals. CONCLUSION: MAC activation appears to play a major role in intraarticular IL-8 generation and in neutrophil recruitment in experimental acute gouty arthritis of the rabbit knee. C6 and MAC activation may represent novel therapeutic targets for suppression of neutrophil-mediated joint inflammation in gout.

Animals↗

PubMed1986

The relationship between the vitamin D system and cancer.

The classic function of 1,25-dihydroxyvitamin D3, the hormonally active form of vitamin D, is the maintenance of normal levels of calcium and phosphorus in the blood. 1,25-Dihydroxyvitamin D3 binds to a specific receptor protein and exerts its biologic action by a mechanism analogous to that proposed for other steroid hormones, that is, the receptor-ligand complex acts on the chromatin to induce transcription of specific genes. Intracellular receptors that bind 1,25-dihydroxyvitamin D3 with high affinity have been found in a large number of tumor cell lines examined as melanoma, osteosarcoma, and human breast and colonic carcinoma cells. The 1,25-dihydroxyvitamin D3 receptor in these cells has characteristics similar to the receptor in bone and intestine, the known target tissues of the hormone. In fact, 1,25-dihydroxyvitamin D3 inhibits the proliferation of melanoma, osteosarcoma, and breast carcinoma cells. More recently, 1,25-dihydroxyvitamin D3 has been shown to suppress the growth and induce monocytic differentiation of murine and human myeloid leukemia cells in vitro. These results point to a previously unsuspected involvement of vitamin D in cell proliferation and differentiation and suggest that analogs of the vitamin D hormone may be of interest as possible therapeutic agents in the treatment of malignancy.

Calcitriol↗

PubMedDate not supplied

Effect of cyclosporin A in Lewis rats in vivo and HeLa cells in vitro.

The aim of this study was to compare the effect of cyclosporin A (CsA) in inbred Lewis rats with published assessment of immunotoxicity in 'classical' outbred Wistar rats. A second purpose was to consider the contribution of a panel of in vitro assays in cell cultures when added to an immunotoxicity study in vivo. The in vivo effect of CsA was investigated in a 28-day subacute immunotoxicity study in male Lewis rats at three different concentrations: 1.25, 5 and 20 mg kg(-1). The highest dose of CsA exceeded the maximum tolerated dose. A drop in body, spleen and popliteal lymph node weight of exposed animals displayed symptoms of toxicity. At a high toxic dose, haematological changes showed a decrease in the leucocyte count and in the percentage of lymphocytes, and an increase in the percentage of polymorphonuclear leucocytes. The haematocrit was significantly dose-dependently suppressed in all rats exposed to CsA. A similar dose-dependent depression of the mean cell volume of erythrocytes was found in rats given high and middle doses of CsA. The phagocytic activity of polymorphonuclear leucocytes and monocytes also was significantly dose-dependently suppressed. No significant changes in primary antibody response to sheep erythrocytes or in vitro proliferative response of spleen lymphocytes to mitogens were found in those rats.A battery of in vitro cytotoxicity methods was selected for the evaluation of metabolic and functional activity of subcellular organelles (mitochondria, lysosomes) and for the detection of drug-induced superoxide-mediated damage in HeLa cells. This cell line was chosen because it has a lower activity of superoxide dismutase (SOD) than normal cells and is sufficiently sensitive for the detection of the induction of oxygen radicals. The in vitro results indicated a direct relationship between CsA cytotoxicity and a change in the mitochondrial enzyme activity, as well as an induction of superoxide production. The results of the study indicated that a combination of selected in vivo and in vitro methods is an inexpensive way to obtain more complex information on cell status affected by xenobiotics.

Anemia↗

PubMed1992

Benign cutaneous histiocytic tumors in childhood and adolescence, excluding Langerhans' cell proliferations. A clinicopathologic and immunohistochemical analysis.

