Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial damage, synovial oedema, fibrin deposition, polymorphonuclear cell (PMN) invasion, and mild lining cell hyperplasia characterize acute inflammatory arthritis. Later on, perivascular tissue is infiltrated by mononuclear cells. The early events are mediated by interactions between PMNs and endothelial cells. Both parts in the adhesion event are activated with multiple stimuli resulting in complex interactions of varying intensity and duration. Adhesion molecules present on the surface of PMNs (L-selectin) or induced by inflammatory stimuli (beta 2-integrins) mediate PMN adhesion to activated endothelium, which has counter receptors (E-selectin for L-selectin and ICAM-1 and ICAM-2 for beta 2-integrins). At the initial phase L-selectin initiates the rolling of PMNs on endothelial cells. Further stimuli result in a more prolonged adhesion between PMNs and endothelium. At the side of endothelium, induction of P-selectin and PAF by histamine, thrombin and LTC4 contribute to the acute rolling of PMNs on endothelial surface. Tumor necrosis factor (TNF), interleukin-1 (IL-1) and lipopolysaccharide activate endothelial cells to synthesize interleukin-8 (IL-8), a potent chemotactic and proadhesive mediator for PMNs, and further adhesion molecule (E-selectin), a mediator of long-term adhesion between PMN and endothelium. After adhesion and migration to the focus of inflammation, PMNs induce inflammation by aggregating, releasing hydrolyzing enzymes, generating lipid peroxidation products such as prostaglandins and LTB4, and oxygen derived free radicals. In studies on the pathogenesis of seronegative spondyloarthropathies, we have shown persistently aberrant PMN function evidenced by enhanced chemotaxis and high production of toxic oxygen derived free radicals by PMN.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The present knowledge of the inflammatory process and the inflammatory mediators. 781 74

Metabolites of arachidonic acid have been shown to be potent biological modulators of macrophage function. While the role of cyclooxygenase metabolites of arachidonic acid have been well studied, metabolites of lipoxygenase have not. In this report, we evaluate the role that select 5'-lipoxygenase (5'-LO) products may play in macrophage activation for select tumoricidal functions. When thioglycollate-elicited macrophages were treated with inhibitors of 5'-LO during activation, cytolytic capacity, nitric oxide production, and tumor necrosis factor-alpha production were significantly inhibited. Moreover, both an inhibitor of the 5'-LO-activating protein and an inhibitor of glutathione-s-transferase (GST) significantly decreased macrophage tumoricidal function. The activating agents used were able to stimulate 5'-LO activity which was measured by quantitating secreted LTC4. Increased production of PGE2 by shunting could have been the cause for decreased macrophage tumoricidal function. However, treatment of macrophages with inhibitors of 5'-LO during lipopolysaccharide stimulation did not increase formation of PGE2. When select 5'-LO metabolites were added to cultures during activation and 5'-LO inhibition, tumoricidal activity could not be restored, even when the metabolites were encapsulated in liposomes. These results suggest that the activity of 5'-LO and GST are important for macrophage activation. However, the specific role of 5'-LO metabolites has not been completely established.
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PMID:Role of 5'-lipoxygenase metabolites in the activation of peritoneal macrophages for tumoricidal function. 784 77

In order to determine the contribution of suppressive factors secreted from macrophages to the age-associated decline in T-cell mediated mitogenic responses, experiments were conducted to characterize eicosanoid and H2O2 production, total cellular fatty acid, and vitamin E composition of splenocytes isolated from young (4 mo) and old (24 mo) C57BL/6NIA mice. An age-related increase was observed in Ca++ ionophore A23187-stimulated ex-vivo production of prostaglandin (PG) E2, leukotriene (LT) B4, and LTC4 (p < .01), and in concanavalin A (ConA)-stimulated PGE2 production (p < .01). No age-related difference was observed in ex-vivo production of 12- and 15-hydroxyeicosatetranoic acid (HETE). The age-related increase in PGE2 production was also observed in lipopolysaccharide-stimulated peritoneal macrophages of C57BL/6NIA mice and ConA and phytohemagglutinin (PHA)-stimulated splenocytes isolated from DBA mice. Inhibition of cyclooxygenase with indomethacin resulted in increased ConA-stimulated proliferation of splenocytes from old mice (p < .01), while 5-lipoxygenase inhibition did not have an effect on mitogen induced proliferation. Furthermore, PGE2 addition to purified splenic T-cells decreased their proliferation. No age-related differences were observed in total cellular fatty acid composition, vitamin E level, or ex-vivo production of H2O2 from splenocytes stimulated with 10 or 100 ng phorbol myristate acetate (PMA). These data indicate that aging is associated with increased production of PG and LT from activated splenocytes. Inhibition of PGE2 but not LT production enhances mitogenic responses of old mice, suggesting a contributory role for PGE2 in the age-associated decline of T-cell responsiveness to polyclonal mitogens.
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PMID:Age differences in eicosanoid production of mouse splenocytes: effects on mitogen-induced T-cell proliferation. 805 32

