From the Center for Experimental Therapeutics and Reperfusion Injury,
Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical
School, Boston, Mass (A.A., G.L.S.); Alexion Pharmaceuticals, New Haven, Conn
(S.A.R., L.A.M., L.L.); and Haartman Institute, Department of Bacteriology and
Immunology, University of Helsinki, Finland (A.P.V.).
Correspondence to Gregory L. Stahl, PhD, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail gstahl{at}zeus.bwh.harvard.edu
Background—Myocardial
ischemia and reperfusion (MI/R)–induced tissue injury involves
necrosis and apoptosis. However, the precise contribution of
apoptosis to cell death, as well as the mechanism of
apoptosis induction, has not been delineated. In this study, we
sought to define the contribution of the activated terminal
complement components to apoptosis and necrosis in a rat model
of MI/R injury.
Methods and Results—Monoclonal antibodies (mAbs; 18A and 16C)
raised against the rat C5 complement component bound to purified rat C5
(ELISA). 18A effectively blocked C5b-9–mediated cell lysis and
C5a-induced chemotaxis of rat polymorphonuclear leukocytes (PMNs),
whereas 16C had no complement inhibitor activity. A single
dose (20 mg/kg IV) of 18A blocked >80% of serum hemolytic activity
for >4 hours. Administration of 18A before myocardial ischemia
(30 minutes) and reperfusion (4 hours) significantly reduced (91%)
left ventricular free wall PMN infiltration compared with
16C treatment. Treatment with 18A 1 hour before ischemia or 5
minutes before reperfusion significantly reduced infarct size compared
with 16C treatment. A significant reduction in infarct size (42%) was
also observed in 18A-treated rats after 30 minutes of ischemia
and 7 days of reperfusion. DNA ladders and DNA labeling (eg, TUNEL
assay) demonstrated a dramatic reduction in MI/R-induced
apoptosis in 18A-treated compared with 16C-treated rats.
Conclusions—Anti-C5 therapy in the setting of MI/R significantly
inhibits cell apoptosis, necrosis, and PMN infiltration in the
rat despite C3 deposition. We conclude that the terminal complement
components C5a and C5b-9 are key mediators of tissue injury in MI/R.
© 1998 American Heart Association, Inc.
Basic Science Reports
Myocardial Infarction and Apoptosis After Myocardial Ischemia and Reperfusion
Role of the Terminal Complement Components and Inhibition by Anti-C5 Therapy
Key Words: infarction • complement C3b • reperfusion • complement C5
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