scholarly journals Etanercept Suppresses Arteritis in a Murine Model of Kawasaki Disease: A Comparative Study Involving Different Biological Agents

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Ryuji Ohashi ◽  
Ryuji Fukazawa ◽  
Makoto Watanabe ◽  
Hanako Tajima ◽  
Noriko Nagi-Miura ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Alternative Therapy ◽  
Suppressive Effect ◽  
Water Soluble ◽  
Ivig Treatment ◽  
Cytokines And Chemokines ◽  
Plasma Cytokines ◽  
Active Inflammation ◽  
Necrosis Factor

Coronary arteritis, a complication of Kawasaki disease (KD), can be refractory to immunoglobulin (IVIG) treatment. To determine the most effective alternative therapy, we compared the efficacy of different agents in a mouse model of KD. Vasculitis was induced by injection ofCandida albicanswater-soluble fractions (CAWS) into a DBA/2 mouse, followed by administration of IVIG, etanercept, methylprednisolone (MP), and cyclosporine-A (CsA). At 2 and 4 weeks, the mice were sacrificed, and plasma cytokines and chemokines were measured. CAWS injection induced active inflammation in the aortic root and coronary arteries. At 2 weeks, the vasculitis was reduced only by etanercept, and this effect persisted for the subsequent 2 weeks. At 4 weeks, IVIG and CsA also attenuated the inflammation, but the effect of etanercept was more significant. MP exerted no apparent effect at 2 or 4 weeks. The suppressive effect exerted by etanercept on cytokines, such as interleukin- (IL-)6, IL-12, IL-13, and tumor necrosis factor-α(TNF-α), was more evident than that of others. The extent of arteritis correlated with the plasma TNF-αlevels, suggesting a pivotal role of TNF-αin KD. In conclusion, etanercept was most effective in suppressing CAWS-induced vasculitis and can be a new therapeutic intervention for KD.

scholarly journals GM-CSF primes cardiac inflammation in a mouse model of Kawasaki disease

2016 ◽  
Vol 213 (10) ◽  
pp. 1983-1998 ◽  
Author(s):  
Angus T. Stock ◽  
Jacinta A. Hansen ◽  
Matthew A. Sleeman ◽  
Brent S. McKenzie ◽  
Ian P. Wicks
Keyword(s):  
Kawasaki Disease ◽  
Mouse Model ◽  
Immune Cell ◽  
Cardiac Fibroblasts ◽  
Developed Countries ◽  
Water Soluble ◽  
Cardiac Inflammation ◽  
Gm Csf ◽  
Cytokines And Chemokines ◽  
Macrophage Colony

Kawasaki disease (KD) is the leading cause of pediatric heart disease in developed countries. KD patients develop cardiac inflammation, characterized by an early infiltrate of neutrophils and monocytes that precipitates coronary arteritis. Although the early inflammatory processes are linked to cardiac pathology, the factors that regulate cardiac inflammation and immune cell recruitment to the heart remain obscure. In this study, using a mouse model of KD (induced by a cell wall Candida albicans water-soluble fraction [CAWS]), we identify an essential role for granulocyte/macrophage colony-stimulating factor (GM-CSF) in orchestrating these events. GM-CSF is rapidly produced by cardiac fibroblasts after CAWS challenge, precipitating cardiac inflammation. Mechanistically, GM-CSF acts upon the local macrophage compartment, driving the expression of inflammatory cytokines and chemokines, whereas therapeutically, GM-CSF blockade markedly reduces cardiac disease. Our findings describe a novel role for GM-CSF as an essential initiating cytokine in cardiac inflammation and implicate GM-CSF as a potential target for therapeutic intervention in KD.

scholarly journals Multimodality Cardiac Imaging in a Patient with Kawasaki Disease and Giant Aneurysms

2016 ◽  
Vol 2016 ◽  
pp. 1-7
Author(s):  
Ranjini Srinivasan ◽  
Rachel Weller ◽  
Anjali Chelliah ◽  
Andrew J. Einstein
Keyword(s):  
Kawasaki Disease ◽  
Cardiac Disease ◽  
Multimodality Imaging ◽  
Adult Population ◽  
Giant Aneurysm ◽  
The United States ◽  
Ivig Treatment ◽  
Serious Illness ◽  
Integral Role

Kawasaki disease is a well-known cause of acquired cardiac disease in the pediatric and adult population, most prevalent in Japan but also seen commonly in the United States. In the era of intravenous immunoglobulin (IVIG) treatment, the morbidity associated with this disease has decreased, but it remains a serious illness. Here we present the case of an adolescent, initially diagnosed with Kawasaki disease as an infant, that progressed to giant aneurysm formation and calcification of the coronary arteries. We review his case and the literature, focusing on the integral role of multimodality imaging in managing Kawasaki disease.

