Balancing the Inflammatory Response in Sepsis

Abstract

Human sepsis is associated with the activation and systemic expression of host inflammatory pathways via stimulation of the host immune effector cells to synthesize and release potent mediators of cell inflammation [1]. Accordingly, some have suggested that it be referred to as the systemic inflammatory response syndrome (SIRS) [2]. Although some of the initial mediators of this process are cytokines, a vast array of protein and lipid mediator species is expressed subsequently in a complex network [3,4]. We [5] and others [6, 7] have documented that sustained elevations of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α and the immunomodulating cytokine interleukin (IL)-6, rather than their peak serum levels, identify those patients who will subsequently develop multiple organ dysfunction and death. However, in patients with established sepsis pro-inflammatory cytokines, such as TNF-α, IL-1, IL-6, and IL-8, and anti-inflammatory species, such as IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF-α receptors I and II (sTNFrII and sTNFrII), co-exist in the circulation and presumably within the tissues [8–10]. Thus, sepsis may be more accurately described as a dysregulation of the systemic inflammatory response to external stress, rather than merely the over expression of either pro- or anti-inflammatory substances. Accordingly, we proposed over 10 years ago to use the term “malignant intravascular inflammation” to describe this process.