Reviews of Physiology, Biochemistry and Pharmacology, Vol. 172

104 Pages·2016·2.924 MB·English

by  Bernd Nilius, Pieter de Tombe, Thomas Gudermann, Reinhard Jahn, Roland Lill, Ole H. Petersen (eds.)

Reviews of
Physiology,
Biochemistry and
Pharmacology
172
Reviews of Physiology, Biochemistry
and Pharmacology
More information about this series at http://www.springer.com/series/112
(cid:1) (cid:1)
Bernd Nilius Pieter de Tombe
(cid:1) (cid:1)
Thomas Gudermann Reinhard Jahn
(cid:1)
Roland Lill Ole H. Petersen
Editors
Reviews of Physiology,
Biochemistry and
Pharmacology
172
EditorinChief
BerndNilius
KULeuven
Leuven
Belgium
Editors
PieterdeTombe ThomasGudermann
CardiovascularResearchCenter Walther-Straub-Institutfu¨r
LoyolaUniversityChicago PharmakologieundToxikologie
Maywood,Illinois Mu¨nchen,Bayern
USA Germany
ReinhardJahn RolandLill
DepartmentofNeurobiology DepartmentofCytobiology
Max-Planck-Institute UniversityofMarburg
Go¨ttingen,Niedersachsen Marburg
Germany Germany
OleH.Petersen
CardiffSchoolofBiosciences
CardiffUniversity
Cardiff
UnitedKingdom
ISSN0303-4240 ISSN1617-5786 (electronic)
Reviews of Physiology,Biochemistry and Pharmacology
ISBN978-3-319-49901-7 ISBN978-3-319-49902-4 (eBook)
DOI10.1007/978-3-319-49902-4
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Contents
HepaticStellateCellsinLiverFibrosisandsiRNA-BasedTherapy ....... 1
RefaatOmar,JiaqiYang,HaoyuanLiu,NealM.Davies,andYuewenGong
Exosomes:FromFunctionsinHost-PathogenInteractions
andImmunitytoDiagnosticandTherapeuticOpportunities ............. 39
JessicaCarrie`re,NicolasBarnich,andHangThiThuNguyen
TheStress-ResponseMAPKinaseSignalinginCardiacArrhythmias ... 77
XunAi,JiajieYan,ElenaCarrillo,andWenmaoDing
v
RevPhysiolBiochemPharmacol(2016)172:1–38
DOI:10.1007/112_2016_6
©SpringerInternationalPublishingSwitzerland2016
Publishedonline:8August2016
Hepatic Stellate Cells in Liver Fibrosis
and siRNA-Based Therapy
RefaatOmar,JiaqiYang,HaoyuanLiu,NealM.Davies,andYuewenGong
Abstract Hepaticfibrosisisareversiblewound-healingresponsetoeitheracuteor
chronicliverinjury caused byhepatitisBorC,alcohol,andtoxic agents. Hepatic
fibrosis is characterized by excessive accumulation and reduced degradation of
extracellular matrix (ECM). Excessive accumulation of ECM alters the hepatic
architecture leading to liver fibrosis and cirrhosis. Cirrhosis results in failure of
commonfunctionsoftheliver.Hepaticstellatecells(HSC)playamajorroleinthe
developmentofliverfibrosisasHSCarethemainsourceoftheexcessiveproduc-
tionofECMinaninjuredliver.RNAinterference(RNAi)isarecentlydiscovered
therapeutictoolthatmayprovideasolutiontomanagemultiplediseasesincluding
liverfibrosisthroughsilencingofspecificgeneexpressionindiseasedcells.How-
ever, gene silencing using small interfering RNA (siRNA) is encountering many
challenges in the body after systemic administration. Efficient and stable siRNA
deliverytothetargetcellsisakeyissueforthedevelopmentofsiRNAtherapeutic.
For that reason, various viral and non-viral carriers for liver-targeted siRNA
delivery have been developed. This review will cover the current strategies for
the treatment of liver fibrosis as well as discussing non-viral approaches such as
cationic polymersandlipid-based nanoparticlesfor targeteddelivery ofsiRNAto
theliver.
Keywords BMPs(cid:129)Liverfibrosis(cid:129)siRNA(cid:129)Stellatecells(cid:129)Targeteddelivery
R.Omar,J.Yang,H.Liu,andY.Gong(*)
CollegeofPharmacy,FacultyofHealthSciences,UniversityofManitoba,750McDermot
Avenue,Winnipeg,MB,CanadaR3E0T5
e-mail:[email protected]
N.M.Davies
CollegeofPharmacy,FacultyofHealthSciences,UniversityofManitoba,750McDermot
Avenue,Winnipeg,MB,CanadaR3E0T5
FacultyofPharmacy&PharmaceuticalSciences,UniversityofAlberta,8613-114Street,
Edmonton,AB,CanadaT6G2H1
2 R.Omaretal.
Contents
1 Introduction................................................................................... 2
2 HepaticStellateCells........................................................................ 4
2.1 FunctionsofHSCintheNormalandintheInjuredLiver........................... 4
2.2 HSCandLiverFibrosis................................................................ 6
3 ResolutionofFibrosis........................................................................ 8
3.1 Anti-fibroticTherapeuticApproaches................................................. 8
3.2 GeneTherapy........................................................................... 9
3.3 RNAInterference...................................................................... 11
4 Lipid-BasedsiRNADelivery................................................................ 13
4.1 CationicLiposomes.................................................................... 13
4.2 NeutralLipids.......................................................................... 16
4.3 StableNucleicAcid–LipidParticles(SNALPs)...................................... 17
5 PolymericNanoparticles..................................................................... 18
5.1 Polyethyleneimine...................................................................... 18
5.2 Poly(Lactic-co-GlycolicAcid)(PLGA)............................................... 20
