Sepsis is a clinical condition that was originally assumed to be a systemic response to bacterial infection, but it is now clear that other infectious agents (e.g.
viral, fungal and parasitic organisms) can also trigger sepsis. Sepsis can develop secondary to release of various bacterial components [e.g.
lipopolysaccharide (LPS) from Gram negative bacteria, lipoteichoic acid from Gram positive bacteria] that interact with toll-like receptors (TLRs) to trigger inflammatory responses. More recently, it has been discovered in cases of ‘sterile infection’ that a sepsis-like condition can also develop (Chen & Nunez, 2010
). Examples of ‘sterile infection’ resulting in sepsis-like responses include severe non-penetrating polytrauma (such as multiple bone fractures and soft tissue injury), ischemia-perfusion injury and haemorrhagic shock. In such cases, the TLR system is also activated. In bacterial sepsis, the agonists for TLRs are referred to as pathogen-associated molecular patterns (PAMPs; Bianchi, 2007
; Zipfel & Robatzek, 2010
; ). PAMPs are exogenous signals usually derived from infectious agents and are interactive with pattern recognition receptors (PRRs) including TLRs (present on cell surfaces and intracellularly) and NOD receptors (present in the cytosol) involving numerous cell types. Products released in ‘sterile sepsis’ are referred to as danger-associated molecular patterns (DAMPs) that can trigger inflammatory responses often via interaction with TLRs. DAMPs include endogenous danger signals such as DNA, histones, heat shock proteins, hyaluronins and heparin sulphate released from damaged or necrotic cells and other products (). A subset of DAMPs are the ‘alarmins’ that were recently described (Bianchi, 2007
; Oppenheim et al, 2007
; Yang et al, 2009
) and include cell constituents such as granulolysins, defensins, lactoferrin, cathepsin G, HMGB1, urate crystals, ATP, etc. Some DAMPs are enzymes (e.g.
ATPases). Other DAMPs, such as HMGB1, are peptides reactive with TLRs and other receptors. When DAMPs appear extracellularly, they react with cell surface receptors or with other proteins or substrates (e.g.
ATPases) to trigger inflammatory responses. Intracellular TLRs (3,7,9) react with double or single stranded RNA. DAMPs have also been shown to play roles in inflammatory responses following ischemia/reperfusion injury in the heart, kidneys, liver and lungs (Pardo et al, 2008
). Collectively, sufficient amounts of DAMPs can trigger a sepsis-like response resulting in a ‘cytokine storm’ [defined as presence of proinflammatory cytokines/chemokines in plasma and also referred to as the systemic inflammatory response syndrome (SIRS)].
Figure 1 Intrinsic (DAMPs) and extrinsic (PAMPs) signals develop during an infectious condition (e.g. bacterial pneumonia) that causes inflammation and sepsis which is often associated with development of SIRS, buildup of ROS and RNS in tissues, multiorgan failure (more ...)
In spite of a great deal of investment of time and money in basic and clinical research in sepsis, including more than 40 clinical trials in septic humans, it is disconcerting that there is no FDA-approved drug for use in sepsis. Recently, Xygris (recombinant activated protein C) and Eritoran (an inhibitor of TLR4) were withdrawn because of lack of clinical efficacy in sepsis (Angus, 2011
). This has caused great consternation in the investigative community and has resulted in large pharmaceutical companies being very risk-adverse for investing in drug development and clinical trials in sepsis. It is not entirely clear why there has been such dismal failure. Part of the problem may be the relevance of animal models as surrogates of human sepsis. Some of the difficulty may also be in clinical trial design, both of which are described in this review.
Sepsis in humans is linked to the presence of an infectious organism in approximately 50% of cases. This calculation is probably an underestimate due to the fact that by the time patients have been admitted to the intensive care unit (ICU), they are often on ventilator support and on vasopressors to maintain adequate blood pressure and often have already been treated with broad spectrum antibiotics before admission to the ICU, complicating the ability to identify a causative organism. Clinically, sepsis has been classified as: sepsis, severe sepsis (with SIRS), followed by the presence of multiorgan dysfunction (MOF), and septic shock (Tang et al, 2010
). Progression of sepsis may be due to the inability to contain infectious agents, an example being a leak at a surgical anastomotic site in the colon. Sepsis can also progress because of release of PAMPs or DAMPs. Whatever triggered development of sepsis, the ensuing result is development of SIRS, together with tissue buildup of reactive oxygen species [ROS; including superoxide anion (
, and myeloperoxidase products of H2
, and the hydroxyl radical (HO.
)]. Reactive nitrogen species [RNS; such as NO.
(nitric oxide) and peroxynitrite anion (ONOO.
)] are also produced. ROS and RNS are reactive with proteins, lipids and DNA, forming adducts. ROS can eventually form a variety of products such as exocyclic ethano-DNA adducts with deoxyadenosine or deoxycytidine (Fang, 2004
). In the case of DNA, this can ultimately lead to DNA strand breaks, which then activates the repair enzyme, polyadenosine ribose polymerase (PARP). PARP activation can cause substantial depletion of mitochondrial ATP (Angus, 2010
) resulting in defective mitochondrial transfer of electrons and contributing to the buildup of ROS.
