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Biologia Molecular de La Sepsis
Biologia Molecular de La Sepsis
Background: Remarkable progress has been made during the dysfunction, sepsis-related immunosuppression, late mediators of
last decade in defining the molecular mechanisms that underlie systemic inflammation, control mechanisms for coagulation, and
septic shock. This rapidly expanding field is leading to new reprogramming of immune response genes all have critical roles in
therapeutic opportunities in the management of severe sepsis. the development of sepsis.
Aim: To provide the clinician with a timely summary of the Conclusions: Many of these basic discoveries have direct impli-
molecular biology of sepsis and to better understand recent cations for the clinical management of sepsis. The translation of
advances in sepsis research. these “bench-to-bedside” findings into new therapeutic strategies is
Data Selection: Medline search of relevant publications in already underway. This brief review provides the clinician with a
basic mechanisms of sepsis/severe sepsis/septic shock, and se- primer into the basic mechanisms responsible for the molecular
lected literature review of other manuscripts about the signalo- biology of sepsis, severe sepsis, and septic shock.(Crit Care Med
some, inflammasome, apoptosis, or mechanisms of shock. 2009; 37:291–304)
Data Synthesis and Findings: The identification of the toll-like KEY WORDS: sepsis; inflammation; toll like receptors; inflamma-
receptors and the associated concept of innate immunity based upon some; signalosome; apoptosis; neutrophils; mitochondrial dys-
pathogen- or damage-associated molecular pattern molecules al- function; reactive oxygen species; nitric oxide; peroxynitrite; ac-
lowed significant advances in our understanding of the pathophys- tivated protein C; a disintegrin-like and metalloproteinase with
iology of sepsis. The essential elements of the inflammasome and thrombospondin type-1 motifs-13; pathogen associated molecular
signal transduction networks responsible for activation of the host patterns; danger associated molecular patterns
response have now been characterized. Apoptosis, mitochondrial
I n sepsis, the expected and appropri- damage. In addition, a reduction in their (TLRs); 2) nucleotide-oligomerization
ate inflammatory response to an in- antimicrobial capacity may set the stage for domain leucine-rich repeat (NOD-LRR)
fectious process becomes amplified opportunistic and/or super infections (2). proteins; and 3) cytoplasmic caspase ac-
leading to organ dysfunction or risk Severe sepsis may also be associated with tivation and recruiting domain heli-
for secondary infection. A continuum exists an exaggerated procoagulant state. This cases such as retinoic-acid-inducible
from a low grade systemic response associ- may lead to ischemic cell injury, an effect gene I (RIG-I)-like helicases (RLHs) (4,
ated with a self-limited infection to a that further amplifies the damage caused 5). These receptors initiate the innate
marked systemic response with solitary or by inappropriate inflammation. A micro- immune response and regulate the
multiorgan dysfunction, i.e., severe sepsis. vasculature injured by inflammation and adaptive immune response to infection
As a clinical syndrome, sepsis occurs when ischemia, in turn, further deranges the or tissue injury.
an infection is associated with the systemic host response by altering leukocyte traffick- Gram-positive and Gram-negative bac-
inflammatory response. ing, generating apoptotic microparticles, teria, viruses, parasites, and fungi all pos-
The complex toll-like receptor signaling and increasing cellular hypoxia (3). Mito- sess a limited number of unique cellular
and associated downstream regulators of chondrial dysfunction, an acquired intrin- constituents not found in vertebrate ani-
immune cell functions play a crucial role in sic defect in cellular respiration termed “cy- mals. These elements are now referred to as
the innate system as a first line of defense topathic hypoxia,” also has an important PAMPs, or more appropriately microbial-
against pathogens (1). However, signaling role by decreasing cellular oxygen con- associated molecular patterns, as these
is sometimes conflicting and a sustained sumption in this chaotic process. In this molecules are also common in nonpatho-
inflammatory response can result in tissue review, we highlight the current under- genic and commensal bacteria (6). PAMPs
standing of the basic molecular mecha- bind to PRRs, such as TLRs, expressed on
nisms that modulate these events so as to the surface of host cells. Cytoplasmic PRRs
From the Division of Critical Care Medicine (IC), The produce sepsis. exist to detect invasive intracellular patho-
Robert Wood Johnson School of Medicine, The University gens (7). The NOD proteins recognize com-
of Medicine and Dentistry of New Jersey, Camden NJ; mon fragments of bacterial peptidoglycan.