Clinical and light-microscopic findings were reviewed in 60 benign histiocytic tumors of the skin arising in patients who were 19 years of age or younger. These lesions were placed in five categories, based on the presence or absence of Touton giant cells, the relative content of vacuolated polygonal cells and spindle cells, and the extent of stromal collagen in the proliferations. The resulting distribution included 16 cases of classic juvenile xanthogranuloma (JXG), four examples of xanthomatous JXG, 11 "transitional" JXG, 11 histiocytomas, and 18 dermatofibromas. The histological appearances of the lesions were related to the elapsed time between their clinical presentation and biopsy sampling. Intervals of 3.5, 3.5, 3.6, 7, and 13.4 months were noted for each histologic group, respectively. Hence, "early" lesions (JXG variants) showed no differences in clinical duration, but significantly longer evolutions were observed for histiocytomas and dermatofibromas. Immunohistochemical studies were conducted utilizing antibodies to several "histiocytic" markers (CD68, cathepsin B, MAC387), CD45 antigen, and S-100 protein. Cathepsin B was universally expressed by all tumors, but its intensity and scope were variable. In addition, only dermatofibromas failed to show CD68 positivity. Scattered mononuclear inflammatory cells in the lesions were CD45 reactive, whereas other cell types were not so labeled. MAC387 was absent in all cases. These findings suggest that these lesions do indeed show histiocytic differentiation, and that they are probably related to peripheral blood monocytes antigenically. Differences in the histologic appearances of these cutaneous histiocytic proliferations of childhood may simply reflect dissimilar periods of clinical growth before biopsies are performed.

Adolescent↗

PubMed2005

Macrophages and neurodegeneration.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Demyelination is a classical feature of MS lesions, and neurological deficits are often ascribed to the reduced signal conduction by demyelinated axons. However, recent studies emphasize that axonal loss is an important factor in MS pathogenesis and disease progression. Axonal loss is found in association with cellular infiltrates in MS lesions. In this review, we discuss the possible contribution of the innate immune system in this process. In particular, we describe how infiltrated macrophages may contribute to axonal loss in MS and in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. An overview is given of the possible effects of mediators, which are produced by activated macrophages, such as such as pro-inflammatory cytokines, free radicals, glutamate and metalloproteases, on axonal integrity. We conclude that infiltrated macrophages, which are activated to produce pro-inflammatory mediators, may be interesting targets for therapeutic approaches aimed to prevent or reduce axonal loss during exacerbation of inflammation. Interference with the process of infiltration and migration of monocytes across the blood-brain barrier is one of the possibilities to reduce the damage by activated macrophages.

Animals↗

PubMed1983

[Automatic blood smear differentiation using the Coulter Electronics Diff 3-50 system].

The Coulter Electronics Diff 3-50 consists of a slide spinner, a slide stainer and a cell classifier. The cell analyzer is composed of an optical system with a microscope, microprocessor, video camera and printer. The system used in this laboratory is supplemented by a video monitor. The Diff 3-50 analyzes blood cells according to the classical criteria used in hematology. It classifies 11 types of nucleated blood cells and it processes an average of 45 blood smears per hour. It features a visual control of each cell classified with a built-in mechanism for change of classification by the operator if necessary. Moreover, the system estimates leukocyte and platelet count and generates a quantitative estimate of platelet number. Blood smears of 507 blood samples from patients admitted to the hospital were included in the present study. They were analyzed twice, first by the Diff 3-50, and secondly by visual checking of the automatic classification of each cell. The results of the two procedures were then compared. The findings indicate an overall false negative error of 1.4% and an overall false positive error of 4.3%. Major differences were found, though not consistently, only when the classification by the Diff 3-50 of the band neutrophils was compared with the visual classification performed by the operator. Lymphocytes and monocytes correlated well when both procedures were compared. Blasts present in 5 blood smears were recognized by the classifier. The Diff 3-50 identified immature granulocytes in 47 out of 48 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Cell Count↗

PubMed2004

Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-kappaB binding activity and CCR7 expression.

