The Systemic Pro-Inflammatory Response in Sepsis

The systemic inflammatory response syndrome (SIRS) is the predominantly cytokine-mediated, pro-inflammatory response of the host to invading pathogens and is considered the hallmark sign of sepsis. Molecular components of this response can be divided into cytokines, plasma cascades and acute phase proteins while the predominant cellular components are leukocytes and the endothelium. Highthroughput genetic profiling studies have led to increased insights into leukocyte regulation during sepsis. New players in the pro-inflammatory cytokine network include interleukin-17, high-mobility group box-1 protein, macrophage migration inhibitory factor, the myeloid-related proteins Mrp8 and Mrp14, and soluble triggering receptor expressed on myeloid cells-1. Activation of coagulation with concurrent downregulation of anticoagulant systems and fibrinolysis are almost universally present in septic patients with SIRS. Increasing evidence points to an extensive cross-talk beReceived: February 22, 2010 Accepted after revision: April 5, 2010 Published online: June 8, 2010 Journal of Innate Immunity Dr. Willem Joost Wiersinga Department of Internal Medicine Academic Medical Centre, University of Amsterdam Room G2-132, Meibergdreef 9, NL–1105 AZ Amsterdam (The Netherlands) Tel. +31 20 566 9111, Fax +31 20 697 7192, E-Mail w.j.wiersinga @ amc.uva.nl © 2010 S. Karger AG, Basel 1662–811X/10/0025–0422$26.00/0 Accessible online at: www.karger.com/jin The Systemic Pro-Inflammatory Response in Sepsis J Innate Immun 2010;2:422–430 423 Definition and Epidemiology of the Systemic Pro-Inflammatory Response in Sepsis Sepsis is regarded as the response of the host towards invading pathogens or its toxins [1] . Since this often overwhelming systemic pro-inflammatory response, which can lead to fatal multiorgan failure (MOF) and septic shock, is regarded as the key feature of sepsis, sepsis is clinically defined as a confirmed infection (or a strong suspicion of) plus the reactive systemic response called SIRS. To fulfill the SIRS criteria, two or more of the following conditions should be present: temperature 1 38 ° C or ! 36 ° C; heart rate 1 90 beats/min; respiratory rate 1 20 breaths/min, PaCO 2 ! 4.3 kPa; indication for mechanical ventilation and a white blood cell count 1 12 ! 10 9 /l or ! 4 ! 10 9 /l or 1 10% immature (band) forms [1] . In a recent cohort of critically ill patients admitted to the intensive care unit it was shown that organ system failure and mortality increase as the number of SIRS criteria increase [2] . Severe sepsis is defined as sepsis plus organ dysfunction, whereas septic shock refers to severe sepsis with refractory hypotension [1] . Septic shock is defined as sepsis with arterial hypotension (systolic pressure ! 90 mm Hg or a mean arterial pressure ! 60 mm Hg) despite adequate fluid resuscitation and in the absence of other causes of hypotension [1] . In the last two decades, the incidence of sepsis increased annually by 9% to reach 240 cases per 100,000 population in the United States by 2000 [3] . In a European cohort of 3,147 critically ill adult patients who were admitted to an intensive care unit, it was shown that almost 25% had sepsis on admission [2] . The increasing incidence of sepsis and its associated mortality is probably mainly caused by an increase in the number of immunocompromised patients, the increase in antibiotic resistance and the aging population [4, 5] . In this respect it is of interest that the majority of the 750,000 patients who develop sepsis each year in the United States are above 65 years. Sepsis is associated with a high mortality: in a cohort of 192,980 patients in the United States with severe sepsis the mortality was 28.6% [4] . Initiation of the Pro-Inflammatory Response Pathogen recognition receptors (PRRs), such as Tolllike receptors (TLRs) and the nucleotide binding oligomerization domain-like receptors (NLRs), are central in host defense against pathogens. TLRs recognize pathogen-associated molecular patterns (PAMPs) of invading microorganisms, initiate the immune response and are a crucial link between adaptive and innate immunity [reviewed in detail in 5, 6 ]. Humans have 10 closely collaborating TLRs [6] . TLRs and NLRs are also able to recognize endogenous danger signals, called alarmins or dangerassociated molecular patterns (DAMPs). For instance, heat shock proteins, fibrinogen, hyaluronic acid and high-mobility group box-1 protein (HMGB-1) are DAMPs that are released during inflammation and cause further amplification of the pro-inflammatory response through TLR4. TLRs recognize pathogens at either the cell surface or lysosome/endosome membranes, suggesting that the TLR system is not used for the detection of pathogens that have invaded the cytosol [6] . These pathogens can be further detected by various cytoplasmic PRRs, including NLRs. Differences in the N-terminal domains of NLRs are used to further subcategorize the NLR protein members [7] . The largest group, comprising 14 members, has an N-terminal pyrin domain and is therefore called ‘NLRP’ (previously ‘NALPs’) [7] . Several members of the NLR family, including NLRP1 and NLRP3, can assemble multimolecular complexes termed ‘inflammasomes’ in response to various activators, leading to the activation of inflammatory caspases. Activation of the NLRP3 inflammasome by PAMPs or DAMPs induces activation of caspase-1, which causes the processing of the pro-inflammatory cytokines interleukin (IL)-1 and IL-18 [6, 7] . Overproduction of IL-1 and IL-18 will contribute to the detrimental effects of the pro-inflammatory response syndrome in sepsis. The innate immune system needs to be strictly controlled: the host needs to be protected from invading pathogens by activation of the immune response, at the same time however too much activation of the TLRs and NLRs can contribute to the detrimental effect of systemic inflammation, MOF and disseminated intravascular coagulation (DIC). Gene-Expression Profiling of Leukocytes in Sepsis In recent years the application of high-throughput genomic technologies has permitted a more complete dissection of the host response during sepsis. Calvano et al. [8] took the lead in this field when in 2005 the global reprioritization of the leukocyte transcriptome was revealed in vivo in human volunteers receiving lipopolysaccharide (LPS) as an inflammatory stimulus. LPS administration to healthy subjects caused changes in expression in over 4,000 genes during the first 24 h, while surprisingly the expression of over half of the genes de-