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.

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.

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.

Abstract 103: Incomplete Kawasaki Disease - Patients With ≦ 5 Days Of Fever Successfully Treated By Antibiotics But Left With Coronary Aneurysms -

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Kenji Suda ◽  
Hiroshi Nishino ◽  
Yoshiyuki Kudo ◽  
Hironaga Yoshimoto ◽  
Shintaro Kishimoto ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Case Series ◽  
Artery Aneurysm ◽  
Ivig Treatment ◽  
Incomplete Kawasaki Disease ◽  
Antithrombotic Treatment ◽  
Coronary Aneurysms ◽  
Appropriate Treatment ◽  
Echocardiographic Examination

Objective: We report four patients with incomplete Kawasaki disease (KD) successfully treated by antibiotics without intravenous immunoglobulin (IVIG) treatment with ≦ 5 days of fever but left with coronary artery lesion. Result: The patients were 2 babies and 2 young children age ranged from 2 months to 2 years old and 9 months. They showed fever and other signs of KD, but did not fulfill diagnostic criteria. The numbers of symptoms compatible with KD were 2 or 3 and included conjunctival injection, oral or lip injection, and eruption. Within 5 days, they became afebrile by antibiotics without IVIG treatment. However, they were noted to have coronary artery aneurysm (CAA) on day from 7 to 33 of illness. All patients had been placed on antithrombotic treatment including aspirin or aspirin plus warfarin and, fortunately, showed regression of CAA within 2 years. Conclusions: This case series indicates that there are patients with incomplete KD successfully treated by antibiotics without IVIG but left with CAA. These cases must be underdiagnosed if intentional echocardiographic examination are scheduled and might be left without appropriate treatment, antithrombotic treatment. Further collection of data of these patients is indispensable.

scholarly journals Recurrent Kawasaki Disease: A Case Report of Three Separate Episodes at >4-Year Intervals

Children ◽  
2018 ◽  
Vol 5 (11) ◽  
pp. 155 ◽  
Author(s):  
Nikita Goswami ◽  
Katherine Marzan ◽  
Elizabeth De Oliveira ◽  
Sharon Wagner-Lees ◽  
Jacqueline Szmuszkovicz
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Systemic Vasculitis ◽  
High Dose ◽  
Z Score ◽  
Coronary Aneurysms ◽  
Increased Risk ◽  
The Right ◽  
Work Up ◽  
High Dose Aspirin

Kawasaki disease (KD) is a self-limited systemic vasculitis, most often occurring in children 1–5 years old. It has a 2% recurrence rate and is associated with coronary aneurysms (CA), which can develop within two weeks of onset. A 25% increased risk is noted in patients who are recalcitrant to treatment. We describe a patient with recurrence of KD three times, approximately four years apart. A 10-year-old female with two previous episodes of KD, at 11 months and five years of age), in which she met five out of five criteria for KD and had no coronary involvement, presented with 15 days of fever, conjunctivitis and mucocutaneous changes. Infectious work-up was negative, and she was diagnosed with incomplete KD meeting three out of five criteria. An echocardiogram (ECHO) on day 12 revealed dilation of the right coronary artery (RCA) and left coronary artery (LCA). Treatment with intravenous immunoglobulin (IVIG) and high-dose aspirin was started at an outside hospital. After transfer, serial ECHOs showed evolving coronary aneurysms, left anterior descending (LAD) z-score + 8.2 and RCA z-score + 4.0. She received 10 mg/kg infliximab (day 18) and began clopidogrel. A cardiac MRI (day 20) demonstrated progression of the LAD aneurysm, with a z-score + 13, and warfarin was started. To our knowledge, this is the first report of recurrent KD occurring three times at ~5 year intervals.

scholarly journals AB1002 IS KAWASAKI DISEASE OR SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS IN CHILDREN WITH FEVER WITHOUT A SOURCE?

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1794.2-1794
Author(s):  
B. Sözeri ◽  
F. Demir ◽  
T. Merter ◽  
M. Karacan
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Kawasaki Disease ◽  
Clinical Features ◽  
Systemic Vasculitis ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Clinical Feature ◽  
Unknown Etiology ◽  
Ivig Treatment ◽  
Factors Affecting ◽  
The Mean

