| 1. |
- Fei, Ying, et al.
(författare)
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The combination of a tumor necrosis factor inhibitor and antibiotic alleviates staphylococcal arthritis and sepsis in mice.
- 2011
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 204:3, s. 348-57
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Tidskriftsartikel (refereegranskat)abstract
- (See the editorial commentary by Chow, on pages 332-4) Background.Despite advances in medical practices, in recent decades permanent reductions in joint function have not been achieved, and the high mortality rate of patients with staphylococcal septic arthritis has not substantially improved. Methods.We evaluated the effects of a combined tumor necrosis factor (TNF) inhibitor and antibiotic therapy on the course of Staphylococcus aureus arthritis and sepsis in mice. Results.Treatment with the combination of a TNF inhibitor and an antibiotic resulted in a quicker relief of clinical arthritis in mice with septic arthritis, compared with an antibiotic monotherapy. Both histopathologically verified synovitis and the extent of joint destruction were reduced by this combined treatment. Importantly, anti-TNF treatment significantly improved the survival rate of mice with S. aureus sepsis and staphylococcal enterotoxin shock syndrome; this effect might be the result of a partial restoration of the hemostatic balance between coagulation and fibrinolysis. Finally, we demonstrated that anti-TNF treatment downregulates high-mobility group protein B1 in staphylococcal enterotoxin shock syndrome. Conclusions.Thus, simultaneous systemic TNF inhibition and antibiotic therapy has beneficial effects on the outcome of S. aureus arthritis and sepsis in a mouse model, suggesting that the combination of a TNF inhibitor and antibiotics represents a novel therapeutic strategy for the treatment of staphylococcal infections.
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| 2. |
- Gillett, Alan, et al.
(författare)
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TNF production in macrophages is genetically determined and regulates inflammatory disease in rats.
- 2010
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 185:1, s. 442-50
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of TNF is an important pathophysiological phenotype for many diseases. Recently, certain genetically regulated loci have been identified to regulate several inflammatory diseases. We hypothesized that a region on rat chromosome 4 known to regulate experimental autoimmune encephalomyelitis, experimental arthritis and experimental autoimmune neuritis harbors a gene regulating central inflammatory molecules, such as TNF. We therefore mapped TNF production using linkage analysis in the 12th generation of an advanced intercross line between DA and PVG.AV1 rats, which differ in susceptibility to several inflammatory conditions. A single TNF-regulating quantitative trait locus with a logarithm of odds score of 6.2 was identified and its biological effect was confirmed in a congenic rat strain. The profound TNF regulation mapped in congenic strains to the macrophage population. Several TLR signaling cascades led to the same reduced proinflammatory phenotype in congenic macrophages, indicating control of a convergence point for innate inflammatory activity. The decreased TNF potential and reduced proinflammatory macrophage phenotype in congenic rats was also associated with reduced clinical severity in experimental autoimmune encephalomyelitis, pristane-induced arthritis and sepsis experimental models. Determination of genes and mechanisms involved in this genetically determined TNF regulation will be valuable in understanding disease pathogenesis and aid treatment development.
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| 3. |
- Jin, Tao, 1973, et al.
(författare)
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Decreased Serum Levels of TGF-β1 are associated with Renal Damages in Female Patients with Systemic Lupus Erythematosus.
- 2012
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Ingår i: Lupus. - : SAGE Publications. - 1477-0962 .- 0961-2033. ; 21:3, s. 310-318
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Transforming growth factor β1 (TGF-β1) has a large role in the control of autoimmunity. TGF-β1 production by lymphocytes is reduced in systemic lupus erythematosus (SLE). Decreased levels of TGF-β1 might associate to disease susceptibility, activity and organ damage in SLE. However, the correlation between TGF-β1 levels and severity of renal damage in SLE has not been examined. Methods: The present study was undertaken to assess the serum levels of total and active TGF-β1 in 150 female patients with SLE and 31 healthy women. Simple and multiple regression analyses between TGF-β1 levels and the diseases-related variables were performed in patients with SLE. Results: Serum levels of both total and active TGF-β1 were significantly reduced in patients with SLE compared with levels in healthy controls (p < 0.01). Total TGF-β1 levels correlated positively with white blood cell, platelet counts, calculated glomerular filtration rate (GFR), and active TGF-β1 level, and inversely with erythrocyte sedimentation rate (ESR). In multiple regression analysis, ESR and platelet counts remained determinants of total TGF-β1. Total TGF-β1 levels were lower in patients with high disease activity (SLEDAI > 10) and severe organ damage (SLICC > 3). Significantly lower levels of total TGF-β1 were found in patients with severe renal damage, i.e. lower TGF-β1 in patients with 24-h urine protein over 3.5 g than in those with below 3.5 g (p < 0.05); lower TGF-β1 in patients with GFR less than 50 ml/min than in those with over 50 ml/min (p < 0.05). In contrast, active TGF-β1 only correlated with platelet counts. There was no association between renal damage and the levels of active TGF-β1. Conclusion: This study demonstrates significantly reduced serum levels of both total and active TGF-β1 in women with SLE compared with healthy women. Total TGF-β1 levels are correlated negatively with ESR and positively with blood platelets. Total TGF-β1 levels were lower in SLE patients with high disease activity and severe organ damage. Importantly, the severity of the renal damage was associated with decreased serum levels of total TGF-β1, suggesting that TGF-β1 might be involved in pathogenesis of renal damage caused by lupus nephritis.
