Figure 3-2

Roles of induced NO in hemorrhagic shock. The figure depicts the dual roles of inducible NO synthase-generated NO in hemorrhagic shock. The NO generated during resuscitation combines with the superoxide, forming peroxynitrite. Peroxynitrite generated during resuscitation can exert direct cellular toxicity through oxidative and nitrosative damage and PARS activation. NO and perhaps peroxynitrite can activate inflammatory cascades through the upregulation of NFκB. This results in inflammation manifested by cytokine expression, STAT3 activation, and neutrophil accumulation. Combined, these actions result in organ damage and organ failure. Source: Reprinted, with permission, from Szabó and Billiar (in press). Copyright 1999 by BioMedical Press.

cascade, which triggers DNA fragmentation and cellular apoptosis (Endres, 1998; Szabó, 1998; Virág et al., 1998; Yaoita et al., 1998).

Clearly, hemorrhagic shock produces local and whole-body ischemia; and fluid resuscitation, regardless of the type of fluid administered, increases perfusion of previously ischemic or hypoperfused tissues, triggering the production of numerous free radicals and likely contributing to cellular injury.

Activated Neutrophils

In addition to the generation of free radicals by reperfusion of hemorrhage-induced ischemia, recent attention has focused on the role of activated neutrophils in resuscitation-mediated cellular injury. Intracellular adhesion molecules 1 and 2 (ICAM-1 and ICAM-2, respectively) have been shown to be upregulated by lactated Ringer's fluid resuscitation from hemorrhagic shock (Rhee, 1998). These adhesion molecules are instrumental in binding leukocytes to the

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