Abstract 65: T cell Differentiation in Human Kawasaki Disease and a Murine Model of Coronary Arteritis

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
I-Chun Lin ◽  
Hsuan-Chang Kuo ◽  
Ying-Jui Lin ◽  
Shao-Ju Chien ◽  
Chien-Fu Huang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Kawasaki Disease ◽  
Murine Model ◽  
Th17 Cells ◽  
T Cell Differentiation ◽  
Ivig Treatment ◽  
Th1 Cells ◽  
Coronary Arteritis

The role of T cell differentiation in the immunopathogenesis of Kawasaki disease (KD) remains unclear. The aim of this study is to elucidate the role of T cell subsets in coronary artery lesion (CAL) of KD. Peripheral blood was obtained in 10 patients with acute KD before and 1 week after intravenous gamma-immunoglobulin (IVIG) treatment and in 20 patients with past history of KD for more than 5~20 years. Meanwhile, induction of coronary arteritis was performed on wild type BALB/c mice by Lactobacillus casei cell wall extract (LCWE). Human peripheral blood leukocytes were analyzed by using flow cytometric analysis and murine hearts were examined for immunofluorescence study and for RNA expression levels. Results: Compared to the febrile controls, KD patients prior to IVIG treatment had increased percentage of CD3 + /CD4 + /interferon-γ + (T helper 1, Th1) cells and CD3 + /CD4 + /interleukin-17A + (Th17) cells (mean ± SD, 1.36% ± 1.39% and 0.51% ± 0.25%, respectively) among Th cells (CD3 + /CD4 + ). Both increases declined after IVIG treatment (0.71% ± 0.74% and 0.33% ± 0.18%) despite no statistically difference by Mann-Whitney test. None of these 10 acute KD patients developed CAL after IVIG treatment. However, patients with previous KD and definite CALs (n= 11) seemed to have higher percentage of Th17 cells (0.50% ± .025% versus 0.35% ± 0.23%) but similar level of Th1 cells (0.93% ± 0.51% versus 1.05% ± 0.64%) when compared to those without CAL (n= 9). Murine cardiac tissues displayed the presence of Th1 (double-stained with CD3 and T-bet) and Th17 cells (double-stained with CD3 and RORγt) during days 7 and 14 after LCWE treatment but not in PBS-treated mice. Compatible with these, cardiac mRNA levels showed both increased levels of IFN-γ and IL17A mRNA in LCWE-treated mice. Conclusions: Our initial data suggests that specific T cell differentiation into Th1 and Th17 cells occurred in both human KD and mice stimulated with LCWE. IVIG treatment was associated with the recovery of such T cell differentiation. However, the clinical application to predict IVIG responsiveness and future CAL development by such increase in the peripheral Th17 remains unclear. Further studies to elucidate the detailed immune regulation of these T subsets on CAL are warrant by using this LCWE murine model.

Abstract 69: Possible Involvement Of Proline-rich Tyrosine Kinase 2 (pyk2) In The Pathogenesis Of Kawasaki Disease

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Chinatsu Suzuki ◽  
Akihiro Nakamura ◽  
Mitsuhiko Okigaki ◽  
Noriko Miura ◽  
Naohito Ohno ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Tyrosine Kinase ◽  
Nuclear Translocation ◽  
Experimental Studies ◽  
Water Soluble ◽  
Wild Type ◽  
Knock Out ◽  
Cytokines And Chemokines ◽  
Tyrosine Kinase 2

Introduction: Although etiology of Kawasaki disease (KD) remains elusive, a line of recent experimental studies implies that some kinds of infectious stimuli are implicate in the vasculitis through uncontrolled innate immune systems such as pattern recognition receptor (PPR)-mediated inflammatory signaling. It has already known that Candida albicans water-soluble fraction (CAWS) inducing KD-like vasculitis in mice function through PRP. Furthermore, it is reported that proline-rich tyrosine kinase (Pyk2), which is molecule involved in the PRPs-dependent signaling pathways, plays an important role in activation of NF-κB. Therefore, we investigated a possible relevance of Pyk2 in the pathogenesis of KD. Methods: Pyk2-knock out (Pyk2-KO) and wild-type C57BL/6 mice (WT) were administered CAWS to induce KD-like vasculitis. Extension of the experimental vasculitis was immunohistochemically determined with anti-MPO antibody. CAWS-stimulated NF-κB activation was evaluated by quantifying nuclear translocation of NF-κB p65 subunit in peritoneal macrophages isolated from PYK2-KO and wild-type mice in vitro. Cytokines and chemokines across each mice were compared by cytokine array. Results: Pyk2-KO mice didn’t show any apparent defective phenotype. While marked inflammation was observed in the aortic root of CAWS-treated WT mice, such vasculitis was barely detected in CAWS-treated Pyk2-KO mice. CAWS-induced NF-κB activation was also less observed in macrophages from Pyk2-KO mice. There were differences in some cytokines and chemokines production between mice. Conclusion: We speculate that Pyk2 is involved in the pathogenesis of KD. Pyk2 might be a potential therapeutic target for KD.