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| 4. |
- Jin, Tao, 1973, et al.
(författare)
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Soluble E-cadherin in systemic lupus erythematosus.
- 2013
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 40:10, s. 1677-82
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: E-cadherin is a potent adherens junction molecule implicated in tissue morphogenesis, epithelial functioning, and immune regulation. Serum levels of soluble E-cadherin (sE-cadherin), an end product of proteolytic cleavage of E-cadherin, is increased in patients with cancer, infections, and inflammation-related diseases. The aim of our study was to measure serum levels of sE-cadherin in systemic lupus erythematosus (SLE) and to determine associations between serum levels of sE-cadherin and markers of inflammation and organ damage in female patients with SLE.METHODS: Serum levels of sE-cadherin were analyzed by ELISA in 150 female patients with SLE and 31 healthy women. Simple and multiple regression analyses between sE-cadherin levels and disease-related variables were performed in patients with SLE.RESULTS: Serum levels of sE-cadherin were elevated in patients with SLE compared with levels in healthy controls. sE-cadherin levels correlated positively with age, disease duration, SLE Collaborating Clinics Damage Index, erythrocyte sedimentation rate (ESR), s-creatinine, cholesterol, triglycerides, interleukin 6, and matrix metalloproteinase-3. In multiple regression analysis, s-creatinine, age, ESR, and triglycerides remained determinants of sE-cadherin. Within the patients with SLE, higher sE-cadherin levels were found only in patients with renal damage, i.e., s-creatinine > 90 μmol/l, glomerular filtration rate < 50 ml/min, or renal involvement ever by SLE.CONCLUSION: Our study demonstrates significantly elevated serum levels of sE-cadherin in women with SLE compared with healthy women. The levels of sE-cadherin were positively correlated to s-creatinine, age, ESR, and triglycerides. Significantly elevated sE-cadherin levels were observed only in patients with renal damage.
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| 5. |
- Kłak, Marcin, et al.
(författare)
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Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis.
- 2010
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Ingår i: Scandinavian journal of infectious diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 42:5, s. 351-358
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Haemostatic balance shifts towards pro-coagulation during infection. Plasminogen, a key molecule of fibrinolysis, may play an important role in the pathogenesis of staphylococcal infections. In the present study, we assessed the impact of inhibition of plasminogen activation by tranexamic acid on the course of staphylococcal sepsis and septic arthritis in mice. We found significantly down-regulated plasmin activity and increased D-dimer levels in the blood from the mice with staphylococcal sepsis. Treatment with tranexamic acid significantly increased the severity and mortality of staphylococcal infection. In addition, tranexamic acid reduced the survival rate in a murine model for staphylococcal enterotoxin A-induced death. The aggravation of diseases by tranexamic acid was due neither to the pro-inflammatory cytokine network, nor to impairment of bacterial clearance. Modulation of fibrinolysis, either by supplement of fibrinolytic molecules (tissue plasminogen activator or plasmin) or by fibrinogen depletion, did not reduce the mortality of staphylococcal sepsis. In conclusion, we report that treatment with tranexamic acid led to distinct aggravation of staphylococcal septic arthritis and sepsis in mice, suggesting the clinical importance of fibrinolytic balance in staphylococcal infection.
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| 6. |
- Kwiecinski, Jakub, 1985, et al.
(författare)
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Activation of plasminogen by staphylokinase reduces the severity of Staphylococcus aureus systemic infection.
- 2010
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 202:7, s. 1041-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Staphylokinase (SAK) is produced by the majority of Staphylococcus aureus strains. It is an extracellular protein that activates the conversion of human plasminogen (plg) to plasmin. The role played by SAK in staphylococcal infection is unclear. METHODS: Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms--(1) linked to its own promoter and (2) fused to the promoter of the protein A gene--which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production. RESULTS: Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild-type mice infected with a SAK-deficient strain. CONCLUSIONS: The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus sepsis.
