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Review ArticleHeat Shock Protein 72 Expressing Stress inSepsis: Unbridgeable Gap between Animal and HumanStudiesA Hypothetical Comparative Study
George Briassoulis,1 Efrossini Briassouli,2 Diana-Michaela Fitrolaki,1 Ioanna Plati,3
Kleovoulos Apostolou,4 Theonymfi Tavladaki,1 and Anna-Maria Spanaki1
Pediatric Intensive Care Unit, University Hospital, School of Health Sciences, University of Crete,Voutes Area, Heraklion, Crete, Greece
st Department of Propaedeutic Internal Medicine, Laiko, University General Hospital, University of Athens, Agiou Toma, Athens, Greece
Department of Clinical Chemistry, School of Medicine, University of Crete, Voutes Area, Heraklion, Crete, Greece National and Kapodistrian University of Athens, First Critical Care Department, Evaggelismos Hospital,
Ipsilantou , , Athens, Greece
Correspondence should be addressed to George Briassoulis; [email protected]
Received April ; Accepted October ; Published January
Academic Editor: Wolgang Neuhoer
Copyright George Briassoulis et al. Tis is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Heat shock protein (Hsp) exhibits a protective roleduring timeso increasedrisk o pathogenic challengeand/or tissue damage.Te aim o the study was to ascertain Hsp protective effect differences between animal and human studies in sepsis using ahypothetical comparative study model. Forty-one in vivo (.%), in vitro (.%), or combined (.%) animal and in vivo ()or in vitro () human Hsp studies ( < 0.0001) were enrolled in the analysis. O the human studies, % showed a protectiveHsp effect compared to .% protection shown in septic animal studies ( < 0.0001). Only human studies reported Hsp-associated mortality (.%) or inection (.%) or reported results (.%) to be nonprotective ( < 0.001). In animal models,any Hsp induction method tried increased intracellular Hsp (%), compared to .% o human studies ( < 0.02), reducedproinammatory cytokines (/), and enhanced survival (/). Animal studies show a clear Hsp protective effect in sepsis.Human studies are inconclusive, showing either protection or a possible relation to mortality and inections. Tis might be dueto the act that using evermore puried target cell populations in animal models, a lot o clinical inormation regarding the netresponse that occurs in sepsis is missing.
1. Introduction
Sepsis is an inammation-induced syndrome resulting roma complex interaction between host and inectious agents. Itis considered severe when associated with acute organ dys-unction, which accounts or the main cause underlyingsepsis-induced death. Despite increasing evidence in sup-port o antioxidant [], anti-inammatory [], or immune-enhancing [] therapies in sepsis, recent studies ailed toestablish a correlation between antiseptic pathway-based
therapies and improvement o sepsis [] or septic shock []or among immune-competent patients [].
Rapid expression o the survival gene heat shock protein (Hsp) was shown to be critical or mounting cytoprotec-tion against severe cellular stress, like elevated temperature[]. Intracellular Hsps are upregulated in cells subjected tostressul stimuli, including inammation and oxidative stressexerting a protective effect against hypoxia, excess oxygenradicals, endotoxin, inections, and ever []. Recent stud-ies imply that different biological disease processes and/or
Hindawi Publishing CorporationBioMed Research InternationalVolume 2014, Article ID 101023, 17 pageshttp://dx.doi.org/10.1155/2014/101023
http://dx.doi.org/10.1155/2014/101023http://dx.doi.org/10.1155/2014/101023 -
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simple interventions may interere with high temperaturestress, leading to different clinical outcome in patients withand without sepsis []. In septic patients, administration oantipyretics independently associated with -day mortality,without association o ever with mortality []. Importantly,ever control using external cooling was sae and decreased
vasopressor requirements and early mortality in septic shock[].Inducible Hsp is also ound extracellularly where
it exhibits a protective role by acilitating immunologicalresponses during times o increased risk o pathogenic chal-lenge and/or tissue damage []. Experimental data provideimportantinsights intothe anti-inammatory mechanismsostress proteins protection and may lead to the development oa novel strategy or treatment o inectious and inammatorydisorders []. However, although overexpression o stressproteins signals danger to inammatory cells and aids inimmune surveillance by transporting intracellular peptidesto immune cells [], it has also been linked to a deleteriousrole in some diseases []. In addition, serum Hsp levelswere shown to be modulated according to the patient oxidantstatus whereas increased serum Hsp was associated withmortality in sepsis [].
