Pugin, Jérôme

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Intensive Care Med (2008) 34:218–221DOI 10.1007/s00134-007-0888-4 E D I T O R I A LJérôme Pugin Dear SIRS, the conceptof “alarmins” makes a lot of sense!Received: 26 August 2007Accepted: 26 August 2007Published online: 17 October 2007© Springer-Verlag 2007This editorial refers to the article available at:http://dx.doi.org/10.1007/s00134-007-0887-5.J. Pugin ()University Hospital of Geneva, Department of Intensive Care,1211 Geneva 14, Switzerlande-mail: jerome.pugin@medecine.unige.chTel.: +41-22-3729236The late Roger Bone [1, 2] coined the term “systemic in-flammatory response syndrome, SIRS” more than 15 yearsago to describe a clinical entity highly prevalent in our in-tensive care units (ICUs) [3, 4]. Patients with SIRS usuallypresent with fever and leukocytosis in addition to tachy-chardia and tachypnea. Sepsis was defined as patients witha documented bacterial infection and at least two SIRScriteria [5]. It was also recognized by Bone and othersthat many patients without infection have SIRS, later de-fined as “aseptic SIRS” or “sterile shock” [6, 7]. Examplesof such conditions include acute respiratory distress syn-drome, trauma, pancreatitis, major surgery, and ischemia-reperfusion injury in patients recovering from shock.The search for host molecules mediating SIRS hasbeen fruitless for a long period of time. It was initiallybelieved that SIRS is mediated by circulating proin-flammatory mediators, such as tumor necrosis factorα and interleukin 1β. This concept served as a basisfor conducting anticytokine clinical trials in a seriesof conditions with SIRS—including sepsis—whichsystematically failed. This led to a reappraisal of theSIRS concept [8, 9]. It was shown that the systemiccompartment of critically ill patients with SIRS is alreadyprofoundly anti-inflammatory [10–12]. This state is dueto the presence of high concentrations of natural solubleinhibitors of proinflammatory cytokines, and monocytedeactivating cytokines such as interleukin 10 [10, 12–14],leading to systemic immune suppression [15]. In addition,ICU therapies such as catecholamines, antimicrobials, andsedatives have frequently unsuspected anti-inflammatoryeffects [16]. Finally, a certain degree of inflammationis necessary for neutralizing pathogens and clearing theinfectious process [17].Patients with SIRS have in common tissue injurywith cells suffering or dying by necrosis. The systemicconsequences of tissue injury such as shock and severebacterial infections involve an integrated and complexresponse of various systems including neural, immune,hormonal, coagulation, and metabolic pathways [16].It has long been thought that the immune system hadevolved with the discrimination between noninfectiousself from infectious nonself [18]. This concept can easilybe challenged in human pathophysiology. Clearly tissueinjury induces a systemic inflammatory response andan immune dysfunction, in the absence of infection.Conversely, an immune tolerance to infections is alsocommon, such as in bacteremia following tooth brushing.Another concept of immunity was proposed in 1994 byMatzinger [19, 20], the “danger model”. She hypoth-esized that the immune system has evolved with thediscrimination of what is dangerous and what is not. Inaddition, she has put forward the notion that in orderfor the immune system to be significantly activated bymicro-organisms two simultaneous or sequential signalsare needed: one microbial signal, such as Gram-negativelipopolysaccharide, and an endogenous “danger signal”,a mediator signaling tissue injury [21]. This concept nowmakes substantial sense to the ICU physician, and addsmeat to the bone of the “two-hit concept” frequentlyobserved in the pathogenesis of sepsis [7]. This notionis also found in the stimulation of an adaptive immune219response to a vaccine. A vaccine usually works betterwhen adjuvants create a certain amount of local tissueinjury, helping the recognition of the microbial antigen(s)to enhance the immune response [22].When significant, tissue injury alone is capable ofinducing the clinical syndrome known as SIRS [7]. In thepast 5 years candidate endogenous mediators potentiallysustaining these effects have been discovered. The mostprominent is certainly the high-mobility group box 1(HMGB1) protein, but other endogenous molecules suchas antibacterial peptides, S100, and heat-shock proteinsmay also play a role [23, 24]. These molecules, now knownas “alarmins” [25, 26] have in common an intracellularcompartmentalization in physiological conditions. In situ-ations of cell suffering or cell death, alarmins are releasedin the extracellular milieu and activate immune cells [27].This is due to both an active secretion of alarmins byinjured (or activated) tissue cells, and a passive releaseby cells undergoing necrosis. They also enhance immunefunctions to microbial antigens [28]. Interestingly, someof