Interleukin-6 (IL-6) is produced during bacterial and viral infections and by various malignant tumors. Here, we describe novel immunosuppressive properties of IL-6 in dendritic cells (DC). In the presence of GM-CSF, IL-4, and a maturation stimulus, IL-6 skewed monocyte differentiation into phenotypically mature but functionally impaired DC. In DC matured with the toll-like receptor (TLR)4 stimulus lipopolysaccharide (LPS) or other pro-inflammatory stimuli, IL-6 inhibited CCR7 chemokine receptor up-regulation. As demonstrated for LPS-stimulated DC, IL-6 impaired chemotaxis to CCR7-activating chemokines required for recruiting DC to lymphoid tissues in vivo. Moreover, IL-6 inhibited production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma inducible protein-10 (IP-10) in DC, and DC-driven allogeneic T cell proliferation in mixed lymphocyte reactions. CCR7 expression was blocked at the transcriptional level. IL-6 led to inhibition of nuclear factor-kappaB (NF-kappaB) binding activity, regulating CCR7 transcription. Neutralization experiments revealed that autocrine IL-10 partially contributed to CCR7 suppression in IL-6-treated DC. Thus IL-6, a cytokine once labeled as "pro-inflammatory" can mediate immunosuppressive functions, which may involve induction of the classical "anti-inflammatory" cytokine IL-10. Because IL-6 is expressed in response to various pro-inflammatory stimuli in vivo, this mechanism may contribute to down-regulating the immune response initiated by pathogens, in persistent infections or tumors.

Chemotaxis, Leukocyte↗

PubMed2004

Inflammation and the degenerative diseases of aging.

Chronic inflammation is associated with a broad spectrum of neurodegenerative diseases of aging. Included are such disorders as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, the Parkinson-dementia complex of Guam, all of the tauopathies, and age-related macular degeneration. Also included are such peripheral conditions as osteoarthritis, rheumatoid arthritis, atherosclerosis, and myocardial infarction. Inflammation is a two-edged sword. In acute situations, or at low levels, it deals with the abnormality and promotes healing. When chronically sustained at high levels, it can seriously damage viable host tissue. We describe this latter phenomenon as autotoxicity to distinguish it from autoimmunity. The latter involves a lymphocyte-directed attack against self proteins. Autotoxicity, on the other hand, is determined by the concentration and degree of activation of tissue-based monocytic phagocytes. Microglial cells are the brain representatives of the monocyte phagocytic system. Biochemically, the intensity of their activation is related to a spectrum of inflammatory mediators generated by a variety of local cells. The known spectrum includes, but is not limited to, prostaglandins, pentraxins, complement components, anaphylotoxins, cytokines, chemokines, proteases, protease inhibitors, adhesion molecules, and free radicals. This spectrum offers a huge variety of targets for new anti-inflammatory agents. It has been suggested, largely on the basis of transgenic mouse models, that stimulating inflammation rather than inhibiting it can be beneficial in such diseases as AD. If this were the case, administration of NSAIDs, or other anti-inflammatory drugs, would be expected to exacerbate conditions such as AD, PD, and atherosclerosis. However, epidemiological evidence overwhelmingly demonstrates that the reverse is true. This indicates that, at least in these diseases, the inflammation is harmful. So far, advantage has not been taken of opportunities indicated by these epidemiological studies to treat AD and PD with appropriate anti-inflammatory agents. Based on this evidence, classical NSAIDs are the most logical choice. Dosage, though, must be sufficient to combat the inflammation. Analysis of mRNA levels of inflammatory mediators indicates that the intensity of inflammation is considerably higher in AD hippocampus and in PD substantia nigra than in osteoarthritic joints. Thus, full therapeutic doses of NSAIDs, or combinations of anti-inflammatory agents, are needed to achieve the suggested neurological benefits.

Aging↗

PubMedDate not supplied

Chemotaxis of human and rat leukocytes by the delta-selective non-peptidic opioid SNC 80.