5.3 Chitosan................................................................................ 21
5.4 Cyclodextrin............................................................................ 21
6 SiRNA-NanotherapeuticsandLiverFibrosis............................................... 22
7 Conclusion.................................................................................... 24
References........................................................................................ 25
1 Introduction
Fibrosis of the liver is a reversible response following liver injury (Lee and
Friedman 2011). Although fibrosis is an attempt to minimize the liver injury, the
liver function is significantly impaired. The major causes of liver injury include
chronic viral infection by hepatitis B and C; excessive alcohol consumption;
nonalcoholic steatohepatitis (NASH); iron overload; autoimmune disorders, such
as primary biliary cirrhosis and autoimmune hepatitis; drug-related toxicity; cho-
lestasis; and inherited metabolic diseases such as hemochromatosis as well as
Wilson’s disease and Alfa 1-antitrypsin deficiency (Li et al. 2008; Adrian
etal.2007;LeeandFriedman2011).
Hepaticfibrosisischaracterizedbyexcessiveaccumulationandreduceddegra-
dation of extracellular matrix (ECM). Accumulation of ECM is due to increased
productionanddecreaseddegradationofECM(Arthur2000;BatallerandBrenner
2005). Decreased degradation of ECM is due to imbalance between matrix
metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase
(TIMPs) that regulate the ECM degradation processes (Knittel et al. 1999b;
Tacke and Weiskirchen 2012). After liver injury, TIMP-1 is overexpressed
resultingindecreasedremovalofECM(BatallerandBrenner2005).
AccumulationofECMalters thehepaticarchitecture byformingafibrousscar
and development of nodules leading to cirrhosis (Friedman 2003). Cirrhosis
increases the intrahepatic resistance to blood flow, which results in hepatic insuf-
ficiency and portal hypertension (Fig. 1). This effect leads to failure of common
functionsoftheliver includingmetabolism ofproteins,carbohydrates,andlipids;
protein synthesis; and detoxification of chemicals, drugs, and other xenobiotic
HepaticStellateCellsinLiverFibrosisandsiRNA-BasedTherapy 3
hepatocytes
space of disse
HSC
heptatic sinusoid
KC
EC
Fig.1 Schematicrepresentationoftheliver.Kupffercells(KC)arefoundinsinusoids.Hepatic
stellate cells (HSC) are located in the space of Disse, between endothelial cells (ECs) and
hepatocytes.ECsfeaturethewallsofsinusoidsandpossessfenestrationthatprovideaselective
barrierbetweenthebloodstreamandthespaceofDisse
compoundsandtheirclearancefromthebody(HuiandFriedman2003).Thereare
variouscellsthatareinvolvedinthedevelopmentofliverfibrosissuchashepato-
cytes,Kupffercells(KCs),endothelialcells(ECs),andhepaticstellatecells(HSC).
However,HSCarestillthemajorplayerinthedevelopmentofliverfibrosisasHSC
arethemainsourceoftheexcessiveproductionofECMinaninjuredliver(Maher
andMcGuire1990;WuandZern2000).
4 R.Omaretal.
2 Hepatic Stellate Cells
Hepatic stellate cells (HSC) are also referred to as vitamin A-storing cells,
fat-storing cells, lipocytes, and Ito cells. HSC are non-parenchymal cells of the
liverrepresenting1.4%oftotallivervolumeand5–8%ofthetotallivercells.HSC
are located in the perisinusoidal space which is known as the space of Disse
between hepatocytes and sinusoidal endothelial cells. This anatomical position of
HSC provides physical contact to the sinusoidal endothelial cells and to the
hepatocytes(HuiandFriedman2003).HSCarepresentintwodifferentphenotypes
thatexhibitvariousstructuresandbehaviors:thequiescentphenotypeinthenormal
liverandtheactivatedmyofibroblast-likephenotypeintheinjuredliver
2.1 FunctionsofHSCintheNormalandintheInjuredLiver
2.1.1 StorageofVitaminA
TheprimaryfunctionofquiescentHSCinthehealthyliveristhestorageofretinoid
(vitamin A). The liver stores around 70% of the total retinoid found in the body.
HSCstoreabout90–95%ofhepaticretinoidintheirlipiddropletsasretinylesters
with the help of retinol-binding protein (RBP). Therefore, HSC constitute the
largestreservoirofvitaminAinthebody(Blaneretal.2009).
2.1.2 ExtracellularMatrix(ECM)SynthesisandDegradation
HSC are mainly responsible for the production of ECM in the liver and for the
synthesisofenzymesthatregulate ECMdegradation(MaherandMcGuire 1990);
consequently, HSC are the major players in the development of liver fibrosis.
Generally, the quiescent HSC in the normal liver secrete adequate amount of
ECMproteinssuchascollagentypeIII,collagentypeIV,andlaminin.Inaddition,
HSCsecreteseveraldegradingenzymescalledmatrixmetalloproteinases(MMPs),
such as MMP-1, MMP-8, and MMP-13 which promote ECM degradation. HSC
also produce inhibitors called tissue inhibitors of matrix metalloproteinase
(TIMPs), such as TIMP-1 and TIMP-2. The balance between MMPs and TIMPs
regulate the ECM degradation processes (Tacke and Weiskirchen 2012; Knittel
etal.1999b).
2.1.3 LiverDevelopmentandRegeneration
HSCplayanimportantroleinlivergrowthandregenerationduetotheiranatomical
position. HSC surround sinusoids in a cylindrical manner that enables them to