Background:Fever without a source (FWS) is caused by various diseases, making differential diagnosis difficult. Clinical similarities between Kawasaki disease (KD) and systemic Juvenile Idiopathic Arthritis (sJIA) are well known. Kawasaki disease (KD), a self-limiting systemic vasculitis, remains of unknown etiology and can cause irreversible coronary artery aneurysms (CAAs). SoJIA is sometimes confused with incomplete KD because both diseases have overlapping clinical features and can be accompanied with CAAs and/or SJIA with macrophage activation syndrome (MAS).Objectives:In this study, the frequency of both KD and SJIA among the patients evaluated with FWS and the clinical features of patients diagnosed with Kawasaki disease.Methods:Medical records of patients who first visited our department between January 2016 and December 2019 were reviewedResults:A total of 107 patients were enrolled in this study, including 43 patients (40.2%, 23 males) who fulfilled the criteria of Kawasaki disease and 64 patients (59.8%, 39 males) who did not fulfill them. In patients who fulfilled the criteria of classical FWS, 36(33.6%, 20 males) patients were diagnosed with systemic juvenile idiopathic arthritis. The mean age of the patients with Kawasaki disease was 30.0±20,4 months (median 25 months), the mean age of other patients was 52,6±40 months (median 39,5 months). The mean age of the patients with sJIA patients was 87,6±49,8 (median 80months). Kawasaki patients were younger than others (p=0.01). There was no difference in gender between groups.In Kawasaki patients, the most common clinical feature at diagnosis was fever (100%) followed by conjunctival congestion and mucosal changes (69%). The last two findings are more significant in kawasaki patients than others (p<0,00). Twenty-six (59%) patients had completed KD while 25% had incomplete KD. 7 (16%) patients had atypical KD. The mean fever duration was longer in sJIA patients than KD and others (median 14,8 and 7 days, p<0.00). All patients with KD received IVIG (2 g/kg, infusion in 12 h) and aspirin (60 mg/kg/day). 13.6% of the patients also received oral corticosteroids because of IVIG resistance. Thirty-one patients (72.1%) responded to IVIG treatment, whereas 12 (6 female, 6 male) were IVIG resistant. CAI was detected in echocardiography at diagnosis in 10 (22.7%) (6 female; 4 male) patients. We also detected 4 patients pericarditis with /without CIA.Conclusion:The clinical presentations of KD and sJIA are quite similar with fever, rash, hepatomegaly, and lymphadenopathy. All 2 entities may provide clues to potentially shared immunopathology.References:[1]Arslanoglu Aydin E et al. The factors affecting the disease course in Kawasaki disease. Rheumatol Int. 2019 Aug;39(8):1343-1349[2]Dong S et al. Diagnosis of systemic-onset juvenile idiopathic arthritis after treatment for presumed Kawasaki disease. J Pediatr. 2015 May;166(5):1283-8.Disclosure of Interests:None declared

scholarly journals Effects of TNFα receptor TNF-Rp55- or TNF-Rp75- deficiency on corneal neovascularization and lymphangiogenesis in the mouse

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0245143
Author(s):  
Anna-Karina B. Maier ◽  
Nadine Reichhart ◽  
Johannes Gonnermann ◽  
Norbert Kociok ◽  
Aline I. Riechardt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mrna Expression ◽  
Lymphatic Vessels ◽  
Corneal Neovascularization ◽  
Wild Type ◽  
Delayed Effect ◽  
Corneal Inflammation ◽  
Tnf Α ◽  
Mrna And Protein Expression

Tumor necrosis factor (TNF)α is an inflammatory cytokine likely to be involved in the process of corneal inflammation and neovascularization. In the present study we evaluate the role of the two receptors, TNF-receptor (TNF-R)p55 and TNF-Rp75, in the mouse model of suture-induced corneal neovascularization and lymphangiogenesis. Corneal neovascularization and lymphangiogenesis were induced by three 11–0 intrastromal corneal sutures in wild-type (WT) C57BL/6J mice and TNF-Rp55-deficient (TNF-Rp55d) and TNF-Rp75-deficient (TNF-Rp75d) mice. The mRNA expression of VEGF-A, VEGF-C, Lyve-1 and TNFα and its receptors was quantified by qPCR. The area covered with blood- or lymphatic vessels, respectively, was analyzed by immunohistochemistry of corneal flatmounts. Expression and localization of TNFα and its receptors was assessed by immunohistochemistry of sagittal sections and Western Blot. Both receptors are expressed in the murine cornea and are not differentially regulated by the genetic alteration. Both TNF-Rp55d and TNF-Rp75d mice showed a decrease in vascularized area compared to wild-type mice 14 days after suture treatment. After 21 days there were no differences detectable between the groups. The number of VEGF-A-expressing macrophages did not differ when comparing WT to TNF-Rp55d and TNF-Rp75d. The mRNA expression of lymphangiogenic markers VEGF-C or LYVE-1 does not increase after suture in all 3 groups and lymphangiogenesis showed a delayed effect only for TNF-Rp75d. TNFα mRNA and protein expression increased after suture treatment but showed no difference between the three groups. In the suture-induced mouse model, TNFα and its ligands TNF-Rp55 and TNF-Rp75 do not play a significant role in the pathogenesis of neovascularisation and lymphangiogenesis.

