Endothelial response to cardiopulmonary bypass surgery

Abstract

Background: The vascular endothelium has been shown to actively participate in maintaining normal cardiovascular homeostasis by influencing the regulation of membrane permeability, lipid transport, vasomotor tone, coagulation, fibrinolysis, and inflammation. Endothelial cells are very responsive to a wide range of local and systemic stimuli that occur during cardiopulmonary bypass (CPB) operation. Major pathologic conditions result from impaired vascular function secondary to CPB, including vasospasm, coagulopathy, and widespread neutrophil adhesion secondary to a systemic inflammatory response. Additionally, more chronic responses to endothelial cell injury include the development of intimal hyperplasia and arteriosclerosis, both of which limit the long-term success of coronary artery bypass grafting.

Methods: Because of the increasingly recognized role of the endothelium in the maintenance of normal cardiovascular function, this article will review the normal structure and function of the endothelium, as well as the major pathologic conditions that result in response to CPB.

Results: Potential treatments to counteract endothelial cell dysfunction secondary to CPB are under active investigation. Strategies may be directed toward blocking single cytokines, integrins, or adhesion molecules involved in endothelial dysfunction or, alternatively, toward targeting a molecular event that governs the expression of these proinflammatory, procoagulant, and vasoactive genes. In our laboratory, we have used both strategies to study the pathologic response to CPB. We blocked neutrophil adhesion in subhuman primates with a monoclonal antibody. Alternatively, we targeted the transcriptional activation of multiple genes involved in the endothelial cell's response to CPB.

Conclusions: Although both therapies help elucidate the multiple, redundant pathways involved in the pathologic response to CPB, it is through molecular biology that we are beginning to understand the mechanics of transcriptional control and translational expression that occurs in the endothelial cell in response to CPB. This knowledge will allow the development of therapies that inhibit not a single cytokine or adhesion molecule, but rather an array of substances that result in the endothelial cell's pathologic response to CPB.