Te purpose o this basic research-related review incritical care is to document the available evidence on therole o Hsp in sepsis, reporting both the state o theart and the uture research directions. It might be thatpotential therapeutic use o stress proteins in prevention ocommon stress-related diseases involves achieving optimalbalance between protective and immunogenic effects o thesemolecules []. In this review, we will attempt to classiyexperimental and clinical studies on Hsp in sepsis and tocompare their results on inammation, organ unction, andoutcome; we will also briey discuss the mechanisms on howstress proteins might exert their protective or negative rolein the disease development and highlight the potential clinictranslation in the research eld.
2. Materials and Methods
Human or animal in vivo or in vitro studies examining thebenecial effect o intra- or extracellular Hsp expression insepsis were included in this study. Te PRISMA [] searchmethod or identication o studies consisted o searches oPubMed database ( to September ) and a manual
review o reerence lists using the search term: Hsp or .Te search output was limited with the search lter or anyo: sepsis; severe sepsis; bacterial lipopolysaccharide (LPS);endotoxin. Reerences in selected studies were examinedalso. Te title and abstract o all studies identied by theabove search strategy were screened, and the ull text orall potentially relevant studies published in English wasobtained. Te ull text o any potentially relevant studies wasassessed by ve authors (DMF, EB, IP, AK, and ). Te sameauthors extracted data rom the published studies.
.. Statistical Analysis. Proportions o methods used and
results ndings were compared by the 2 test. A two-sided
alpha o . was used or statistical signicance. Te resultswere analyzed using SPSS sofware (version ., SPSS,Chicago, IL, USA).
3. Results
Our search identied PubMed titles and abstracts.Afer excluding duplicates, studies with no original data, ordata insufficient to evaluate or those whose outcome wasischemia/reperusion injury or others, articles were nallyincluded or analysis. Te aim o this minireview was notto examine the quality o studies, but to describe inductionmethods and to compare in vivo and in vitro methods andresults regarding a potential protective role or Hsp inhuman and animal sepsis.
.. Animals. Forty-one in vivo (, .%), in vitro (,.%), or combined (, .%) animal studies ullling theresearch criteria regarding the role o Hsp in sepsis were
enrolled in analysis (ables (a), (b), and (c)). In only studies transgenic animals (Hsp/ (.%), overexpressingthe human Hspab gene (.%)) were used (.%), all inmice ( < 0.03). Hsp induction methods used in ratsdiffered rom those used in mice ( < 0.0001). Hspinduction was attempted most ofen using heat shock (rats, .%; mice , .%), glutamine (Gln) (rats , .%; mice, %; sheep , %), or combined Gln with additionalinducer (rats , .%; mice , .%). In rats Hsp wasinduced through adenoviral vector Hsp (AdHSP) (, .%o studies in rats) or various recombinant Hsp (rHsp)preparations (, .%) compared to mice studies whereAdHSP, bovine rHsp preconditioning, or overexpressed
Hsp within the intestinal epithelium was used (.%).Hsp gene-transected models (, .%) or cecal ligationand puncture (CLP) with LPS or injection o microorganisms(, .%) were used only in mice studies.
In more than hal o the studies induction was attemptedin a pretreatment mode (, .% or mice; , .% orrats induction afer LPS injection or CLP), ollowed by aconcomitant mode in rats (, %) or a posttreatment onein mice (, %). Te different time intervals used beore orafer experimental sepsis, most ofen - hours, did not differamong groups. Preventive effect was achieved by most induc-tion methods used in mice or rats (/, .%), irrespectiveo the challengeperiod or timing used (Figures(a)and(b)).
wo studies, one carried out in sheep and one in rats,were inconclusive. In all septic animal models, any Hspinduction method tried increased intracellular Hsp (/,%), reduced proinammatory cytokines (/ studiesinvolving cytokine measurements), organ damage (/),clinical deterioration (/), and enhanced survival (/).
.. Patients. Only human in vivo () and in vitro ()Hsp studies were identied (ables(a) and(b)): humanperipheral blood mononuclear cells (hPBMC) studies,.%; polymorphonuclear leukocytes (hPMNL) studies,.%; lymphocytes (hPBLC) study, .%; in vivo (childrenor adults serum levels) studies, .%. O those, hPBMC
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T:(a)Resultsoanimalinvivostudiesexaminingthepreventiveroleointra-
orextracellularHsp(Hsp)expression
andHsp(Hsp)expressioninexperim
entalsepsisorsepsis-
relatedpathophysiology.(
b)Resultsoan
imalinvitrostudiesexaminingthepreventiveroleointracellularHsp(Hsp)expressioninexperimentalsepsisorsepsis-relatedpathophysiology.
