© 2000 American Heart Association, Inc.
Editorials |
Cellular and Molecular Dissection of Reperfusion Injury
ROS Within and Without
From the Institute of Genetic Medicine, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Gregg L. Semenza, MD, PhD, Johns Hopkins Hospital, CMSC-1004, 600 North Wolfe St, Baltimore, MD 21287-3914. E-mail gsemenza@jhmi.edu
Key Words: apoptosis • ceramide • ischemia • tumor necrosis factor-
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Introduction |
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Reperfusion injury in the heart can occur either as a result of transient arterial occlusion (eg, due to vasospasm or thrombus formation with spontaneous lysis) or as an iatrogenic consequence of thrombolytic or angioplastic therapy. A basic research objective is to delineate pathogenesis in order to devise effective prevention and/or treatment strategies. This, of course, applies to most biomedical research, and one general approach to this and other conditions is a reductionist model in which the responses of isolated cell types are investigated in tissue culture. This experimental approach has the advantage of distinguishing primary responses to the stimulus from those that are secondary to the responses of other cell types within the organ. Not only the target cell but also the inciting stimulus can be well defined in cell culture. Arterial occlusion leads to ischemia, which involves deprivation of energy substrates (glucose and oxygen) and accumulation of toxic metabolites (H+ and K+), as well as secondary alterations in endothelial and inflammatory cell function. In contrast, cultured cells (eg, cardiac myocytes) can be subjected to anoxia/hypoxia under highly controlled conditions. Furthermore, the expression of specific proteins can be experimentally manipulated in an attempt to establish molecular mechanisms. Two obvious limitations of tissue culture systems involve the analysis of responses that are not cell autonomous (ie, involve more than one cell type) and those that are cell-type or developmental-stage specific (eg, adult versus neonatal cardiomyocytes). Thus, the relevance of responses in tissue culture to organ function in vivo must be
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