Circulation, Vol 88, 2812-2826, Copyright © 1993 by American Heart Association
SM Shandelya, P Kuppusamy, A Herskowitz, ML Weisfeldt and JL Zweier
BACKGROUND. Complement-mediated neutrophil activation has been hypothesized
to be an important mechanism of reperfusion injury. It has been proposed
that soluble complement receptor 1 (sCR1), a potent inhibitor of both
classical and alternative complement pathways, may prevent the
complement-dependent activation of polymorphonuclear leukocytes (PMNs) that
occurs within postischemic myocardium and thereby inhibit PMN-derived free
radical generation and prevent postischemic contractile failure. Therefore,
we performed studies to determine the effects of sCR1 on contractile
function, PMN adhesion, complement deposition, and PMN-derived free radical
generation in the postischemic heart. METHODS AND RESULTS. Studies were
performed in an isolated rat heart model in which the isolated effects of
given cellular or humoral factors could be determined. Plasma and PMNs were
present to study the effects of sCR1 on contractile function, coronary
flow, leukocyte adhesion, complement deposition, and PMN-derived free
radical generation. Isolated rat hearts were perfused by the method of
Langendorff (n = 10 in each group) and subjected to 20 minutes of global
ischemia and reperfusion with PMNs and plasma in the presence or absence of
sCR1. Left ventricular developed pressure (LVDP), coronary flow (CF), left
ventricular end-diastolic pressure (LVEDP), and rate- pressure product
(RPP) were measured during the preischemic period, during 1-minute control
infusion of PMNs and plasma, and on reflow following 20 minutes of global
ischemia. During the preischemic control infusion, no significant
alterations in the physiologic parameters were observed, and there was no
measurable free radical generation. Reperfusion with sCR1 markedly improved
the recovery of postischemic contractile function. LVDP after 45 minutes of
reperfusion was 76 +/- 9.8% compared with 32 +/- 6.2% (P < .001). In
addition, significant improvements in LVEDP, RPP, and CF were observed in
hearts treated with sCR1. Additional experiments were also performed to
determine the effect of sCR1 on complement-mediated PMN activation.
Measurements of PMN-derived free radical generation were performed in both
isolated PMNs and the coronary effluent of hearts using electron
paramagnetic resonance spectroscopy (EPR) with the spin trap
5,5-dimethyl-1- pyrroline-N-oxide (DMPO). EPR measurements in both isolated
PMNs and coronary effluent demonstrated that sCR1 blocked
complement-mediated free radical generation from the PMNs. Increased
accumulation of PMNs was observed both in hearts treated with sCR1 and in
those not treated with sCR1. Immunohistochemical staining of the
postischemic myocardial tissue demonstrated marked complement deposition on
the endothelial surface of small arterioles and capillaries, which was
prevented by sCR1 treatment. Thus, sCR1 did not prevent PMN adhesion but
did prevent complement deposition with activation of the PMN oxidative
burst. CONCLUSIONS. The potent complement inhibitor sCR1 was found to be
effective at preventing postischemic myocardial contractile dysfunction and
enhancing the recovery of coronary flow. This study demonstrated that
complement activation occurs in postischemic myocardium and is necessary
for activation of the neutrophil oxidative burst with the generation of
reactive oxygen free radicals. The process of neutrophil adhesion, however,
was not affected by sCR1 and was independent of complement factors. These
findings demonstrate the sCR1 is a highly potent agent at preventing
complement-mediated PMN activation and secondary free radical generation in
the postischemic heart. This genetically engineered protein appears to be a
promising therapeutic agent in the prevention of myocardial reperfusion
injury.
ARTICLES
Soluble complement receptor type 1 inhibits the complement pathway and prevents contractile failure in the postischemic heart. Evidence that complement activation is required for neutrophil-mediated reperfusion injury
Department of Medicine, Johns Hopkins Medical-Institutions, Francis Scott Key Medical Center, Baltimore, MD 21224.
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