Monosodium Urate Crystal-induced Inflammation Research Articles

A Role of Piperine on Monosodium Urate Crystal-Induced Inflammation—An Experimental Model of Gouty Arthritis

In the present study, the anti-inflammatory effect of piperine was investigated on monosodium urate crystal-induced inflammation in mice, an experimental model for gouty arthritis, and compared it with that of the nonsteroidal anti-inflammatory drug, indomethacin. The levels of lysosomal enzymes, lipid peroxidation, tumor necrosis factor-α, and paw volume were increased significantly, and the activities of antioxidant status were in turn decreased in monosodium urate crystal-induced mice, whereas these changes were reverted to near normal levels upon piperine (30 mg/kg b.wt, i.p.) treatment. In vitro, piperine (50/100 ug/ml) suppressed the level of β-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated polymorphonuclear leucocytes in concentration-dependent manner when compared to control cells. Thus, the present study clearly indicated that piperine inhibit the monosodium urate crystal-induced inflammation and can be regarded as therapeutic drug for the treatment of acute gouty arthritis.

Crystal‐induced neutrophil activation

Monosodium urate (MSU) crystals are among the most potent pro-inflammatory stimuli and an innate immune inflammatory response to the crystal surface is intimately involved in the pathology of gouty arthritis. The responses of human neutrophils to MSU crystals represent an integral part of this innate response and a key component of the acute inflammatory response associated with gout. A significant, though incomplete, body of information concerning the implication of human neutrophils in MSU crystal-induced inflammation and the signal transduction pathways activated in response to these agonists in neutrophils has accumulated over the last few years. This review focuses on the current state of knowledge concerning the activation of human neutrophils by MSU crystals specifically in the context of acute gout, as recent data begin to draw a comprehensive picture of the events leading to the often excessive functional responses of neutrophils to these particulate agonists. A non-exhaustive list of the most important questions that remain to be assessed to further describe the physio-pathological mechanisms of gouty arthritis is presented here.

Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome

Gout is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in the joint. Recent studies have significantly advanced our knowledge on the understanding of mechanisms underlying MSU crystal-induced inflammation. MSU crystals act as a 'danger signal' that can be recognized by pattern recognition receptors both at cell surface and cytoplasm, indicating the importance of innate immunity in gout. This review focuses on the critical role of intracellular NALP3 inflammasome in MSU crystal-induced inflammation.

6-Shogaol inhibits monosodium urate crystal-induced inflammation – An in vivo and in vitro study

Gout is a rheumatic disease that is manifestated by an intense inflammation secondary to monosodium urate crystal deposition in joints. In the present study, we assessed the effect of 6-shogaol (isolated active principle from ginger) on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, indomethacin. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-α were determined in control and monosodium urate crystal-induced mice. The levels of β-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL) in vitro. The levels of lysosomal enzymes, lipid peroxidation, and inflammatory mediator tumour necrosis factor-α and paw volume were increased significantly and the activities of anti-oxidant status were in turn decreased in monosodium urate crystal-induced mice, whereas these changes were reverted to near normal levels upon 6-shogaol administration. In vitro, 6-shogaol reduced the level of β-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated polymorphonuclear leucocytes in concentration dependent manner when compared to control cells. The present results clearly indicated that 6-shogaol exerted a strong anti-inflammatory effect and can be regarded as useful tool for the treatment of acute gouty arthritis.