and The Infectious Disease Division (SMO), Memorial
Pattern Recognition Receptors,
Hospital of RI, The Warren Alpert School of Medicine of Pathogen-Associated Molecular Diamino-pimelate from Gram-negative
Brown University, Providence, RI. Patterns (PAMPs) and Danger- bacteria is the ligand for NOD1 and mu-
Dr. Opal has received grants from Wyeth and Eisai
Associated Molecular Patterns ramyl dipeptide from peptidoglycan is the
Inc. Dr. Cinel has not disclosed any potential conflicts ligand for NOD2 in the cytosol (see Figs. 1
of interest. (DAMPs)
For information regarding this article, E-mail:
and 2). The PRRs also recognized damage
cinel-ismail@cooperhealth.edu The initiation of the host response signals from the release of endogenous pep-
Copyright © 2008 by the Society of Critical Care during sepsis or tissue injury involves tides and glycosaminoglycans from apopto-
Medicine and Lippincott Williams & Wilkins three families of pattern recognition re- tic or necrotic host cells (8 –10) Caspase
DOI: 10.1097/CCM.0b013e31819267fb ceptors (PRRs): 1) toll-like receptors activation and recruiting domain helicases
Figure 1. Specific host immune response to each pathogen is mediated by various sets of pathogen TLRs induce pro-interleukin(IL)-1beta
associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) as detailed in Figure production and prime NLR-containing
1. PRRs are essential for initiating the host’s immune defenses against invading pathogens, yet they multiprotein complexes, termed “inflam-
can also contribute to persistent and deleterious systemic inflammation. PRRs also serve as receptors masomes,” to respond to bacterial prod-
for endogenous danger signals, hemodynamic changes in sepsis (tissue hypoperfusion and ischemia/ ucts and products of damaged cells (17,
reperfusion phenomenon), thus same signaling systems that alerts the highly advantageous, host 19). This results in caspase-1 activation
defense mechanisms, also contributes to the disadvantageous, pathologic events of systemic inflam- and the subsequent processing of pro-
mation, coagulation, tissue damage in target organs in sepsis. Heat shock proteins, fibrinogen,
IL-1 to its active extracellular form
fibronectin, hyaluran, biglycans and high mobility group box-1 (HMGB-1) have been defined as danger
associated molecular patterns (DAMPs) which are likely relevant for sepsis. Toll-like receptors (TLRs),
IL-1 (19). Caspases are a set of cysteine
especially TLR4, are involved in the recognition of these endogenous or harmful self-antigens ligands proteases that alter the enzymatic activity
which are released during noninfectious injury, such as trauma or ischemia/reperfusion suggesting of target proteins at specific peptide se-
their function may not be restricted to the recognition of extrinsic pathogens. NOD-LRR, nucleotide- quences adjacent to aspartate moieties.
oligomerization domain leucine-rich repeat; ASC, apoptosis-associated speck-like protein containing Caspases are important in process of ap-
caspase activation and recruiting domain; NF-, nuclear factor . optosis, cellular regulation, and inflam-
mation (Figs. 1 and 3). One of the many
targets of the caspase cascade is caspase
activated DNase (CAD). CAD activation
induces DNA fragmentation characteris-
tic of programmed cell death (apoptosis).
The posttranslational activation of
caspase-1 is tightly regulated by inflam-
masome, the known components of
which include caspase-1, ASC (apoptosis-
associated speck-like protein containing a
caspase activation and recruiting do-
main), NALP1 (NACHT, leucine rich re-
peat and pyrin domain containing 1), and
caspase-5 (20). Additionally, alternate in-
Figure 2. Binding of toll-like receptors (TLRs) activates intracellular signal-transduction pathways that flammasome constructions have been
lead to the activation of transcriptional activators such as interferon regulator factors, phosphoino- suggested to contain pyrin, NALP3, and
sitide 3-kinase (PI3K)/Akt, activator protein-1, and cytosolic nuclear factor-kappa  (NF-). Activated
other members of the NOD-LRR family
NF- moves from the cytoplasm to the nucleus, binds to transcription sites and induces activation
of an array of genes for acute phase proteins, inducible nitric oxide synthase, coagulation factors,
(21–23). ASC facilitates inflammasome
proinflammatory cytokines, as well as enzymatic activation of cellular proteases. TLR9 DNA, TLR 3 assembly thus triggering caspase-1 acti-
dsRNA, and TLR7/8 ss RNA are endosomal. TLR 10 ligand is not defined and TLR1 forms heterodimers vation and IL-1 processing. Interest-
with TLR2. LPS, lipopolysaccharide; IRF, interferon regulatory factor; JNK; c Jun N-terminal kinase. ingly, ASC can also regulate the nuclear
factor (NF)-B pathway, thus linking the
inflammasome to the signalosome
primarily recognize viral nucleic acids and ates danger-associated molecular pat- (Fig. 1) (24).