Opioids like morphine, represent a major source of relief for most chronic moderate to severe nonmalignant pain. However, opioid abuse may lead to infections such as hepatitis and AIDS because opioids have been associated with suppressing various parameters of immune function including antimicrobial resistance, antibody production, monocyte-mediated phagocytosis, and both neutrophil and monocyte chemotaxis. We have previously reported immunopotentiating properties of non-peptidic opioid receptor selective agonists and antagonists. In this study, we evaluated the effects of the nonpeptidic delta-opioid receptor agonist (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC 80) on chemotaxis of rat thymic and human peripheral blood mononuclear cells by using a modified Wilkinson chamber. Cell recruitment is an essential process in acute and chronic inflammatory responses. We observed that SNC 80 at concentrations of 10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) M, significantly (p < 0.01) stimulated rat thymic (1.3, 1.55, 1.58, 1.75, and 1.8-fold increases respectively) and human leukocyte (1.13, 1.37, 1.43, 1.7, 1.83 fold-increases respectively) chemotaxis (demonstrated by checkerboard assays), compared with untreated control. The effects of SNC 80 on chemotaxis of rat and human leukocytes were antagonized by naloxone, indicating that the modulation of chemotaxis by SNC 80 is via a classic opioid receptor. The development and use of non-peptidic opioids like SNC 80 could have an immediate impact not only as potent analgesics, but in immunoregulation.

Animals↗

PubMed1998

Structure, organization, and chromosomal mapping of the gene encoding macrosialin, a macrophage-restricted protein.

Murine macrosialin and its human homologue CD68 are heavily glycosylated transmembrane proteins expressed specifically in macrophages and macrophage-related cells. Macrosialin is predominantly a late endosomal protein but is also found on the cell surface where it binds oxidized LDL, an important factor in atherogenesis. We have cloned and sequenced the murine macrosialin gene (Cd68) and localized it by linkage analysis to chromosome 11. The gene is 1908 nucleotides long from the start site of transcription to the end of the 3'UTR. It has six exons, which range in size from 79 to 434 nucleotides. The promoter lacks a classical TATA box but contains other protein binding sites consistent with preferential monocyte/macrophage gene expression. Although the function of macrosialin is unknown, it might play a role in lipoprotein regulation given its binding of oxidized LDL in vitro and its colocalization to a region on chromosome 11 involved in the control of HDL levels.

Animals↗

PubMed2005

Caspase-1 dependent macrophage death induced by Burkholderia pseudomallei.

Burkholderia pseudomallei is the causative agent for melioidosis, an infectious disease endemic in South-east Asia and northern Australia. Infection can result in a wide spectrum of clinical outcomes, including asymtomatic, acute or chronic conditions. The ability of the bacteria to survive intracellularly within phagocytes and non-phagocytes is postulated to help this pathogen persist in the body during latent chronic conditions. In some Gram-negative bacteria, such as Shigella and Salmonella, the ability to evade macrophage killing involves inducing rapid macrophage cell death. In several of these instances, these bacteria activate cellular caspase-1 to induce cell death, which is increasingly described to exhibit features more characteristic of oncosis than classical apoptosis. We found that B. pseudomallei is also capable of inducing caspase-1 dependent death in macrophages and this process requires a functional bsa Type III Secretion System (TTSS). Bacterial internalization and pore formation in the cell membrane is necessary for death. Furthermore, cell death is accompanied by the release of IL-1beta and IL-18. We believe that this novel description of macrophage death induced by B. pseudomallei could shed light on the pathogenesis of the bacteria in disease.

Adult↗

PubMed2003

Quinolinic acid up-regulates chemokine production and chemokine receptor expression in astrocytes.

Within the brain, quinolinic acid (QUIN) is an important neurotoxin, especially in AIDS dementia complex (ADC). Its production by monocytic lineage cells is increased in the context of inflammation. However, it is not known whether QUIN promotes inflammation. Astrocytes are important in immuno-regulation within the brain and so we chose to examine the effects of QUIN on the astrocyte. Using purified cultures of primary human foetal astrocyte, we determined chemokine production using ELISA assays and RT-PCR, and chemokine receptor expression using immunocytochemistry and RT-PCR with QUIN in comparison to TNF-alpha/IFN-gamma. We found that QUIN induces astrocytes to produce large quantities of MCP-1 (CCL2), and lesser amounts of RANTES (CCL5), IL-8 (CXCL8). QUIN also increases SDF-1alpha (CXCL12), HuMIG (CXCL9) and fractalkine (CX3CL1) mRNA expression. Moreover, QUIN leads to up-regulation of the chemokine receptor expression of CXCR4, CCR5, and CCR3 in human foetal astrocytes. Most of these effects were comparable to those induced by TNF-alpha/IFN-gamma. The present work represents the first evidence that QUIN induces chemokine and chemokine receptor expression in astrocytes and is at least as potent as classical mediators such as inflammatory cytokines. These results suggest that QUIN may be critical in the amplification of brain inflammation particularly in ADC.