scholarly journals Effect of Hepcidin and Iron Deficiency  Anemia on Clinical Outcome in patients  with Kawasaki Disease

2019 ◽  
Author(s):  
Hyun Jung Kim ◽  
Eun Hye Choi ◽  
Hong Ryang Kil
Keyword(s):  
Iron Deficiency ◽  
Kawasaki Disease ◽  
Iron Deficiency Anemia ◽  
Ivig Therapy ◽  
Acute Stage ◽  
Deficiency Anemia ◽  
Ivig Treatment ◽  
Enzyme Linked Immunosorbent Assay ◽  
Subacute Phase

Abstract Background: The role of iron in children with Kawasaki disease (KD) and the importance of iron deficiency anemia (IDA) in children with KD are not fully known. We aimed to evaluate the effects of IDA on clinical outcomes of KD patients and the role of inflammation-induced hepcidin and leptin in the development of anemia in patients with KD. Methods: A total of 50 children with KD and 47 age-matched children with controls were enrolled. Hepcidin, leptin, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were measured by an enzyme-linked immunosorbent assay and IDA work-up was performed before and after IVIG therapy, and in the convalescent phase in patients with KD and control patients. Results: (1) Pre-IVIG iron and transferrin saturations in KD children were significantly lower than those in controls ( P =0.001). (2) Pre-IVIG hemoglobin and iron levels were positively correlated with leptin levels ( P =0.018 and P =0.021, respectively). (3) Serum hepcidin levels were significantly elevated after IVIG treatment in patients with KD (1.53 ± 1.36 ng/ml in the acute stage vs 3.09 ± 4.22 ng/mL in the subacute phase, P = 0.001). (4) There was no difference in parameters of IDA, leptin, and hepcidin levels between KD patients with and without coronary artery lesion (CAL). Conclusion: Serum iron and transferrin saturations were lowest in the acute phase, while hepcidin levels were highest in the subacute phase of KD. Although the presence of iron deficiency in the acute stage of KD did not predict CAL, further studies are necessary to clarify the association of hepcidin on the pathogenesis of anemia in KD.

Mechanism of suppressed neutrophil mobilization in a mouse model for binge drinking: role of glucocorticoids

1998 ◽  
Vol 275 (4) ◽  
pp. R1049-R1057 ◽  
Author(s):  
Robert B. Vinson ◽  
Jennifer L. Carroll ◽  
Stephen B. Pruett
Keyword(s):  
Peritoneal Cavity ◽  
Propionibacterium Acnes ◽  
Suppressive Effect ◽  
Neutrophil Accumulation ◽  
Ru 486 ◽  
Tnf Α ◽  
Per Se ◽  
Factor Α ◽  
Necrosis Factor

The goals of this study were to determine if suppression of neutrophil accumulation and TNF-α production in the peritoneal cavity occurs in mice exposed to a chemical stressor [ethanol (EtOH)], to evaluate the role of EtOH-induced increases in endogenous glucocorticoids in any such suppression, and to determine if decreased tumor necrosis factor-α (TNF-α) production is responsible for decreases in neutrophil accumulation in EtOH-treated mice. An inflammatory response induced in the peritoneal cavity of mice by administration of heat-killed Propionibacterium acnes ( P. acnes) was suppressed by a single dose of EtOH given 1 h before administration of the bacteria, as indicated by decreased accumulation of neutrophils in the peritoneal cavity. The concentration of TNF-α in the peritoneal cavity was also decreased by EtOH, but exogenous TNF-α did not prevent the suppression of neutrophil accumulation. The glucocorticoid antagonist RU-486 did not prevent the suppression of neutrophil accumulation in mice treated with EtOH, but RU-486 did block suppression of neutrophil accumulation caused by administration of exogenous corticosterone. The suppression of neutrophil accumulation caused by exogenous corticosterone was less than produced by EtOH. These observations suggest that the increase in endogenous corticosterone induced by EtOH may explain some of the suppression of neutrophil accumulation, but other neuroendocrine mediators (or EtOH per se) are sufficient to cause the full suppressive effect when the action of corticosterone is blocked by RU-486. The results also demonstrate that EtOH decreases TNF-α production, but this is not the mechanism by which neutrophil accumulation is decreased in this model.