activate antiviral measures including the terns (i.e., high mobility group box-1, The inflammasome pathways contrib-
type I interferons. heat shock proteins, S100 proteins, hya- ute to the inflammatory response in sep-
TLR expression is significantly up- luran, etc.) that augment TLR expression sis (25). Caspase-1 knock out mice are
regulated in experimental models of sep- like PAMPs. It also primes the innate im- protected from sepsis (26) while a natu-
sis and in patients with sepsis (11–14). mune system for enhanced TLR reactiv- rally occurring polymorphism for human
Trauma including thermal injury gener- ity, resulting in excess lipopolysaccharide caspase-12, a putative regulator of
TNF, tumor necrosis factor; LPS, lipopolysaccharide; NO, nitric oxide; TLR, toll-like receptor, LHRI, Lawson Human Resources Institute; CBC, Critical
Biologics Corporation; MU, Maastricht University; NIMS; National Institute of Medical Sciences; MUV, Medical University of Vienna; UASLP, Universidad
Autonoma de San Luis Potosi; HCPA, Hospital de Clinical de Porto Alegre.
properties (169). APC can cleave and ac- of rhAPC regarding the bleeding compli- ADAMTS-13 levels are associated with dif-
tivate PAR1-dependent cellular pathways cation (175). A nonanticoagulant from of ferences in morbidity, mortality, and
(170). APC competes for PAR-1 binding APC reduces mortality in experimental variables of inflammation and endothelial
with thrombin, but in vitro studies sug- models of endotoxemia and sepsis (176). dysregulation in severe sepsis patients
gest that APC is 103- to 104-fold less po- von Willebrand Factor, A Disintegrin-Like (182, 187).
tent that thrombin in cleaving PAR-1. and Metalloproteinase with Thrombospondin The Ashwell receptor, which is the
The critical receptors required for both Type-1 Motifs 13 and Ashwell Receptor. major lectin of hepatocytes, modulates
PC activation and APC cellular signaling The discovery of a disintegrin-like and met- VWF homeostasis. It has been recently
(i.e., thrombomodulin, EPCR and PAR-1) alloproteinase with thrombospondin type-1 demonstrated that the marked thrombo-
are co-localized in lipid rafts on endothe- motifs 13 (ADAMTS-13) has provided new cytopenia associated with S. pneumoniae
lial cells (171). EPCR is associated with insights in pathogenesis of thrombosis in sepsis is the result of Ashwell receptor-
caveolin-1 on lipid rafts and EPCR bind- sepsis. ADAMTS-13, the principal physio- dependent clearance of platelets (188).
ing to the gamma-carboxyglutamic acid logic modulator of von Willebrand factor The ensuing reduction in platelet counts
domain of protein C/APC leads to its dis- (VWF) is produced mainly stellate cells in at the onset of sepsis protects the host
sociation from caveolin-1 (Fig. 7). APC the liver (177). VWF is synthesized in vas- against the development of disseminated
then engages PAR-1 generating a protec- cular endothelial cells and released into the intravascular coagulation. Homeostatic
tive signaling pathway through coupling plasma as unusually large VWF multimers adaptation by this receptor moderates the
of PAR-1 to the pertussis toxin-sensitive which are rapidly degraded into smaller onset and severity of disseminated intra-
G(i)-protein. Thus, when EPCR is bound VWF multimers by ADAMTS-13. Deficiency vascular coagulation during sepsis sug-
by protein C, the PAR-1-dependent pro- of the ADAMTS-13, as observed in most gesting the improvement in host survival
tective signaling responses in endothelial forms of thrombotic thrombocytopenic probability (189). At present, it remains
cells can be mediated by either thrombin purpura, increases the level of unusually unclear whether blocking the Ashwell re-
or APC. These results explain how PAR-1 large VWF multimers in plasma and leads ceptor may have a beneficial effect in
and EPCR participate in protective sig- to platelet aggregation and/or thrombus severe sepsis.
naling events in endothelial cells (172). formation, especially in small arterioles, re-
Therapeutic administration of recom- sulting in microvascular failure (178 –180). CONCLUSION
binant human APC (rhAPC) is currently Recently, inflammation associated-
in use as a treatment strategy for severe ADAMTS-13 deficiency has been de- A unifying concept of innate immu-
sepsis patients with a high risk of death scribed in patients with systemic inflam- nity is based upon pathogen-, or damage-
(173, 174). Genetically engineered vari- matory response syndrome and severe associated molecular pattern molecules
ants of APC have been designed with sepsis (Fig. 7) (181–185). Decreased lev- and downstream signaling pathways. This
greater antiapoptotic activity and reduced els of ADAMTS-13 have been reported in has facilitated significant advances in our
anticoagulant activity relative to wild- healthy volunteers following endotoxin understanding of the pathophysiology of
type APC to increase the risk/benefit ratio infusion (186). Furthermore, reduced sepsis and led to a multitude of clinical