Suppressive effect of Spirulina fusiformis in relation to lysosomal acid hydrolases, lipid peroxidation, antioxidant status, and inflammatory mediator TNF-alpha on experimental gouty arthritis in mice

The anti-inflammatory effect of Spirulina fusiformis on monosodium urate crystal-induced inflammation in mice has been investigated and compared with the non-steroidal anti-inflammatory drug Indomethacin. The paw volume, lysosomal enzyme activities, lipid peroxidation, anti-oxidant status and inflammatory mediator tumour necrosis factor-<TEX>$\alpha$</TEX> were studied in control and monosodium urate crystal-induced mice after oral administration of Spirulina platensis in an experimental model for gouty arthritis. In the induced mice, the levels of lysosomal enzymes, inflammatory mediator tumour necrosis factor-<TEX>$\alpha$</TEX>, lipid peroxidation and the paw volume increased significantly, whereas the antioxidant status decreased when compared to control mice. <TEX>$\beta$</TEX>-glucuronidase and lactate dehydrogenase level were also found to be increased in untreated monosodium urate crystal-incubated polymorphonuclear leucocytes. After the oral administration of Spirulina fusiformis, the physical and biochemical changes observed in monosodium urate crystal-induced animals were significantly restored to near normal levels. The results clearly indicated the anti-inflammatory role of Spirulina fusiformis, a promising drug for gouty arthritis.

Sesquiterpene dialdehydes inhibit MSU crystal-induced superoxide production by infiltrating neutrophils in an in vivo model of gouty inflammation

A hallmark feature of monosodium urate (MSU) crystal-induced inflammation in gouty arthritis is the infiltration of activated neutrophils into the joint. Therefore inhibition of neutrophil superoxide production is a rational target for treating inflammation in gout. The natural product polygodial and related sesquiterpene dialdehyde analogs were tested in vitro and in vivo for their ability to inhibit neutrophil infiltration and superoxide production in response to MSU crystal stimulation. Polygodial and other sesquiterpene dialdehydes exhibited dose-dependent inhibition of MSU-induced superoxide production in the micromolar and submicromolar ranges. Inhibition of superoxide production was dependent on the presence of the dialdehyde functional groups and was sensitive to blockade with the thiol-containing amino acid cysteine. Polygodial, 6-hydroxypaxidal and sesquiterpene 2 inhibited both neutrophil infiltration and neutrophil superoxide production in an MSU crystal-induced mouse model of gouty inflammation. Together, these data highlight the potential of sesquiterpene dialdehydes for development as anti-inflammatory agents for the treatment of neutrophil-driven inflammatory diseases including gout.

Inhibition of Monosodium Urate Crystal-Induced Inflammation by Withaferin A

Gouty arthritis is a characteristically intense acute inflammatory reaction resulting from the formation of sodium urate crystals in the joint cavity. In the present study, the effect of withaferin A, a steroidal lactone was investigated on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, indomethacin. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-alpha were determined in control and monosodium urate crystal-induced mice. The levels of beta-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL). Paw volume, the levels of lysosomal enzymes, lipid peroxidation, and inflammatory mediator tumour necrosis factor-alpha were found to be increased significantly and the activities of antioxidant status were in turn decreased in monosodium urate crystal-induced mice; however these changes were reverted back to near normal levels in withaferin A (30 mg/kg/b.wt, i.p.) treated monosodium urate crystal-induced mice. In addition, beta-glucuronidase and lactate dehydrogenase level were reduced in withaferin A (100microg/ml) treated monosodium urate crystal-incubated polymorphonuclear leucocytes. The present findings clearly indicated that withaferin A exerted a strong anti-inflammatory effect against gouty arthritis.

Melanocortin peptides inhibit urate crystal-induced activation of phagocytic cells

