A serine elastase inhibitor reduces inflammation and fibrosis and preserves cardiac function after experimentally-induced murine myocarditis

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Abstract

In viral myocarditis, inflammation and destruction of cardiac myocytes leads to fibrosis, causing progressive impairment in cardiac function. Here we show the etiologic importance of serine elastase activity in the pathophysiology of acute viral myocarditis and the therapeutic efficacy of an elastase inhibitor. In DBA/2 mice inoculated with the encephalomyocarditis virus, a more than 150% increase in myocardial serine elastase activity is observed. This is suppressed by a selective serine elastase inhibitor, ZD0892, which is biologically effective after oral administration. Mice treated with this compound had little evidence of microvascular constriction and obstruction associated with myocarditis-induced ischemia reperfusion injury, much less inflammation and necrosis, only mild fibrosis and myocardial collagen deposition, and normal ventricular function, compared with the infected nontreated group.

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Figure 1: a, Coronary microvascular perfusion assessed on day 14 in experiment I.
Figure 2: a, Myocardial elastolytic activity in experimental groups at different time points.
Figure 3: a, 'Planimetered' area of diseased myocardium expressed as a percentage of total myocardial cross-sectional area.
Figure 4: ad, Photomicrographs (light microscopy) of hematoxylin and eosin-stained myocardial sections on day 14.
Figure 5: Myeloperoxidase (MPO) activity in EMC-infected hearts assessed on day 14.
Figure 6: Collagen concentration in the myocardium assessed by hydroxyproline assay on day 28.

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Acknowledgements

We thank J. Jowlabar and S. Taylor for secretarial assistance and C. Coulber, S. Ciura, E. Sitarz and K. Aitken for technical assistance. We also thank the staff of the Animal Care Facility at The Toronto Hospital General Division for their support with animal care, and members of the Department of Pathology at The Hospital for Sick Children for preparing the specimens for microscopy. This work was supported by a grants #74026 and T-2373 from the Heart and Stroke Foundation of Ontario and from the Medical Research Council of Canada.

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Correspondence to Marlene Rabinovitch.

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