(c)ResultsogeneticanimalstudiesexaminingthepreventiveroleointracellularHsp(Hsp)expressioninexperimenta
lsepsisorsepsis-relatedpathophysiology.
(a)
Invivo
Induction
Organsst
udied
Expressionin
cells/Hsp
challenge
Extracellular
Hsplevels
Inhibitors
Functional
Pathways
Interleukins
Organ
damage
Survival
CLPsepsis
rats[,]
LPS-treated
rats[]
LPS-treated
mice[]
Heatstress
Lungs()
Heart()
Splenocytes()
Rostral
Ventrolateral
medulla(
)
Mitochon
drial
unction()
Brain()
Induced()
Hsp
inhibitors
(KNKor
pithrin-m)
abrogatedthe
abilityothe
thermal
treatmentto
enhanceTNF-
()
Alleviated
hypotension,
bradycardia,
sympathetic
vasomotor
activity()EEG
andepileptic
spikes
attenuated()
Suppre
ssediNOS
mRNA
NF-B
activation,I
Bkinase
activation,I
B
degrad
ation()
Preven
ted
downregulationo
Grp,preserved
cytoch
romec
oxidase()enhanced
phosphorylationo
IKK,IkB,N
F-B
nuclear
translo
cation,
bindingtothe
TNF-promoter()
Cytokines
declined()
HMGB
inhibited()
enhanced
LPS-induced
TNF-
production()
Reduced
()
Prevented
sepsis-
associated
encepha
lopa-
thy()
Enhanced()
LPS-treated
mice[,]
rats[]
sheep[]
CLPsepsis
rats[,]
CPLsepsis
mice[,]
Glutamine
Heart()
Lungs()
Liver()
Aorta()
Kidneys(
)
Brain()
Blood()
Multipleorgans
()
Induced()
Bloodsamples:
increasedHsp
onlyafercoad-
ministrationo
Glnand
ciprooxacin
[]
Quercetin
blocked
Gln-mediated
enhancemento
Hspand
HSF--p
expressionsand
survivalbenet
()
LDdoseoP.
aeruginosaand
ciprooxacinin
combinations
()
Prevented
ARDS()
arterial
pressure,
cardiac
contractility
restoredinthe
Glnthaninthe
LPSshock()
Quercetin
preventedGln
protection()
Nodifferencein
hemodynamic
parameters()
Inhibitedactivation,
translo
cationo
NF-B
tothe
nucleu
sdegradation
oIKBalpha,
phosphorylationo
pMAPK,E
RK,
increasedMKP-()
lungH
MGB-
expressionNF-B
DNA-binding
activitysuppressed
()Red
uced
peroxide
biosynthesis()
Attenuated
TNF-alpha(),
IL-.I
L-,
MDA,H
MGB-,
apoptosis()
increasedIL-
()
Reduced
()
Enhanced()
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(a)Continued.
Invivo
Induction
Organsst
udied
Expressionin
cells/Hsp
challenge
Extracellular
Hsplevels
Inhibitors
Functional
Pathways
Interleukins
Organ
damage
Survival
LPS-treated
ratsbovineor
Advirusor
rHsp[]
CLPsepsis
ratsand
tracheas
AdHSP[]
Exogenous
rHsp
AdTrackor
Advirus
Liver()
Peritonea
l
macrophages
()
MLE-c
ells()
Myocardium()
Lungs()
Induced()
Normalized
hemostasis()
hemodynamics
()
Biochemical
parameters()
Inhibited
LPS-in
duced
decreaseNO
expressionin
macrophages,
norma
lized
neutro
philapoptosis
()inhibitedIB
degrad
ationand
NF-B
,pnuclear
translo
cation()
apopto
ticcellular
pathwayscaspases,
,()
Modied
myeloidcells
responsetoLPS
()prevented
LPS-induced
increasein
TNF-andIL-
()Reduced
ICAM-,
attenuated
cardiac
dysunction()
Attenuated
cardiac
dysunction
()reduced
alveolar
cell
apoptosis()
Enhanced()
(b)
Invitro
Induction
Organsstudied
Intracellular
Hspexpression
Inhibitors
Pathways
Interleukins
Organdamage
Survival
Murine
macrophage-
likeRAW
.cells
[]
Heatshocked
Macrophages()
CellsromHS
overexpressed
Hsp()
Inhibited
phosphorylationo
p,J
NK,
ERK/MAPK,IB
degradation,
NF-Bpnuclear
translocation()
HSinhibited
HMGB-
induced
cytokines
TNF-and
IL-
()
Enhanced()
CLP-treated
murine
peritoneal
macrophage
cellline
RAW.