IntroductionThe melanocortin peptides have marked anti-inflammatory potential, primarily through inhibition of proinflammatory cytokine production and action on phagocytic cell functions. Gout is an acute form of arthritis caused by the deposition of urate crystals, in which phagocytic cells and cytokines play a major pathogenic role. We examined whether alpha-melanocyte-stimulating hormone (α-MSH) and its synthetic derivative (CKPV)2 influence urate crystal-induced monocyte (Mo) activation and neutrophil responses in vitro.MethodsPurified Mos were stimulated with monosodium urate (MSU) crystals in the presence or absence of melanocortin peptides. The supernatants were tested for their ability to induce neutrophil activation in terms of chemotaxis, production of reactive oxygen intermediates (ROIs), and membrane expression of CD11b, Toll-like receptor-2 (TLR2) and TLR4. The proinflammatory cytokines interleukin (IL)-1β, IL-8, and tumor necrosis factor-alpha (TNF-α) and caspase-1 were determined in the cell-free supernatants. In parallel experiments, purified neutrophils were preincubated overnight with or without melanocortin peptides before the functional assays.ResultsThe supernatants from MSU crystal-stimulated Mos exerted chemoattractant and priming activity on neutrophils, estimated as ROI production and CD11b membrane expression. The supernatants of Mos stimulated with MSU in the presence of melanocortin peptides had less chemoattractant activity for neutrophils and less ability to prime neutrophils for CD11b membrane expression and oxidative burst. MSU crystal-stimulated Mos produced significant levels of IL-1β, IL-8, TNF-α, and caspase-1. The concentrations of proinflammatory cytokines, but not of caspase-1, were reduced in the supernatants from Mos stimulated by MSU crystals in the presence of melanocortin peptides. Overnight incubation of neutrophils with the peptides significantly inhibited their ability to migrate toward chemotactic supernatants and their capacity to be primed in terms of ROI production.Conclusionsα-MSH and (CKPV)2 have a dual effect on MSU crystal-induced inflammation, inhibiting the Mos' ability to produce neutrophil chemoattractants and activating compounds and preventing the neutrophil responses to these proinflammatory substances. These findings reinforce previous observations on the potential role of α-MSH and related peptides as a new class of drugs for treatment of inflammatory arthritis.

RETRACTED: Effects of ethanol on monosodium urate crystal-induced inflammation

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Image duplication has been observed within Figure 3. The corresponding author has been asked to provide an acceptable explanation for this duplication but has not been able to do so, neither have the original source files been supplied.

An in vivo and in vitro potential of Indian ayurvedic herbal formulation Triphala on experimental gouty arthritis in mice

In the present study, we have investigated the efficacy of Indian ayurvedic herbal formulation Triphala on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, Indomethacin. The anti-arthritic effect of Triphala was evaluated by measuring changes in the paw volume, lysosomal enzyme activities, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-α in control and monosodium urate crystal-induced mice. The levels of β-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL). Triphala treatment (1 gm/kg/b.w. orally) significantly inhibited the paw volume and the levels of lysosomal enzymes, lipid peroxidation and inflammatory mediator tumour necrosis factor-α; however the anti-oxidant status was found to be increased in plasma, liver and spleen of monosodium urate crystal-induced mice when compared to control mice. In addition, β-glucuronidase and lactate dehydrogenase level were reduced in Triphala (100 μg/ml) treated monosodium urate crystal-incubated polymorphonuclear leucocytes. In conclusion, the results obtained clearly indicated that Triphala exerted a strong anti-inflammatory effect against gouty arthritis.

Recent developments in crystal-induced inflammation pathogenesis and management

Crystal-induced inflammation pathogenesis is undergoing a transition with respect to monosodium urate, calcium pyrophosphate dihydrate, and even basic calcium phosphate crystals. It is now recognized that innate immunity could be involved in the earlier pathogenic events and that the inflammasome, along with other signaling pathways, is activated and results in interleukin-1 processing and secretion, ultimately activating cells as a paracrine or autocrine cytokine. Management of acute and chronic monosodium urate crystal-induced inflammation, namely gout, has been critically reviewed by a dedicated European working group, and on the behalf of the European League against Rheumatism, 12 evidence-based recommendations have been reported. Calcium pyrophosphate dihydrate chronic inflammation could benefit from colchicine and from methotrexate as an anti-inflammatory agent.

A pilot study of IL-1 inhibition by anakinra in acute gout

Monosodium urate crystals stimulate monocytes and macrophages to release IL-1β through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study.