This study examined the differential effects of endotoxin on renal and splanchnic vascular (SV + SI) eicosanoid synthesis. Dogs were anesthetized and subjected to a challenge of 1 mg/kg (i.v.) bolus of B-lipopolysaccharide endotoxin followed by a 3 h infusion of endotoxin at 0.5 mg/kg/h. The kidney and SV + SI were cannulated and perfused in vitro with Krebs buffer. The venous effluent from the kidney and SV + SI were assayed for 6-keto-PGF1a (PGI2), PGE2, Leukotriene B4 (LTB4), LTC4, and thromboxane B2 (TXB2) by enzyme immunoassay. Endotoxin treatment markedly increased splanchnic PGI2 release (splanchnic vasodilator) two fold and decreased release of all other measured eicosanoids. Endotoxin treatment markedly increased renal PGE2 (renal vasodilator) but did not significantly increase PGI2. These data showed that endotoxin treatment stimulated both the splanchnic vascular bed and kidney to increase synthesis and release of their major endogenous vasodilator eicosanoids.
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PMID:Endotoxic shock has differential effects on renal and splanchnic eicosanoid synthesis. 839 95

The acute phase response to chemically-induced organ damage involves inflammation and the production of leukotrienes. The liver ordinarily takes up, metabolizes and excretes into bile cysteinyl leukotrienes, but the effect of hepatic injury on these processes is unknown. The hepatic uptake and biliary excretion of LTC4 was studied in male Sprague-Dawley rats after exposure to either streptozotocin (45 mg/kg iv 30 days before experimentation), estradiol-17 beta-valerate (1 mg/kg sc once a week for 3 weeks) or lipopolysaccharide/D-galactosamine (33 micrograms/ kg ip; 300 mg/kg ip at 6 h and 3 h, respectively, before experimentation). Acute liver injury is produced by these treatment paradigms. Glucose concentrations and activities of several marker enzymes in plasma were measured to demonstrate hepatic injury. Biliary excretion of 3H-LTC4 was similar to normal control rats in the three types of acute liver injury. Bile flow rates after 3H-LTC4 injection were reduced in lipopolysaccharide-pretreated rats and increased in estradiol-treated animals. Total biliary excretion of leukotrienes was not altered in any disease group. Thus, these models of acute hepatic injury do not appear to influence the hepatobiliary clearance of leukotrienes.
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PMID:Hepatobiliary excretion of cysteinyl leukotrienes in three experimental models of acute hepatic injury. 891 18

The liver plays a major role in metabolism and elimination of leukotrienes (LT). It produces cysteinyl leukotrienes (cLT), and cLT have been implicated in hepatocellular toxicity in several models of lipopolysaccharide (LPS)-associated liver injury. However, the liver cell types responsible for cLT production are poorly defined, and the expression of the LT-synthesis enzymes, 5-lipoxygenase (5-LO) and LTC4 synthase (LTC4-S), in liver cells has never been demonstrated. The aim of the present study was to examine the ability of rat liver cells to produce cLT by determining whether hepatocytes, Kupffer cells, and sinusoidal endothelial cells express mRNA and enzyme activities of the LT-synthesis enzymes and whether expression is altered by LPS. 5-LO mRNA was expressed in whole liver, and expression was enhanced by LPS. Cell fractionation studies demonstrated that expression was present in Kupffer cells and sinusoidal endothelial cells, but not in hepatocytes. LTC4-S mRNA was detected in whole liver, hepatocytes, and sinusoidal endothelial cells, but not in Kupffer cells. Semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR) showed that LPS increased LTC4-S expression in hepatocytes by a factor of 3 (n = 3; P < .03). LTC4-S enzyme activity in the microsomal fraction of hepatocytes was also increased from 0.52 +/- 0.13 to 1.90 +/- 0.66 nmol . mg protein-1 . 5 min-1 (n = 6; P < .015) after LPS treatment. These results indicate that hepatocytes do not possess the ability for de novo synthesis of cLT from arachidonic acid, but they may actively participate in cLT production by conjugation of LTA4 with glutathione to produce LTC4. LPS enhances LTC4-S expression in hepatocytes. This intrinsic cLT production may contribute to hepatocellular injury during inflammation.
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PMID:Expression and regulation of leukotriene-synthesis enzymes in rat liver cells. 979 12