these “danger signals” share with pathogen-associatedmolecular patterns the same innate immune receptors,such as the Toll-like receptors (TLRs) [29].HMGB1 functions as a DNA-binding molecule in nor-mal cell physiology but can surprisingly act as a proin-flammatory cytokine when released by cells [30]. It acti-vates cells via TLR2, TLR4, and the receptor for advancedglycosylation end-products [31, 32]. HMGB1 was initiallyrecognized as a critical endogenous mediator of lethalityin a model of murine endotoxemia [33]. HMGB1 releasewas subsequently documented in a variety of inflamma-tory and infectious animal models, as well as in criticallyill patients with sepsis and other conditions [34, 35]. In ani-mal models of “aseptic SIRS,” such as pancreatitis, hemor-rhagic shock, and trauma, HMGB1 blockade decreases theinflammatory response and improves outcomes [36–38].Coagulation has recently been demonstrated to bea key innate element in the septic response [39]. A certaindegree of disseminated intravascular coagulation is almostinvariably associated with sepsis. This is due to theabnormal intravascular expression of tissue factor and thesubsequent generation of thrombin. Decreased circulatinglevels of endogenous proteins with antithrombin activity(activated protein C, antithrombin, and tissue factorpathway inhibitor) have also been reported by severalgroups. In their contribution to Intensive Care MedicineHagiwara and collaborators [40] now report that treatmentof endotoxemic rats with antithrombin (AT) decreasedboth lung injury and lethality. Importantly, they observedlower lung and systemic HMGB1 concentrations andlower circulating proinflammatory cytokines in AT-treatedrats. Antithrombin, similarly to the activated protein C,exerts anti-inflammatory activity in addition to its anti-thrombotic effects [41]. Interestingly, Hagiwara et al.also show that murine macrophages cultured with ATsecrete less HMGB1 and proinflammatory mediatorsin response to LPS, as a consequence of decreasedNF-κB activation. The anti-inflammatory effect of ATon cells must therefore be at least partially direct andnot only mediated through a decreased thrombin activity.Although it is known that AT binds to cells through aninteraction with glycosaminoglycans, the downstreamevents remain poorly understood [41]. A large AT trialfailed to demonstrate a benefit in patients with severesepsis. However, a subgroup of patients who did notconcomitantly receive heparin seemed to benefit fromAT treatment [42, 43]. In vivo AT could exert bothdirect and indirect protective effects. AT inhibits thegeneration of thrombin with, as a consequence, decreaseddeleterious disseminated intravascular coagulation andpossibly thrombin-associated inflammation. It may alsodirectly prevent tissue injury associated with sepsis byinteracting with endothelial and mononuclear cells andthe release of “danger signals” such as HMGB1. This isin accordance with a recent report showing that HMGB1promotes intravascular coagulation in a similar model,suggesting a participation of this alarmin in the patho-genesis of disseminated intravascular coagulation [44].Although Hagiwara et al. found that AT treatment im-proved outcome in their lipopolysaccharide model andconcomitantly decreased the inflammatory response andHMGB1 release, they did not make a direct associationbetween these three aspects. These crucial points requirefurther studies.We are progressing rapidly with our understanding ofthe systemic consequences of tissue injury and the patho-genesis of multiple organ dysfunction. Undoubtedly theidentification of alarmins—signaling tissue injury—andtheir pathways of cell activation (“danger signals”) opensa new and exciting field and will lead to the recognitionof new therapeutic targets. It appears conceptually soundto block signals originating from tissue necrosis whileleaving intact those originating from pathogens. TargetingHMGB1 in sepsis is tempting since it has been clearlylinked with lethality and is a late mediator, offering thepossibility of delayed treatment [45]. The history of sepsistherapies, however, urges us to be cautious. Nature hasselected alarmins during evolution for good reasons, andit is likely that some of the signals sent by these moleculesbenefit our patients [46].220References1. Bone RC (1991) Let’s agree on termi-nology: definitions of sepsis. Crit CareMed 19:973–9762. Bone RC (1992) Toward an epidemi-ology and natural history of SIRS(systemic inflammatory responsesyndrome). JAMA 268:3452–34553. Brun-Buisson C (2000) The epi-demiology of the systemic in-flammatory response. IntensiveCare Med [Suppl] 26(1):S64–S744. 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Dear SIRS, the concept of "alarmins” makes alot of sense!

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Dear SIRS, the concept of "alarmins” makes alot of sense!

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