Serine Protease Inhibition Prevents Both Cellular and Humoral Responses to Cardiopulmonary Bypass

Serine proteases are ubiquitous and are fundamentally responsible for many of the control processes in plasma. Hemostasis and inflammation have the same evolutionary origins and developed as host-defense mechanisms. This article highlights this development and defines the role of serine proteases in the complex inflammation and coagulation cascades that have evolved to maintain homeostasis. Generation of the serine protease thrombin plays a pivotal role in the regulation of many functions and is able to initiate activation and release of a number of humoral mediators involved in the inflammatory and hemostatic systems. Control processes are required to limit coagulation and inflammation to sites of injury, and a number of these have at their center inhibitors of serine proteases (SERPIN). A vast number of inhibitors are found throughout nature. In addition to these naturally occurring SERPINs, a number of others are available for administration to both animals and humans. Of these, aprotinin is a complex polypeptide; there are other chlormethyl ketones and small synthetic agents that also act as potent SERPINs. A second group of compounds are not protein inhibitors but have a broad spectrum of inhibition, e.g., a gabexate mesylate (FOY) and nefamostat (FUTHAN). The profound actions of aprotinin, FUTHAN, and FOY to inhibit bleeding and prevent the need for donor blood are well known. The potential role of these agents, particularly aprotinin, to reduce the inflammatory effects of cardiac and other kinds of surgery is considered. The data on SERPINs actions to reduce neutrophil-induced tissue injury are reviewed, with particular reference to the inflammatory events that occur during surgery with cardiopulmonary bypass.