Cysteinyl leukotrienes (LTs), including LTC(4), LTD(4), and LTE(4), are well known to induce bronchoconstriction and increase bronchial hyperreactivity, mucus secretion, and vascular permeability. Interestingly, alveolar macrophages (AMs) express LTD(4) high-affinity receptor. These cells represent a major source of inflammatory mediators implicated in the pathophysiology of asthma. Thus, we investigated the immunomodulatory effects of LTD(4) on the production of inflammatory mediators such as macrophage inflammatory protein (MIP)- 1alpha, tumor necrosis factor (TNF), and nitric oxide (NO) by AMs. NR8383 cells, an AM cell line, were pretreated with LTD(4) (10(-11) M) for different periods of time and stimulated or not with lipopolysaccharide (LPS) for 2 h. Although LTD(4) treatment did not modulate the release of MIP-1alpha and TNF, this treatment (6 h) significantly increased the release of these mediators when AMs were further stimulated with LPS (increases of 47 and 21%, respectively). Further, LTD(4) pretreatment increased messenger RNA (mRNA) levels of MIP-1alpha and TNF. These effects of LTD(4) were abrogated by the presence of a LTD(4) receptor antagonist, Verlukast (MK-679), showing the specificity of LTD(4). Interestingly, LTD(4) treatment significantly increased the release of NO by LPS-stimulated AMs without modulating mRNA levels of the inducible NO synthase. Our data suggest that LTD(4) primes AMs to release more MIP-1alpha, TNF, and NO after stimulation. Thus, in addition to its potent bronchoconstrictor effect, LTD(4) may participate in the inflammatory process seen in asthma by potentiating the production of proinflammatory mediators by AMs during immunologic stimuli.
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PMID:Priming of alveolar macrophages by leukotriene D(4): potentiation of inflammation. 1101 25