scholarly journals Recombinant Human Soluble Thrombomodulin Suppresses Arteritis in a Mouse Model of Kawasaki Disease

2021 ◽  
Author(s):  
Hironobu Nakayama ◽  
Hiroyasu Inada ◽  
Tatsuya Inukai ◽  
Kenta Kondo ◽  
Kazuyuki Hirai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kawasaki Disease ◽  
Mouse Model ◽  
Inflammatory Cytokine ◽  
Water Soluble ◽  
Ivig Treatment ◽  
Soluble Thrombomodulin ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Recombinant Human Soluble Thrombomodulin

Abstract Background: Kawasaki Disease (KD) is associated with diffuse and systemic vasculitis of unknown aetiology and mainly affects infants and children. Intravenous immunoglobulin (IVIG) treatment reduces the risk of developing coronary aneurysms, but some children have IVIG-resistant KD, and they are at an increased risk of developing coronary artery injury. Here, we investigated the effect of recombinant human soluble thrombomodulin (rTM), which has anticoagulation, anti-inflammatory and cytoprotective properties, on the development of coronary arteritis in a mouse model of vasculitis. Methods: To prepare an animal model of KD-like vasculitis, Candida albicans water-soluble fraction (CAWS) was intraperitoneally injected into DBA/2 mice for 5 consecutive days, and then rTM (0, 0.2, 1, and 4 mg/kg body weight) was injected. rTM administration was performed at two intervals: one is for 10 consecutive days from the first day and the other is for 5 consecutive days from the 1st to 15th days. Histopathological analysis of the heart was performed 20, 27, 34, and 48 days after CAWS treatment, and the gene expression of anti-inflammatory cytokine interleukin-10 (IL-10), pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α), and tissue factor (TF) in the heart and spleen was investigated.Results: Five consecutive doses of rTM (4 mg/kg) from 1 to 14 days after CAWS treatment significantly suppressed cardiac hypertrophy and arteritis by 34 days after CAWS treatment. The gene expression analysis of samples prepared from the heart and spleen of mice treated with CAWS and/or rTM showed that rTM administration increased the level of IL-10 in the heart. This increase was observed until day 27 and was not observed thereafter. The expression of TNF-α was observed in the heart of mice treated with CAWS and was not altered by rTM treatment. However, in the spleen, CAWS treatment reduced the IL-10 level and increased the TF level, whereas rTM treatment restored normal levels of both factors.Conclusions: These findings suggest that rTM specifically increases IL-10, decreases TF, and suppresses CAWS-induced vasculitis without affecting TNF-α production. Therefore, rTM can be used as a treatment for KD.

Recombinant Human Soluble Thrombomodulin Suppresses Arteritis in a Mouse Model of Kawasaki Disease

2021 ◽  
pp. 1-13
Author(s):  
Hironobu Nakayama ◽  
Hiroyasu Inada ◽  
Tatsuya Inukai ◽  
Kenta Kondo ◽  
Kazuyuki Hirai ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Mouse Model ◽  
Mrna Expression ◽  
Systemic Vasculitis ◽  
Water Soluble ◽  
Ivig Treatment ◽  
Soluble Thrombomodulin ◽  
Coronary Aneurysms ◽  
Tnf Α ◽  
Recombinant Human Soluble Thrombomodulin

<b><i>Introduction and Objective:</i></b> Kawasaki disease (KD) is associated with diffuse and systemic vasculitis of unknown aetiology and primarily affects infants and children. Intravenous immunoglobulin (IVIG) treatment reduces the risk of developing coronary aneurysms, but some children have IVIG-resistant KD, which increases their risk of developing coronary artery injury. Here, we investigated the effect of recombinant human soluble thrombomodulin (rTM), which has anticoagulant, anti-inflammatory, and cytoprotective properties on the development of coronary arteritis in a mouse model of vasculitis. <b><i>Methods:</i></b> An animal model of KD-like vasculitis was created by injecting mice with <i>Candida albicans</i> water-soluble fraction (CAWS). This model was used to investigate the mRNA expression of interleukin (IL)-10, tumour necrosis factor alpha (TNF-α), and tissue factor (TF), in addition to histopathology of heart tissues. <b><i>Results:</i></b> rTM treatment significantly reduces cardiac vascular endothelium hypertrophy by 34 days after CAWS treatment. In addition, mRNA expression analysis revealed that rTM administration increased cardiac IL-10 expression until day 27, whereas expression of TNF-α was unaffected. Moreover, in the spleen, rTM treatment restores IL-10 and TF expression to normal levels. <b><i>Conclusion:</i></b> These findings suggest that rTM suppresses CAWS-induced vasculitis by upregulating IL-10. Therefore, rTM may be an effective treatment for KD.

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