Cecal ligation and puncture (CLP)
Widely used experimental model for sepsis, in which sepsis originates from a polymicrobial infectious focus within the abdominal cavity, followed by bacterial translocation into the blood compartment, which then triggers a systemic inflammatory response.
A family of small cytokines, which induce directed chemotaxis in nearby responsive cells (chemotactic cytokines).
Part of the innate immune system; a group of proteins present in blood plasma and tissue fluid, which combine with an antigen–antibody complex to induce the lysis of foreign cells.
Intercellular protein mediators released by immune cells to regulate the immune response.
Danger-associated molecular patterns (DAMPs)
Also known as damage-associated molecular pattern molecules; molecules, often nuclear or cytosolic proteins like HMGB1, that can initiate and perpetuate immune response in the non-infectious inflammatory response.
The presence of endotoxins in the blood, which may cause haemorrhages, necrosis of the kidneys and shock.
Early phase of sepsis characterized by increased cardiac output, tachycardia, fever, leukocytosis (neutrophilia).
Late phase of sepsis characterized by reduced cardiac output, bradycardia, hypotension, hypothermia, leukopenia.
Components that can either enhance or suppress immune responses.
Agents that will bring about increased immune responsiveness, especially in situations in which immune defenses (whether innate and/or adaptive) have been degraded.
Also known as multiple organ dysfunction syndrome or multisystem organ failure; the presence of altered organ function in a patient who is acutely ill and in whom homeostasis cannot be maintained without intervention.
Pathogen-associated molecular patterns (PAMPs)
Pathogen-derived molecules recognized by cells of the innate immune response that initiate and perpetuate the infectious inflammatory response.
Reactive nitrogen species (RNS)
Family of antimicrobial molecules derived from nitric oxide (.
NO) and superoxide (
) produced via the enzymatic activity of inducible nitric oxide synthase 2 (NOS2) and NADPH oxidase, respectively.
Reactive oxygen species (ROS)
Oxygen radicals that are mainly produced by the mitochondrial respiratory chain. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death.
An illness in which the body has a severe response to bacteria, other pathogens or sterile inflammation. 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.
A state of acute circulatory failure characterized by persistent arterial hypotension despite adequate fluid resuscitation or by tissue hypoperfusion unexplained by other causes.
Sepsis complicated by end-organ dysfunction, as signalled by altered mental status, an episode of hypotension, elevated creatinine concentration or evidence of disseminated intravascular coagulopathy.
Inflammation as a result of trauma, ischemia-reperfusion injury or chemically induced injury that typically occurs in the absence of any microorganisms.
Systemic inflammatory response syndrome (SIRS)
The clinical manifestations that result from the systemic response to infection. These include hyper- or hypothermia, elevated heart rate, elevated respiratory rate or decreased arterial carbon dioxide tension, abnormal white blood cell count.
Animals in the early stages of sepsis often present with a hyperdynamic phase [increased cardiac output, tachycardia, fever, leukocytosis (neutrophilia)], followed, as sepsis progresses, by a hypodynamic phase (reduced cardiac output, bradycardia, hypotension, hypothermia, leukopenia, etc.). Several similar features occur in septic humans, but clinical interventions such as antibiotic therapy and fluid resuscitation make the sequence of events less definitive than those found in animal models of sepsis. The development of MOF is associated with dysfunction of cardiac, renal, hepatic and respiratory organs but also involving the peripheral vasculature. CNS dysfunction (hallucinations, somnolence, confusion, cognitive defects, etc.) may also occur (Hermans et al, 2008
; Vincent et al, 2002
; Winters et al, 2010
). The development of MOF may be related to hypoperfusion of organs due to falling blood pressure. Whether there is a sequential linkage between failing organs is not known. Clinically aggressive attempts are made to treat what has triggered the septic response. Simultaneously, supportive measures may include blood or plasma replacement (in the case of haemorrhagic shock), as well as infusion of resuscitative electrolyte and glucose-containing fluids, and provision of ventilator and vasopressor support. Typically in humans sepsis usually runs its acute course in 4–12 days, although FDA criteria for drug efficacy require survival data at day 28. After convalescence from sepsis, a much longer period of observation (months to years) may be appropriate because of persistence or onset of complications (cognitive defects, skeletal muscle weakness, immunosuppression, etc.).
The causes of such complications are poorly understood (Adrie et al, 2007
; Angus, 2011
; Angus et al, 2001
; Clark & Coopersmith, 2007
; Cruz et al, 2009
; Deitch, 2002
). Another striking feature about the longer term problems is that mortality rate years later was much higher than that found in age-matched individuals who had not experienced sepsis (Bagshaw, 2008
). Accordingly, sepsis presents extremely challenging clinical problems as an acute disease but also as a long-term condition (over years) with a grave prognosis due to reduced survival.