[]Neonatal
ratcardiomy-
ocytes[]
IEC-rat
intestinal
epithelial
cells[]
Glutamine
Peritoneal
ma
crophages()
Cardiomyocytes
()Int
estinal
epithelialcells()
IncreasedHsp
expression()
Gln
protection
mimickedby
PUGNA,
banishedby
alloxan()
DFMO
ornithine
decarboxy-
laseinhibitor
()
ReducedLDH,
increased
O-ClcNAc,HSF-,
transcription
activity()
increasedHSF
bindingtoHSE()
Invitro
TNF-dose-
time-Gln.
DependentIn
vivolower
intracellular
TNF-level
Attenuated
LPS-induced
cardiomyocyte
damage()
Enhanced()
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(b)Continued.
Invitro
Induction
Organsstudied
Intracellular
Hspexpression
Inhibitors
Pathways
Interleukins
Organdamage
Survival
LPS-treated
rats[]
LPS
stimulation-
mouse
macrophage-
likecellline
(RAW.
cells)[,]
Transected
withHsp
plasmidor
HS
Myocardium()
Macrophages()
Hspplasmidor
HSinduced
Hsp()
iNOSmRNA
completely
abolishedbyHS-
Hsptransected
cells()
HSinhibited
LPS-induced
NF-BandHSF-
activity()
increasesboth
cellularSKmRNA
andproteinlevels
()
Enhanced()
CLPrats,
murinelung
epithelial-
cellsin
culture[]
Murine
macrophage-
likeRAW
.cells
[]
Exogenous
Hsp
Lungs()
Macrophages()
Overexpression
oHspin
RAW/Hspcells
()
Limitednuclear
translocationo
NF-B,
phosphorylationo
IkappaBalpha()
Inhibitionothe
MAPkinases(p,
JNK,andERK)()
Inhibitiono
theNF-B-
HMGB-
induced
releaseo
TNF-,I
L-
()
LimitedNF-B
activation()
Enhanced()
CLP-treated
mice[]
Arsenite
(Positive
control)
Lungs()
Induced-
Inhibitors
blockedHsp
expression,(
)
Anti-human
Hsp()
Pretreatmentwith
neutralizing
antibodiesto
Hspdiminished
neutrophilkilling
()
Survivorshigher
oTcells()
Enhanced()
(c)
KOanimals
Induction
Organsstudied
IntracellularHsp
expression
Pathways
Interleukins
Organdamage
Survival
CLPsepsis
Hsp.
//KO
mice[]
Glutamine
Lungs()
Hsp.
//mice
didnotincrease
Hsp()
Hsp.
/((/))
miceincreasedNF-B
binding/activation()
IncreasedTN
F-,
IL-inKO()
Increasedlunginjury
inKO()
DecreasedinKO()
CLPsepsis,
injectiono
microorganisms
Hsp/KO
mice[]
Imipenem/
cilastatin
Gut()
Lungs()
Hsp/micedid
notincreaseHsp
()
Increasedapoptosis
andinammation
Hsp/increased
TNF-,I
L-,I
L-,
IL-b
KO-increasedgut
epithelialapoptosis,
pulmonary
inammation()
D
ecreasedinKOage
dependent()
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(c)Continued.
