Abstract
Models of sepsis have been instructive in understanding the sequence of events in animals and, to an extent, in humans with sepsis. Events developing early in sepsis suggest that a hyperinflammatory state exists, accompanied by a buildup of oxidants in tissues reflective of a redox imbalance. Development of immunosuppression and degraded innate and adaptive immune responses are well-established complications of sepsis. In addition, there is robust activation of the complement system, which contributes to the harmful effects of sepsis. These events appear to be associated with development of multiorgan failure. The relevance of animal models of sepsis to human sepsis and the failure of human clinical trials are discussed, together with suggestions as to how clinical trial design might be improved.
Highlights
Introduction suggest that a hyperinflammatory state exists, accompanied by a buildup of oxidants in tissues reflective of a redox imbalance
Polysaccharide (LPS) from Gram negative bacteria, lipoteichoic danger-associated molecular patterns (DAMPs) are the ‘alarmins’ that were recently described (Bianchi, acid from Gram positive bacteria] that interact with toll-like 2007; Oppenheim et al, 2007; Yang et al, 2009) and include cell receptors (TLRs) to trigger inflammatory responses
When DAMPs appear extracellularly, they react with cell surface receptors or multiple bone fractures and soft tissue injury), ischemia- with other proteins or substrates (e.g. ATPases) to trigger perfusion injury and haemorrhagic shock
Summary
Polysaccharide (LPS) from Gram negative bacteria, lipoteichoic DAMPs are the ‘alarmins’ that were recently described (Bianchi, acid from Gram positive bacteria] that interact with toll-like 2007; Oppenheim et al, 2007; Yang et al, 2009) and include cell receptors (TLRs) to trigger inflammatory responses More constituents such as granulolysins, defensins, lactoferrin, recently, it has been discovered in cases of ‘sterile infection’ that a sepsis-like condition can develop (Chen & Nunez, 2010). When DAMPs appear extracellularly, they react with cell surface receptors or multiple bone fractures and soft tissue injury), ischemia- with other proteins or substrates (e.g. ATPases) to trigger perfusion injury and haemorrhagic shock Stages of clinical sepsis are sepsis (accompanied by a systemic response to infection including fever, neutrophilia, tachycardia, increased breathing rate, etc.); severe sepsis and systemic inflammatory response syndrome (SIRS); multiorgan failure (MOF) involving lungs, liver, kidneys, heart; septic shock.
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