P1931 Microbiological epidemiology of infections related to pace-makers and indwelling cardiac defibrillator

Gout is a rheumatic disease that is manifestated by an intense inflammation secondary to monosodium urate crystal deposition in joints. In the present study, we assessed the effect of 6-shogaol (isolated active principle from ginger) on monosodium urate crystal-induced inflammation in mice; an experimental model for gouty arthritis and compared it with that of the non-steroidal anti-inflammatory drug, indomethacin. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and inflammatory mediator TNF-α were determined in control and monosodium urate crystal-induced mice. The levels of β-glucuronidase and lactate dehydrogenase were also measured in monosodium urate crystal-incubated polymorphonuclear leucocytes (PMNL) in vitro. The levels of lysosomal enzymes, lipid peroxidation, and inflammatory mediator tumour necrosis factor-α and paw volume were increased significantly and the activities of anti-oxidant status were in turn decreased in monosodium urate crystal-induced mice, whereas these changes were reverted to near normal levels upon 6-shogaol administration. In vitro, 6-shogaol reduced the level of β-glucuronidase and lactate dehydrogenase in monosodium urate crystal-incubated polymorphonuclear leucocytes in concentration dependent manner when compared to control cells. The present results clearly indicated that 6-shogaol exerted a strong anti-inflammatory effect and can be regarded as useful tool for the treatment of acute gouty arthritis.

Reduction of urate crystal-induced inflammation by root extracts from traditional oriental medicinal plants: elevation of prostaglandin D2 levels.

Dried roots of the plants Acanthopanax senticosus, Angelica sinensis and Scutellaria baicalensis are used in traditional oriental medicine and reportedly possess anti-inflammatory properties. Using the murine air pouch model of inflammation, we investigated the efficacy and mode of action of an extract from these three plants in crystal-induced inflammation. Air pouches were raised on the backs of 8-week-old BALB/c mice. Mice were fed 100 mg/kg body weight of root extracts (A. senticosus:A. sinensis:S. baicalensis mixed in a ratio of 5:4:1 by weight) or vehicle only on days 3–6. Inflammation was elicited on day 6 by injecting 2 mg of monosodium urate (MSU) crystals into the pouch. Neutrophil density and IL-6 and TNF-α mRNA levels were determined in the pouch membrane, and the leukocyte count and IL-6, prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) levels were determined in the pouch exudate. Treatment with the root extracts led to a reduction in all inflammatory parameters: the leukocyte count in the pouch exudate decreased by 82%; the neutrophil density in the pouch membrane decreased by 68%; IL-6 and TNF-α mRNA levels in the pouch membrane decreased by 100%; the IL-6 concentration in the pouch fluid decreased by 50%; and the PGE2 concentration in the pouch fluid decreased by 69%. Remarkably, the concentration of the potentially anti-inflammatory PGD2 rose 5.2-fold in the pouch exudate (p < 0.005), which led to a normalization of the PGD2:PGE2 ratio. A 3.7-fold rise in hematopoietic PGD synthase (h-PGDS) mRNA paralleled this rise in PGD2 (p = 0.01).Thus, the root extracts diminished MSU crystal-induced inflammation by reducing neutrophil recruitment and expression of pro-inflammatory factors and increasing the level of the potentially anti-inflammatory PGD2. These results support a need for further studies of the efficacy of these extracts in the treatment of inflammatory arthropathies and suggest elevation of PGD2 levels as a novel mechanism for an anti-inflammatory agent.

Innate immunity in triggering and resolution of acute gouty inflammation

Gout has long been recognized as a disease of recurrent bouts of acute inflammation that undergo self-resolution. This inflammation is triggered by the body's response to monosodium urate (MSU) crystals. In this paper, we focus on recent studies that describe how interactions of MSU crystals with the components of the innate immune system trigger acute gouty inflammation as well as mechanisms that are involved in the resolution of this inflammation. Specifically, we describe how toll-like receptors mediate the uptake of MSU crystals involved in the initiation and resolution of gouty inflammation. We also describe recent findings on the role of apoptotic clearance in the resolution of gouty inflammation. In addition, how therapies used to treat gout act on the innate immune system to inhibit MSU crystal-induced inflammation and promote the resolution of inflammation is discussed.