KOanimals
Induction
Organsstudied
IntracellularHsp
expression
Pathways
Interleukins
Organdamage
Survival
LPS-treatedmice
Hsp/or
overexpressed
Hsp[]
LPS
Intestinal
epithelium()
Pharmacologic
Hsp
upregulation
HspreducedTLR
signalingin
enterocytes()
Hspreversed
TLR-cytok
ines,
enterocyteapoptosis
()
Preventedandtreated
experimentalNEC()
LPS-treatedmice
overexpressing
thehuman
Hspabgene[]
LPS
Heart()
Overexpressiono
HSPAB
Preventeddecrement
intheactivationo
PIK/proteinkinaseB
signalingin
myocardium()
Decreasedth
e
expressiono
VCAM-/ICAM-()
Decreasedleucocyte
inltrationin
myocardium()
Attenuatedcardiac
dysunction()
:numberostudies;PBMC:peripheralbloo
dmononuclearcells;LPS:bacteriallipopolysaccharide;CLP:cecalligationandpuncture;TNF
-:tumornecrosisactor-alpha;AdHSP:adenoviralvectorHsp;Gln:
glutamine;HS:heatstress;Hspgene:Hspgene-transectedmodels;HSF:HSactor;HSE
:heatshockelement;IKK:IBkinase;IkB:IkappaBalpha.
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Treatment time related to LPS/CLP
Both Con Post Pre
AdVhsp
CLP+
ExofHsp
Gln
Gln+
HS
Hspgene
Animal iHsp72induction studies
InconclusiveProtective
(a)
LPS/CLP iHsp72 interval (min)
0 10 30 60 120
AdVhsp
CLP+
ExofHsp
Gln
Gln+
HS
Hspgene
Animal iHsp72induction studies
InconclusiveProtective
(b)
F : (a) Preventive effect was achieved by all induction methods used irrespective o the challenge period or (b) time lapse betweenthe sepsis insult and the Hsp induction: LPS, bacterial lipopolysaccharide; CLP, caecal ligation and puncture; iHsp, inducible heat shockprotein ; Pre, pre-treatment; Post, posttreatment; both, trials with pre- and postexperiments; Con, concomitant; AdHSP, adenoviral vectorHsp; exogHsp, exogenous Hsp preparations; Gln, glutamine; +, additional challenge; HS, heat stress; Hspgene, Hsp gene-transectedmodels.
were used in only studies with septic patients but in withhealthy volunteers. Heat stress (HS) or acclimation was usedin studies (.%), Gln administration in in associationwith LPS (.%), recombinant human Hsp in (.%),and either inhibitor or agonist in (.%). In studies nochallenge or only LPS (.%) was used. In only out o (.%) studies in septic patients induction Hsp methodswere attempted compared to % in the studies with healthy() or ARDS () patients ( < 0.006). Protection markersstudied were apoptosis ( studies, .%), HS ( studies,.%), oxidative damage, hospital inections, hemodynamicinstability, and ARDS ( study each, .%).
Intracellular Hsp was induced in in vitro studies(.%, in healthy, in septic) and inhibited in (.%, in
septic, in ARDS patients). O the studies in septic patients,intracellular Hsp was increased in (%), inhibited in (%), and not measured in . With the exception o sodiumarsenite, neither Gln nor HS were tested in these studies.Extracellular Hsp, measured in in vitro and in in vivostudies, was shown to increase in sepsis, especially in septicshock or in those who died (.% o human studies).
Increased intracellular Hsp was protective in hal othe human studies (%); regarding the positive (HS, Gln,exogenous Hsp) in vitro induction Hsp human studies (.%) were protective (Figure (a)) and inconclusive(.%) or nonprotective (.%). O the induction methodsused, protection offered HS (/, %), glutamine (/, %),
rHsp and sodium arsenite (/, % each) (Figure (b)).Incontrast, o the in vivo (serum Hsp measurements), in
vitro endotoxin induced (LPS or CLP), and Hsp inhibitorhuman studies, none was shown to be associated with a betteroutcome ( < 0.02); studies were associated with mortality(%) and with inection (%) or were inconclusive (%).Septic patients studies were positive or protection in only out o (.%) compared to out o (.%) in healthy and% in ARDS patients ( < 0.06).
.. Human Compared to Animal Studies. Out o a total o enrolled studies, only in vivo human studies (.%) havebeen reported on the role o Hsp in sepsis compared to
mice (.%) and rat (.%) in vivo studies ( < 0.0001);in contrast human (.%) studies have been reportedin vitro compared to only in rats (.%) and in mice(.%); mice (.%) and rat (.%) combined in vitro-in vivo studies have also been reported. O the humanstudies, % showed a protective Hsp effect comparedto .% protection shown in animal studies (Figure (a)).When restricted to the septic patients studies, however, only out o (.%) demonstrated an Hsp protective effectcompared to .% protection shown in animal studies (