The complexity of the systemic inflammatory response and the lack of

The complexity of the systemic inflammatory response and the lack of a treatment breakthrough in the treatment of pathogenic infection demand that advanced tools be brought to bear in the treatment of severe sepsis and trauma. of insufficient oxygen delivery to tissues characterized by hypotension and acidosis (Levy 2003). Although the host’s response to sepsis strives to contain contamination and promote repair the intensity of the inflammatory response often leads to compromised tissue function organ failure and death. Severe sepsis accounts for 2-11% AEE788 of all admissions to hospitals approximately 750 000 cases a 12 months with an associated case-fatality mortality of 35 per cent (Angus 2001). Mortality rates from sepsis and septic shock have not changed significantly over recent decades (Martin 2003) Rabbit Polyclonal to Cytochrome P450 26C1. and it affects the very young (Watson 2003) and the very aged disproportionately (Sands 1997). The Centers for Disease Control and Prevention (CDC) reports that this incidence of sepsis increased from 7.4 per million patients in 1979 to 17.6 per million patients in 1987. Multiple organ dysfunction syndrome associated with 80 per cent of deaths in modern ICUs (Angus 2001) is usually causally related to the inflammatory response (Bone 1996) and it is also a common complication of other causes of acute severe inflammation such AEE788 as multiple trauma. The process of death typically includes progressive organ system shutdown requiring support of the circulation ventilation and renal function. In sepsis acute inflammation is initiated by the recognition of danger signals using pathogen-associated molecular pattern (PAMP) receptors on the surface of dedicated surveillance cells typically dendritic cells and tissue macrophages. Such PAMPs associated directly to pathogens or their products (e.g. lipopolysaccharide lipoteichoic acid flagellin or bacterial RNA) activate dendritic cell and tissue macrophage Toll-like receptors (TLRs) (Abreu & Arditi 2004). Activation of TLRs initiates intracellular signalling of specific cascades leading to enhanced expression of early pro-inflammatory proteins such as tumour necrosis factor (TNF) and interleukin-1 (IL-1) active in an autocrine paracrine and endocrine fashion with the purpose of mass mobilization of innate immunity. Regulatory anti-inflammatory proteins such as IL-1 receptor antagonist (IL-1RA) and IL-10 almost synchronously follow. TLRs also have the ability to recognize molecular patterns that although not foreign should not be accessible to those AEE788 receptors in health. These damage-associated molecular patterns (DAMPs) are often the signature of cellular disruption resulting in the failure of intracellular containment of these AEE788 DAMPs (Matzinger 2002). As AEE788 disease progresses it appears probable that there is perpetuation of injury as spreading tissue damage promotes further inflammation and inflammation contributes to tissue damage although competing theories exist as to how this exactly happens (Prince 2006). A pictorial representation of this dual contribution to the initiation and perpetuation of inflammation is usually shown in physique?1. Other important aspects of the acute inflammatory response have been described. Acute inflammation is associated with cell-type-dependent modifications of programmed cell death appropriately retarding cell death in pathogen-fighting neutrophils and hastening cell death in most other cell types. Inflammation promotes the production of inducible nitric oxide synthase (iNOS) leading to local vasodilatation promoting metabolite delivery and export and key components of the complement cascade important for antimicrobial activity. Furthermore trafficking of dendritic cells to local lymph nodes initiates specific target recognition by T-cells and clonal growth of these cells. These actions are necessary for an appropriately controlled host response. However the types of health challenges faced by patients in ICUs trigger inflammation at a scale unlikely to be compatible with survival and therefore there is little guarantee that this evolutionary adaptation to severe infections is indeed appropriate. In other words AEE788 what is a ‘well-oiled machine’ in response to a typical challenge might not be well suited for maximal challenges. How this initial response leads to undesired effects of cellular dysfunction and organ failure.