Original article
A cyclooxygenase-2 inhibitor alters Th1/Th2 cytokine balance and suppresses autoimmune myocarditis in rats

https://doi.org/10.1016/j.yjmcc.2006.01.006Get rights and content

Abstract

Acute myocarditis is a clinically serious disease; however, no effective treatment has been elucidated. Cyclooxygenase (COX)-2 is a key factor for progression of inflammation. Although inflammation is an essential pathological feature of acute myocarditis, the role of COX-2 in this process remains unclear. Thus, the purpose of this study was to clarify the role of COX-2 in acute myocarditis. We used a rat experimental autoimmune myocarditis (EAM) model and a specific COX-2 inhibitor in this study. Lewis rats were immunized on day 0 with porcine cardiac myosin to establish EAM. We administered the COX-2 inhibitor (meloxicam, 0.1 mg/kg per day) daily; the rats were killed on day 21. Echocardiograms, body and heart weight, heart rate, blood pressure, and histological and molecular examinations were performed. Cytokine expression in the hearts and cell proliferation against cardiac myosin were also analyzed. The COX-2 inhibition during the immune response (late) phase attenuated EAM development; however, the inhibition during the antigen priming (early) phase did not attenuate EAM. The COX-2 inhibitor altered Th1/Th2 cytokine balance and inhibited cell proliferation in vitro. The COX-2 inhibitor suppresses the development of EAM. COX-2 regulation is promising for treating acute myocarditis.

Introduction

Acute myocarditis is a serious disease in humans; patients with myocarditis may present rapidly progressive heart failure, shock, or severe arrhythmia. Although acute myocardial inflammation is an essential etiology for the progression, no effective treatment has been elucidated [1], [2], [3], [4], [5]].

Cyclooxygenase (COX)-2 is a key factor in the progression of inflammation [6], [7], [8] and several clinical diseases [9], [10]. In the cardiovascular system, COX-2 is expressed in normal and diseased hearts [11], [12], [13]. Although inflammation is an essential pathological feature of acute myocarditis, the role of COX-2 in this process remains unclear. Experimental autoimmune myocarditis (EAM) in a rat model is characterized by severe myocardial damage and multinucleated giant cell infiltration. This has been used as a disease model for human acute myocarditis [6], [7]. To clarify the role of COX-2 in acute myocarditis, we used the EAM model to evaluate the COX-2 expression in the hearts and to analyze the effect of the specific COX-2 inhibitor. We have revealed that the COX-2 is enhanced in the EAM progression and the inhibitor suppresses the development of the inflammation in this study.

Section snippets

Animals and immunization

Male Lewis rats (7-week-old; body weights 250–350 g) were purchased from Sankyo Laboratories (Tokyo, Japan). They were fed a standard diet and water and were maintained in compliance with animal welfare guidelines of the Institute of Experimental Animals, Tokyo Medical and Dental University. Purified porcine cardiac myosin (Sigma Chemical Co., St. Louis, MO, USA) was dissolved in 0.01 M phosphate-buffered saline (PBS) and emulsified with an equal volume of complete Freund's adjuvant (Difco,

The COX-2 inhibitor suppressed body weight loss, heart rate acceleration and blood pressure decline (Fig. 1)

The non-treated EAM controls (group C) showed significant body weight loss, heart rate acceleration, and decline of mean blood pressure. However, the whole phase oral administration of the COX-2 inhibitor (group P + R) suppressed body weight loss, heart rate acceleration, and decline of mean blood pressure. The priming phase (group P) and response phase (group R) administration could not suppress these values statistically. The non-immunized rats with the treatment (group NT) showed comparable

Discussion

Many clinical trials have been performed to determine whether immunosuppressive therapy improves the severity and outcome of acute myocarditis [21], [22]. Although myocardial inflammation is an essential etiology for the progression of the disease, most results do not support routine treatment of myocarditis with immunosuppressive drugs [23]. However, studies show some rationale for applying the same immunosuppression protocol to selected patients [24]. Giant cell myocarditis is a rare but

Acknowledgments

We would like to thank Ms. Noriko Tamura and Ms. Yasuko Matsuda for excellent technical assistance.

This study was supported by grants from the Takeda Science Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and a Grant-in-aid for Science Research from the Japan Society for the Promotion of Science.

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