Astrocytes↗

PubMed2006

Isoproterenol stimulates monocyte chemoattractant protein-1 expression and secretion in 3T3-L1 adipocytes.

Recently, monocyte chemoattractant protein (MCP)-1 has been characterized as a novel adipocytokine upregulated in obesity and insulin resistance which impairs insulin signaling in muscle and fat in vitro. Growing evidence, on the other hand, suggests that increased activity of the sympathetic nervous system is an integral part in the development of insulin resistance. In the current study, the impact of the beta-adrenergic agonist isoproterenol on MCP-1 mRNA synthesis and secretion was determined in 3T3-L1 adipocytes. Interestingly, isoproterenol increased MCP-1 secretion 3-fold. Furthermore, 10 microM isoproterenol acutely induced MCP-1 mRNA by up to 5.3-fold in a time-dependent fashion with significant stimulation seen at concentrations as low as 0.3 microM effector. Studies using pharmacological inhibitors suggested that basal and isoproterenol-induced MCP-1 expressions are mediated via beta-adrenergic receptors and protein kinase A. Moreover, acute activation of adenylyl cyclase by forskolin was sufficient to mimic the effects of isoproterenol. Taken together, our results demonstrate that isoproterenol induces MCP-1 expression and secretion via a classical GS-protein-coupled pathway and support the notion that MCP-1 might be an interesting novel candidate linking obesity and insulin resistance.

3T3 Cells↗

PubMed2001

Rapidly progressive antineutrophil cytoplasm antibodies associated with pulmonary-renal syndrome in a 10-year-old girl.

CONTEXT: The term pulmonary-renal syndrome has been used frequently to describe the clinical manifestations of a great number of diseases in which pulmonary hemorrhage and glomerulonephritis coexist. The classic example of this type of vasculitis is Goodpasturés syndrome, a term used to describe the association of pulmonary hemorrhage, glomerulonephritis and the presence of circulating antiglomerular basement membrane antibodies (anti-GBM). Among the several types of systemic vasculitides that can present clinical manifestations of the pulmonary-renal syndrome, we focus the discussion on two types more frequently associated with antineutrophil cytoplasm antibodies (ANCA), microscopic polyangiitis and Wegener's granulomatosis, concerning a 10 year old girl with clinical signs and symptoms of pulmonary-renal syndrome, with positive ANCA and rapidly progressive evolution. CASE REPORT: We describe the case of a 10-year-old girl referred to our hospital for evaluation of profound anemia detected in a primary health center. Five days before entry she had experienced malaise, pallor and began to cough up blood-tinged sputum that was at first attributed to dental bleeding. She was admitted to the infirmary with hemoglobin = 4 mg/dL, hematocrit = 14 %, platelets = 260,000, white blood cells = 8300, 74 % segmented, 4 % eosinophils, 19 % lymphocytes and 3 % monocytes. Radiographs of the chest revealed bilateral diffuse interstitial alveolar infiltrates. There was progressive worsening of cough and respiratory distress during the admission day, when she began to cough up large quantities of blood and hematuria was noted. There was rapid and progressive loss of renal function and massive lung hemorrhage. The antineutrophil cytoplasm antibody (ANCA) test with antigen specificity for myeloperoxidase (anti-MPO) was positive and the circulating anti-GBM showed an indeterminate result.

Anti-Glomerular Basement Membrane Disease↗

PubMed1991

Interleukin-1 beta: a possible mediator of lung inflammation and airway hyperreactivity.