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| 7. |
- Kwiecinski, Jakub, 1985, et al.
(författare)
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Fibrinolysis is down-regulated in mouse collagen-induced arthritis, but its normalization does not alleviate the course of disease.
- 2011
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Ingår i: Inflammation research : official journal of the European Histamine Research Society ... [et al.]. - : Springer Science and Business Media LLC. - 1420-908X. ; 60:11, s. 1021-1029
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Down-regulation of fibrinolysis and increased fibrin deposition in joints are hallmarks of rheumatoid arthritis (RA), and are believed to be involved in disease progression. The mouse model of collagen-induced arthritis (CIA) closely resembles RA and has been used to explore mechanism and treatments of RA, but neither the fibrinolytic system nor pro-fibrinolytic therapies were investigated in CIA. MATERIALS AND METHODS: Plasmin activity, levels of plasminogen activator inhibitor (PAI-1), D-dimer, and IL-6 were measured in plasma of CIA mice. Fibrin deposition and PAI-1 levels were also measured in inflamed joints. Mice were treated with plasminogen activators uPA (urokinase-type plasminogen activator) or tPA (tissue-type plasminogen activator). Effects of treatment on disease severity and fibrinolytic system were assessed. RESULTS: CIA caused decrease in plasmin activity, accompanied by increase in PAI-1 levels, in both blood and inflamed joints. This resulted in massive fibrin deposition in synovium. PAI-1 levels correlated negatively with plasmin activity and positively with IL-6. Treatments with uPA and tPA improved plasmin activity and removed fibrin deposits in inflamed joints. However, disease severity remained unchanged. CONCLUSIONS: Fibrinolytic changes in CIA parallel changes in RA, making CIA a suitable model to study fibrinolysis in RA. Normalization of plasmin activity in CIA after treatment with plasminogen activators had no effect on disease severity.
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| 8. |
- Kwiecinski, Jakub, 1985, et al.
(författare)
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Reply to Bouchiat et al.
- 2014
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 210:8, s. 1343-1344
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Comment on: Buchiat Bouchiat C, Mehenni C, Meugnier H, Bes M, Tristan A, Vandenesch F. Limitations of staphylokinase as a marker for Staplylococcus aureus invasive infections in humans. J Infect Dis 2014;210:1341-3
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| 9. |
- Kwiecinski, Jakub, 1985, et al.
(författare)
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Staphylokinase Promotes the Establishment of Staphylococcus aureus Skin Infections While Decreasing Disease Severity
- 2013
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 208:6, s. 990-999
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Tidskriftsartikel (refereegranskat)abstract
- Skin infections are frequently caused by Staphylococcus aureus and can lead to a fatal sepsis. The microbial mechanisms controlling the initiation and progression from mild skin infection to a severe disseminated infection remain poorly understood. Using a combination of clinical data and in vitro and ex vivo assays, we show that staphylokinase, secreted by S. aureus, promoted the establishment of skin infections in humans and increased bacterial penetration through skin barriers by activating plasminogen. However, when infection was established, the interaction between staphylokinase and plasminogen did not promote systemic dissemination but induced the opening and draining of abscesses and decreased disease severity in neutropenic mice. Also, increased staphylokinase production was associated with noninvasive S. aureus infections in patients. Our results point out the dual roles of staphylokinase in S. aureus skin infections as promoting the establishment of infections while decreasing disease severity.
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| 10. |
- Kwiecinski, Jakub, 1985, et al.
(författare)
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Sulfatide attenuates experimental Staphylococcal aureus sepsis through a CD1d-dependent pathway.
- 2013
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Ingår i: Infection and immunity. - 1098-5522. ; 81:4, s. 1114-1120
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer T (NKT) lymphocytes are implicated in the early response to microbial infection. Further, sulfatide, a myelin self-glycosphingolipid, activates a type II NKT cell subset, and can modulate disease in murine models. We examined the role of NKT cells and the effect of sulfatide treatment in a murine model of Staphylococcus aureus sepsis. Lack of CD1d-restricted NKT cells did not alter survival after a lethal inoculum of S. aureus. In contrast, sulfatide treatment significantly improved the survival rate of mice with S. aureus sepsis, accompanied by decreased levels of TNF-α and IL-6 in the blood. The protective effect of sulfatide treatment depended on CD1d, but not on type I NKT cells, suggesting that activation of type II NKT cells by sulfatide has beneficial effects on the outcome of S. aureus sepsis in this model.
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