Cardiac Events in Kawasaki Disease With Coronary Aneurysms Revisited, A Two-center Retrospective Cohort Study in Thailand

2021 ◽  
Author(s):  
Kanokvalee Santimahakullert ◽  
Chodchanok Vijarnsorn ◽  
Yuttapong Wongswadiwat ◽  
Prakul Chanthong ◽  
Sappaya Khrongsrattha ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Artery Bypass ◽  
Coronary Intervention ◽  
Ivig Treatment ◽  
Cardiac Events ◽  
Coronary Aneurysms ◽  
Adverse Cardiac Events ◽  
Percutaneous Coronary

Abstract Kawasaki disease (KD) is a common vasculitis in children, which may be complicated with coronary artery aneurysms (CAAs). We aimed to report the rates of major adverse cardiac events (MACE) and determine the risks of MACE in children diagnosed with KD and CAAs in Thailand. Data of 170 children diagnosed with KD and CAAs in two centers of Thailand between 1994 and 2019 was retrospectively reviewed. The risks of MACE were analyzed using multivariate analysis. Of 170 patients, forty-nine patients (28.8%) had giant CAAs. During the median time of follow-up (5.4 years; ranging from 22 days to 23 years), 19 patients (11.1%) experienced MACE including 12 coronary artery bypass grafting, 2 percutaneous coronary intervention and 5 patients with evidence of coronary occlusion. Coronary interventions were performed at 4 years (ranging from 0.01 to 9.5 years) after the KD diagnosis. Independent risks of MACE in KD with CAAs were from the presence of giant aneurysms (HR 16.55; 95% CI 2.52 to 108.63; p=0.003) and lack of intravenous immunoglobulin (IVIG) treatment (HR 11.43; 95% CI 2.8 to 46.62; p=0.001). The intervention-free rate at 5 and 10 years in patients with giant CAAs was 78.7% and 52.2%, respectively.Trial registration: TCTR20190125004

Abstract 36: FCGR2A Promoter Methylation and Risks for IVIG Unresponsiveness in Kawasaki Disease

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Ho-Chang Kuo ◽  
Kai-Sheng Hsieh ◽  
Wei-Chiao Chang ◽  
Keyword(s):  
Kawasaki Disease ◽  
Promoter Methylation ◽  
Systemic Vasculitis ◽  
Methylation Status ◽  
Cpg Islands ◽  
Gene Promoter ◽  
Ivig Therapy ◽  
Ivig Treatment ◽  
Fc Fragment ◽  
Cpg Sites

Kawasaki disease (KD) is characterized by pediatric systemic vasculitis of an unknown cause and the Fc Fragment of IgG, Low Affinity IIa, Receptor ( FCGR2A ) gene was reported to involve in increasing susceptibility of KD. Because DNA methylation is one of the epigenetic mechanisms that control gene expression, we hypothesized that methylation status of CpG islands in FCGR2A promoter predisposes an individual to Kawasaki disease. We recruited 36 KD patients and 24 healthy subjects with informed consents. And eleven potential methylation loci within the targeted promoter region (chr1:161474603-161475102) of Fc Fragment of IgG, Low Affinity IIa, Receptor were selected for investigation. Methylation at the CpG sites G, H and J displayed a strongly associations with KD, whereas CpG sites B,C,E,F,H,J and K were found to be correlated with non-responsive to IVIG treatment. In addition, CpG sites G, J and K were predicted as the significant transcription factor binding site for NF-kB, Myc-Max and SP2 respectively. Our study reports a significant association between the promoter methylation of FCGR2A , susceptibility of Kawasaki disease and therapeutic outcomes of IVIG treatment. The methylation levels of CpG sites of FCGR2A gene promoter may be an important marker for optimizing IVIG therapy.

Abstract 70: Trial of Ulinastatin treatment for murine model of Kawasaki Desease

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Yuki Tsujita ◽  
Yoichi Kawamura ◽  
Takashi Kanai ◽  
Seiichiro Takeshita ◽  
Shigeaki Nonoyama
Keyword(s):  
Treatment Group ◽  
Kawasaki Disease ◽  
Murine Model ◽  
Neutrophil Elastase ◽  
Muscle Layer ◽  
Water Soluble ◽  
Therapeutic Effects ◽  
Rescue Treatment ◽  
Tnf Α ◽  
Water Soluble Extract

Recently, we reported that the initial Ulinastatin (UTI) therapy combined with intravenous immunoglobulin (IVIG) reduced the proportion of patients with Kawasaki disease requiring additional rescue treatment and the occurrence of coronary artery lesions as compared with IVIG alone (Circulation. 2011;124(25):2822-2828.). However, there have been no reports that histologically examined the therapeutic effects of UTI., In the present study, to investigate the histological efficacy of UTI, we administered UTI in a vasculitis murine model, resembling Kawasaki disease Four-week-old male mice DBA/2 were intraperitoneally administered Candida albicans water soluble extract (CAWS) for 5 days and were treated either with UTI, IVIG, or a combination of UTI and IVIG. Further, we examined the plasma levels of neutrophil elastase andcytokinesandevaluated histopathological features.. Neutrophil elastase, TNF-α, IL-6, IP-10, and MIG significantly increased in the CAWS-treated mice. Large amount of elastase-positive neutrophils infiltrated in the coronary tissue. In addition, the infiltration of elastase-positive neutrophils was reduced in the pathological tissue of the UTI treatment group. Neutrophil elastase is strongly involved in the destruction of the elastic plate and smooth muscle layer. There is a possibility that destruction of the vascular structures can be suppressed by decreasing the elastase-positive neutrophils infiltration in the UTI treatment group.

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