Interleukin-1 (IL-1), a peptide released from monocytes/macrophages, plays an important role in the inflammatory and immune responses. Airway hyperreactivity and the underlying airway inflammation are common features in asthma pathology. We investigated and characterized the inflammatory alterations induced within the guinea-pig respiratory system by IL-1 beta. Injection of IL-1 beta (1-6 micrograms/animal) into the pleural space resulted in a dose-dependent inflammatory response, as shown by the formation of pleural exudate and leucocyte recruitment. A threshold dose of IL-1 beta (1 micrograms/animal) markedly potentiated the inflammatory reaction triggered by the classical proinflammatory agent croton oil, underlining the amplifying role of IL-1 beta in the inflammatory events. The inflammatory process induced by intrapleural injection of IL-1 beta (6 micrograms/animal) was associated with the development of a hyperreactive phenomenon which involved both the peripheral and large airways. In fact, increased contractile activity of histamine was evident in the tracheas and parenchymal strips isolated from guinea-pigs exposed to IL-1 beta. These results provide evidence for a possible role of IL-1 beta in the genesis of airway inflammation and bronchial hyperreactivity.

Animals↗

PubMed2003

Cardiovascular benefits of aldosterone receptor antagonists.

There is considerable evidence in the setting of cardiovascular disease to suggest that, in addition to the classic effects of aldosterone on sodium retention, blood volume, blood pressure and potassium homeostasis, aldosterone is involved in fibrotic end-organ damage by means of intermediate mechanisms involving an interplay between the mineralocorticoid receptor, sodium intake and a variety of molecular messengers. Such processes may help to explain the reduction in mortality that can be achieved in patients with severe heart failure and post-myocardial infarction by the addition of an aldosterone receptor antagonist to standard therapy. Studies in animal models treated with the nitric oxide inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), angiotensin II and salt, with and without adrenalectomy, have demonstrated that myocardial damage can be eliminated by adrenalectomy or by administering an aldosterone receptor antagonist and is induced by adding back aldosterone to adrenalectomized animals. Importantly, at least a modest salt intake is an obligate co-factor. Other animal studies have established that an early stage in aldosterone-associated myocardial damage involves the release of proinflammatory molecules, including cyclo-oxygenase type 2, osteopontin and monocyte chemoattractant protein-1. Taken together, these findings suggest that aldosterone in the presence of salt intake is a major cardiovascular risk factor mediated by inflammatory and fibrotic processes. Thus, mineralocorticoid receptor antagonists are likely to be effective additional agents to treat a broad range of cardiovascular diseases.

Aldosterone↗

PubMed2003

Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes.

Within the brain, quinolinic acid (QUIN) is an important neurotoxin, especially in AIDS dementia complex (ADC). Its production by monocytic lineage cells is increased in the context of inflammation. However, it is not known whether QUIN promotes inflammation. Astrocytes are important in immunoregulation within the brain and so we chose to examine the effects of QUIN on the astrocyte. Using purified primary human fetal astrocyte cultures, we determined chemokine production using ELISA assays and RT-PCR and chemokine receptor expression using immunocytochemistry and RT-PCR with QUIN in comparison to TNFalpha, IL-1beta, and IFNgamma. We found that QUIN induces astrocytes to produce large quantities of MCP-1 (CCL2) and lesser amounts of RANTES (CCL5) and IL-8 (CXCL8). QUIN also increases SDF-1alpha (CXCL12), HuMIG (CXCL9), and fractalkine (CX(3)CL1) mRNA expression. Moreover, QUIN leads to upregulation of the chemokine receptor expression of CXCR4, CCR5, and CCR3 in human fetal astrocytes. Most of these effects were comparable to those induced by TNFalpha, IL-1beta, and IFNgamma. The present work represents the first evidence that QUIN induces chemokine and chemokine receptor expression in astrocytes and is at least as potent as classical mediators such as inflammatory cytokines. These results suggest that QUIN may be critical in the amplification of brain inflammation, particularly in ADC.

Astrocytes↗