A serine elastase inhibitor reduces inflammation and fibrosis and preserves cardiac function after experimentally-induced murine myocarditis.
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.
Lee
J K
JK
Research Institute, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Ontario, Canada.
Zaidi
S H
SH
Liu
P
P
Dawood
F
F
Cheah
A Y
AY
Wen
W H
WH
Saiki
Y
Y
Rabinovitch
M
M
D000284:Administration, Oral; D000818:Animals; D018188:Cardiovirus Infections / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D004195:Disease Models, Animal; D004686:Encephalomyocarditis virus; D005355:Fibrosis / Q000188:drug therapy; D006321:Heart / Q000502:physiology*; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008833:Microcirculation / Q000187:drug effects; D009205:Myocarditis / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D009206:Myocardium / Q000473:pathology; D010477:Perfusion; D009195:Peroxidase / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*
D011758:Pyrroles; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C114412:ZD 0892; D009195:Peroxidase