Monosodium urate and calcium pyrophosphate dihydrate (CPPD) crystals, inflammation, and cellular signaling

Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals are responsible for acute synovial inflammation but also contribute to cartilage degradation and bone lesions within the joint. They activate multiple signal transduction pathways leading to cell activation and recruitment. Some signalling pathways are activated by both types of crystals, and other pathways may only be activated by one type depending on cell type, namely neutrophils, monocytes, macrophages, synovial fibroblasts, endothelial cells and chondrocytes. Cascades of activated proteins involve cytoplasmic membrane related proteins (FAK complex, Src family tyrosine kinases), but also MAPK and NF-kB pathways, leading to NO, prostanoid and cytokine production, and protease activation. This review will also focus on potential therapeutic targets related to cellular signalling in MSU and CPPD crystal-induced inflammation.

Hyperuricemia and gout.

Gout is not a new disease for clinicians; nevertheless, there are still many secrets awaiting discovery for improving knowledge with respect to uric acid metabolism and monosodium urate crystal-induced inflammation. This review of the literature will focus on new insights on the pathogenesis of idiopathic hyperuricemia, and on secondary hyperuricemia and gout. There are also important advances on the pathophysiology of acute gout, especially as a self-limited process (switch from monocyte to macrophage, peroxisome proliferator activated receptor-gamma, and nitric oxide), but also of chronic gouty arthropathy. Armaments for treating hyperuricemia and gout may be already improved by losartan or fenofibrate and, in the future, by urate oxydase-polyethylene glycol 20 and renal handling regulatory molecules. Finally, control of hyperuricemia may also be considered in the prevention and treatment of cardiovascular disease.

Suppression of monosodium urate crystal-induced inflammation by black currant seed oil

The subcutaneous air pouch formed in Sprague-Dawley rats was used to study the effect of diets enriched in black currant seed oil (BCSO) on acute inflammation induced by monosodium urate crystals. The BCSO enriched diet suppressed significantly both the cellular and fluid phases of inflammation (polymorphonuclear leucocyte and exudate accumulation). In contrast, administration of normal chow or of a diet enriched in safflower oil (polyunsaturated fatty acid control) did not influence monosodium urate crystal-induced inflammation in this model. The findings indicate that a diet which provides both n-6 (gammalinolenic acid) and n-3 (alpha-linolenic acid) fatty acids as substrates alternative to arachidonatic acid for oxidative metabolism, modifies monosodium urate crystal-induced acute inflammation.

Suppression of monosodium urate crystal-induced acute inflammation by diets enriched with gamma-linolenic acid and eicosapentaenoic acid.

A subcutaneous air pouch formed in Sprague-Dawley rats was used to study the effect of diets enriched in gamma-linolenic acid (GLA) (in plant seed oil) and eicosapentaenoic acid (EPA) (in fish oil) on acute inflammation induced by monosodium urate crystals. The GLA-enriched diet suppressed significantly the cellular phase of inflammation (polymorphonuclear leukocyte accumulation, crystal phagocytosis, and lysosomal enzyme activity), but it had little effect on the fluid phase (exudate volume and protein concentration). In contrast, the EPA-enriched diet suppressed the fluid phase but not the cellular phase of inflammation. The findings indicate that the fluid and cellular phases of acute inflammation can be controlled independently. A combined diet of fish oil and plant seed oil (EPA-enriched and GLA-enriched) reduced both the cellular and fluid phases of inflammation. Thus, dietary provision of alternative substrates for oxidative metabolism (other than arachidonic acid) modifies monosodium urate crystal-induced acute inflammation.