A CCR1 antagonist prevents the development of experimental autoimmune myocarditis in association with T cell inactivation

Futamatsu, Hideki; Suzuki, Jun–ichi; Koga, Noritaka; Adachi, Susumu; Kosuge, Hisanori; Maejima, Yasuhiro; Haga, Takaaki; Hirao, Kazuyuki; Horuk, Richard; Isobe, Mitsuaki

doi:10.1016/j.yjmcc.2006.03.432

Cited by 22 publications

(7 citation statements)

References 36 publications

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“…The altered T helper 1 (Th1)-Th2 cell balance regulates the clinical course of EAM (39). Previous studies also reported that production of proinflammatory cytokines affected development of EAM (14). Moreover, the excessive production of a number of inflammatory cytokines is suggested to play a crucial role in the pathogenesis of chronic periodontitis (12).…”

Section: Discussionmentioning

confidence: 99%

Periodontal bacteria aggravate experimental autoimmune myocarditis in mice

Ashigaki

Suzuki

Ogawa

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Periodontitis is one of the most common infections in humans. Recently, published reports assert that periodontitis is associated with cardiovascular disease. Although it is said that viral, bacterial infections and autoimmune diseases may be the cause of myocarditis, the pathogenesis of it remains unclear. The aim of this study was to investigate the influence of a periodontal pathogen on experimental autoimmune myocarditis (EAM). Porphyromonas gingivalis (P.g.), PBS as a control, were injected into the mice. Histopathological and immunohistochemical analyses were performed. We examined heart mRNA levels using quantitative RT-PCR. The anti-P.g. IgG antibody level in plasma samples of the P.g.-injected group significantly increased compared with the PBS-injected group. Histopathological analysis detected that the myocarditis-affected areas and the fibrotic area in the P.g.-injected EAM group significantly increased compared with the PBS-injected EAM group (P < 0.05). Immunohistochemical analysis detected that more CD11b-positive cells were shown in the heart of the P.g.-injected EAM group compared with the PBS EAM-injected group (P < 0.05). Hearts from the P.g.-injected EAM group showed significantly increased expression of monocyte chemoattractant protein-1, IFN-γ, and matrix metalloproteinase-9 (MMP-9) mRNA compared with the hearts from the PBS-injected EAM group (P < 0.05). On day 7, serum levels of IL-6 were significantly enhanced in the P.g.-injected EAM group compared with the PBS-injected EAM group (P < 0.05). These results showed that P.g. injection could deteriorate EAM in mice through CD11b-positive cells, cytokines, and MMP-9 expression.

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Section: Discussionmentioning

confidence: 99%

Periodontal bacteria aggravate experimental autoimmune myocarditis in mice

Ashigaki

Suzuki

Ogawa

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…In the recovery phase of the inflammation, immunized animals will progress to DCM [18]. Several studies have demonstrated that early administration of anti-inflammatory therapies can effectively attenuate the induction of EAM [19, 20]. However, it remains unclear whether later anti-inflammatory treatment could further prevent the progression of cardiac remodeling in the stage of postmyocarditis.…”

Section: Discussionmentioning

confidence: 99%

Effects of Methotrexate on Plasma Cytokines and Cardiac Remodeling and Function in Postmyocarditis Rats

Zhang

Zhao²,

Li³

et al. 2009

Mediators of Inflammation

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Excessive immune activation and inflammatory mediators may play a critical role in the pathogenesis of chronic heart failure. Methotrexate is a commonly used anti-inflammatory and immunosuppressive drug. In this study, we used a rat model of cardiac myosin-induced experimental autoimmune myocarditis to investigate the effects of low-dose methotrexate (0.1 mg/kg/d for 30 d) on the plasma level of cytokines and cardiac remodeling and function. Our study showed that levels of tumor necrosis factor-(TNF-)alpha and interleukin-6 (IL-6) are significantly increased in postmyocarditis rats, compared with the control rats. Methotrexate treatment reduced the plasma levels of TNF-alpha and IL-6 and increased IL-10 level, compared to saline treatment. In addition, postmyocarditis rats showed significant cardiac fibrosis characterized by increased myocardial collagen volume fraction, perivascular collagen area, and the ratio of collagen type I to type III, compared with the control rats. However, MTX treatment not only markedly attenuated cardiac fibrosis, diminished the left ventricular end-diastolic dimension, but also increased the left ventricular ejection fraction and fractional shortening. Collectively, these results suggest that low-dose methotrexate has ability to regulate inflammatory responses and improves cardiac function and hence contributes to prevent the development of postmyocarditis dilated cardiomyopathy.

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“…This can be explained by the previously characterized inhibition of monocyte/macrophage and T‐cell recruitment by BX 471. CCR1 has been demonstrated to play a major role in the induction of shear‐resistant arrest of monocytes and T cells (9), and in the recruitment of leukocytes to sites of inflammation in vivo (6,42). BX 471 has been reported to prevent activation of integrin CD11b by the CCR1 ligands CCL5 and CCL3 (4).…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of CCR1 Blockade on the Progression of Chronic Renal Allograft Damage

Bedke

Kiss

Schaefer

et al. 2007

American Journal of Transplantation

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The biology of chemokines and their receptors have been linked to the development of chronic allograft damage. Effects of CCR1 antagonist BX 471 were studied in a Fischer to Lewis renal transplantation model at days 10, 21 and 42 after transplantation. BX 471 treatment did not effectively reduce signs of acute rejection at day 10 but significantly improved allograft function and morphology at day 21 posttransplantation. When therapy was initiated on day 21 after transplantation, glomerulosclerosis and tubulointerstitial fibrosis were significantly inhibited by day 42 posttransplantation. Parallel decrease in infiltrating and proliferating mononuclear cells (ED1, CD8 and Ki67) was observed in treated allografts. Expression of acute phase reactive and proinflammatory genes (HO-1, osteopontin) and molecules associated with fibrosis (PAI-1, TGF-b 1, biglycan) was downregulated at day 21; reduced collagen deposition was observed, parallel to a significant lower number of a -SMA+ interstitial myofibroblasts. In situ hybridization demonstrated that biglycan expression was reduced following CCR1 blockade in interstitium of treated allografts. CCR1 antagonism was found to inhibit CCL5-induced secretion of biglycan by macrophages in vitro. CCR1 blockade significantly inhibited development and progression of chronic allograft damage. CCR1 antagonists may represent a therapeutic option for chronic inflammation and fibrosis in renal grafts.

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A CCR1 antagonist prevents the development of experimental autoimmune myocarditis in association with T cell inactivation

Cited by 22 publications

References 36 publications

Periodontal bacteria aggravate experimental autoimmune myocarditis in mice

Periodontal bacteria aggravate experimental autoimmune myocarditis in mice

Effects of Methotrexate on Plasma Cytokines and Cardiac Remodeling and Function in Postmyocarditis Rats

Beneficial Effects of CCR1 Blockade on the Progression of Chronic Renal Allograft Damage

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