The liver lobule is formed by parenchymal cells, i.e., hepatocytes and nonparenchymal cells. In contrast to hepatocytes that occupy almost 80% of the total liver volume and perform the majority of numerous liver functions, nonparenchymal liver cells, which contribute only 6.5% to the liver volume, but 40% to the total number of liver cells, are localized in the sinusoidal compartment of the tissue. The walls of hepatic sinusoid are lined by three different cell types: sinusoidal endothelial cells (SEC), Kupffer cells (KC), and hepatic stellate cells (HSC, formerly known as fat-storing cells, Ito cells, lipocytes, perisinusoidal cells, or vitamin A-rich cells). Additionally, intrahepatic lymphocytes (IHL), including pit cells, i.e., liver-specific natural killer cells, are often present in the sinusoidal lumen. It has been increasingly recognized that both under normal and pathological conditions, many hepatocyte functions are regulated by substances released from neighboring nonparenchymal cells. Liver sinusoidal endothelial cells constitute the lining or wall of the hepatic sinusoid. They perform important filtration function due to the presence of small fenestrations that allow free diffusion of many substances, but not of particles of the size of chylomicrons, between the blood and the hepatocyte surface. SEC show huge endocytic capacity for many ligands including glycoproteins, components of the extracellular matrix (ECM; such as hyaluronate, collagen fragments, fibronectin, or chondroitin sulphate proteoglycan), immune complexes, transferrin and ceruloplasmin. SEC may function as antigen-presenting cells (APC) in the context of both MHC-I and MHC-II restriction with the resulting development of antigen-specific T-cell tolerance. They are also active in the secretion of cytokines, eicosanoids (i.e., prostanoids and leukotrienes), endothelin-1, nitric oxide, and some ECM components. Kupffer cells are intrasinusoidally located tissue macrophages with a pronounced endocytic and phagocytic capacity. They are in constant contact with gut-derived particulate materials and soluble bacterial products so that a subthreshold level of their activation in the normal liver may be anticipated. Hepatic macrophages secrete potent mediators of the inflammatory response (reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, TNF-alpha, and other cytokines), and thus control the early phase of liver inflammation, playing an important part in innate immune defense. High exposure of Kupffer cells to bacterial products, especially endotoxin (lipopolysaccharide, LPS), can lead to the intensive production of inflammatory mediators, and ultimately to liver injury. Besides typical macrophage activities, Kupffer cells play an important role in the clearance of senescent and damaged erythrocytes. Liver macrophages modulate immune responses via antigen presentation, suppression of T-cell activation by antigen-presenting sinusoidal endothelial cells via paracrine actions of IL-10, prostanoids, and TNF-alpha, and participation in the development of oral tolerance to bacterial superantigens. Moreover, during liver injury and inflammation, Kupffer cells secrete enzymes and cytokines that may damage hepatocytes, and are active in the remodeling of extracellular matrix. Hepatic stellate cells are present in the perisinusoidal space. They are characterized by abundance of intracytoplasmic fat droplets and the presence of well-branched cytoplasmic processes, which embrace endothelial cells and provide focally a double lining for sinusoid. In the normal liver HSC store vitamin A, control turnover of extracellular matrix, and regulate the contractility of sinusoids. Acute damage to hepatocytes activates transformation of quiescent stellate cells into myofibroblast-like cells that play a key role in the development of inflammatory fibrotic response. Pit cells represent a liver-associated population of large granular lymphocytes, i.e., natural killer (NK) cells. They spontaneously kill a variety of tumor cells in an MHC-unrestricted way, and this antitumor activity may be enhanced by the secretion of interferon-gamma. Besides pit cells, the adult liver contains other subpopulations of lymphocytes such as gamma delta T cells, and both "conventional" and "unconventional" alpha beta T cells, the latter containing liver-specific NK T cells. The development of methods for the isolation and culture of main liver cell types allowed to demonstrate that both nonparenchymal and parenchymal cells secrete tens of mediators that exert multiple paracrine and autocrine actions. Co-culture experiments and analyses of the effects of conditioned media on cultures of another liver cell type have enabled the identification of many substances released from non-parenchymal liver cells that evidently regulate some important functions of neighboring hepatocytes and non-hepatocytes. To the key mediators involved in the intercellular communication in the liver belong prostanoids, nitric oxide, endothelin-1, TNF-alpha, interleukins, and chemokines, many growth factors (TGF-beta, PDGF, IGF-I, HGF), and reactive oxygen species (ROS). Paradoxically, the cooperation of liver cells is better understood under some pathological conditions (i.e., in experimental models of liver injury) than in normal liver due to the possibility of comparing cellular phenotype under in vivo and in vitro conditions with the functions of the injured organ. The regulation of vitamin A metabolism provides an example of the physiological role for cellular cross-talk in the normal liver. The majority (up to 80%) of the total body vitamin A is stored in the liver as long-chain fatty acid esters of retinal, serving as the main source of retinoids that are utilized by all tissues throughout the body. Hepatocytes are directly involved in the uptake from blood of chylomicron remnants, and the synthesis of retinol-binding protein that transfers retinol to other tissues. However, more than 80% of the liver retinoids are stored in lipid droplets of hepatic stellate cells. HSC are capable of both uptake and release of retinol depending on the body's retinol status. The activity of some major enzymes of vitamin A metabolism have been found to be many times higher per protein basis in stellate cells than in hepatocytes. Despite progress in the understanding of the roles played by these two cell types in hepatic retinoid metabolism, the way in which retinoids move between the parenchymal cells, stellate cells, and blood plasma has not been fully elucidated. Sinusoidal blood flow is, to a great extent, regulated by hepatic stellate cells that can contract due to the presence of smooth muscle alpha-actin. The main vasoactive substances that affect constriction or relaxation of HSC derive both from distant sources and from neighboring hepatocytes (carbon monoxide, leukotrienes), endothelial cells (endothelin, nitric oxide, prostaglandins), Kupffer cells (prostaglandins, NO), and stellate cells themselves (endothelin, NO). The cellular cross-talk reflected by the fine-tuned modulation of sinusoidal contraction becomes disturbed under pathological conditions, such as endotoxemia or liver fibrosis, through the excess synthesis of vasoregulatory compounds and the involvement of additional mediators acting in a paracrine way. The liver is an important source of some growth factors and growth factor-binding proteins. Although hepatocytes synthesize the bulk of insulin-like growth factor I (IGF-I), also other types of nonparenchymal liver cells may produce this peptide. Cell-specific expression of distinct IGF-binding proteins observed in the rat and human liver provides the potential for specific regulation of hepatic IGF-I synthesis not only by growth hormone, insulin, and IGF-I, but also by cytokines released from activated Kupffer (IL-1, TNF-alpha, TGF-beta) or stellate cells (TGF-alpha, TGF-beta). Hepatic stellate cells may affect turnover of hepatocytes through the synthesis of potent positive as well as negative signals such as, respectively, hepatocyte-growth-factor or TGF-beta. Although hepatocytes seem not to produce TGF-beta, a pleiotropic cytokine synthesized and secreted in the latent form by Kupffer and stellate cells, they may contribute to its actions in the liver by the intracellular activation of latent TGF-beta, and secretion of the biologically active isoform. Many mediators that reach the liver during inflammatory processes, such as endotoxins, immune-complexes, anaphylatoxins, and PAF, increase glucose output in the perfused liver, but fail to do so in isolated hepatocytes, acting indirectly via prostaglandins released from Kupffer cells. In the liver, prostaglandins synthesized from arachidonic acid mainly in Kupffer cells in a response to various inflammatory stimuli, modulate hepatic glucose metabolism by increasing glycogenolysis in adjacent hepatocytes. The release of glucose from glycogen supports the increased demand for energetic fuel by the inflammatory cells such as leukocytes, and additionally enables enhanced glucose turnover in sinusoidal endothelial cells and Kupffer cells which is necessary for effective defense of these cells against invading microorganisms and oxidative stress in the liver. Leukotrienes, another oxidation product of arachidonic acid, have vasoconstrictive, cholestatic, and metabolic effects in the liver. A transcellular synthesis of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) functions in the liver: LTA4, an important intermediate, is synthesized in Kupffer cells, taken up by hepatocytes, converted into the potent LTC4, and then released into extracellular space, acting in a paracrine way on Kupffer and sinusoidal endothelial cells. Thus, hepatocytes are target cells for the action of eicosanoids and the site of their transformation and degradation, but can not directly oxidate arachidonic acid to eicosanoids. (ABSTRACT TRUNCATED)
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PMID:Cooperation of liver cells in health and disease. 1172 49

Leukotrienes (LT) and prostaglandins (PG) are proinflammatory mediators generated by the conversion of arachidonic acid via 5-lipoxygenase (5-LO) and cyclooxygenase (COX) pathways. It has long been proposed that the inhibition of the 5-LO could enhance the COX pathway leading to an increased PG generation. We have found that in in vitro models of inflammation, such as mice-elicited peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma), the deletion of the gene encoding for 5-LO or the enzyme activity inhibition corresponded to a negative modulation of the COX pathway. Moreover, exogenously added LTC(4), but not LTD(4), LTE(4), and LTB(4), was able to increase PG production in stimulated cells from 5-LO wild-type and knockout mice. LTC(4) was not able to induce COX-2 expression by itself but rather potentiated the action of LPS/IFN-gamma through the extracellular signal-regulated kinase-1/2 activation, as demonstrated by the use of a specific mitogen-activated protein kinase (MAPK) kinase inhibitor. The LT-induced increase in PG generation, as well as MAPK activation, was dependent by a specific ligand-receptor interaction, as demonstrated by the use of a cys-LT1 receptor antagonist, although also a direct action of the antagonist used, on PG generation, cannot be excluded. Thus, the balance between COX and 5-LO metabolites could be of great importance in controlling macrophage functions and consequently, inflammation and tumor promotion.
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PMID:Up-regulation of prostaglandin biosynthesis by leukotriene C4 in elicited mice peritoneal macrophages activated with lipopolysaccharide/interferon-{gamma}. 1604 53

Hexanic, dichloromethanic, ethanolic and aqueous extracts from Baccharis obtusifolia HBK, Baccharis latifolia (R. et P.) Pers., Baccharis pentlandii D.C. and Baccharis subulata Wedd., plants used in the traditional medicine of South America have been studied for their in vitro anti-inflammatory activity in cellular systems. Calcium ionophore A23187-stimulated mouse peritoneal macrophages were validated as a source of cyclooxygenase-1 (COX-1) (prostaglandin E2, PGE2) and 5-lipoxygenase (5-LOX) (leukotriene C4, LTC4), and mouse peritoneal macrophages stimulated with Escherichia coli lipopolysaccharide (LPS) were used for testing cyclooxygenase-2 (COX-2) (PGE2), nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha) activity. Most of the extracts tested were active in all assays.
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PMID:Anti-inflammatory activity of four Bolivian Baccharis species (Compositae). 1620 49


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