review-article2018 811294

source: https://doi.org/10.7892/boris.122960 | downloaded: 1.10.2021 2018 TAG 0 0 10.1177/1756284818811294Therapeutic Advances inGastroenterologyM Vilaseca, SGuixé-Muntet current treatmentsdonot targetthemain aggravate PHandliverdysfunction. Notably, and extrahepatic shunt formation,whichfurther leading tosecondarysplanchnic vasodilation tor involvedinincreasingportalpressure(PP) hepatic cellsandliverfibrosisistheprimaryfac- ment, elevationinIHVRduetoderegulationof resistance (IHVR).Duringcirrhosisdevelop- in portal blood flow or in intrahepatic vascular of 10 Clinically significantPHisdefinedasanHVPG pensated cirrhoticpatients. of clinicaldecompensationandsurvivalincom- sure gradient(HVPG)beingapredictoroftherisk CLD, themeasurementofhepaticvenouspres- PH isthemajordriverofcomplications lopathy, varicealhemorrhageorascites.Infact, clinical complicationssuchashepaticencepha- appearance ofportalhypertension(PH)andits ease progression and, thus, is diagnosed after due tolong-timeasymptomaticstagesduringdis- ble diseasesworldwide.Itshighmortalityismainly the fourthcauseofdeathduetononcommunica- Advanced chronicliverdisease(CLD)represents Introduction Received: 20July2018;revisedmanuscriptaccepted:15October2018. Keywords: underlying cellularmechanisms. therapeutics, focusingonthosestrategiesdrivenbythediseasepathophysiologyand The presentreviewcriticallysummarizesthecurrentknowledgeinportalhypertension in recentdecades,noeffectivetreatmenttargetingitsprimarymechanismhasbeendefined. inflow. Althoughextensivepreclinicalandclinicalresearchinthefieldhasbeendeveloped in itsdevelopment,beingsubsequentlyaggravatedbyaparadoxicalincreaseportalblood defines apathologicalincreaseintheintrahepaticvascularresistanceasprimaryfactor liver disease,havingadeepimpactonpatients’prognosisandsurvival.Itspathophysiology Abstract: and JordiGracia-Sancho Marina Vilaseca,SergiGuixé-Muntet,AnabelFernández-Iglesias hypertension Advances intherapeuticoptionsforportal journals.sagepub.com/home/tag 1 Therapeutic AdvancesinGastroenterology mmHg orgreateranddependsonchanges Portal hypertensionrepresentsoneofthemajorclinicalconsequenceschronic cirrhosis, hepatichemodynamic,HVPG,portalpressure,sinusoid mmercial 4.0 License Creative Commons NonCommercial CCBY-NC:This articleisdistributed underthetermsof the CreativeCommons Attribution-NonCommercial 4.0 License provided theoriginal work isattributed asspecified on theSAGE andOpen Accesspages (https://us.sagepub.com/en-us/nam/open-access-at-sage). (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,reproduction anddistribution oftheworkwithoutfurther permission 1,2 to itsanti-α may alsoexertintrahepaticvasodilatationdue case ofNSBB,itshouldbenotedthatcarvedilol infections orencephalopathy.Inthespecific vention ofPH-derivedcomplicationssuchas circulation, orinstrategiesfocusedonthepre- ameliorating PHbyreducingthehyperdynamic blockers (NSBB)andsomatostatin]aimedat patic vasoconstrictors[i.e.nonselectivebeta underlying mechanism,butconsistinextrahe- shown below. logical, cell-derivedorlifestyle interventions,as IHVR. Theseapproaches consist ofpharmaco- knowledge andmainly target theincreased which importantlyderivefrompreclinical apeutic strategiesforthetreatmentofPH, In thisreviewwesummarizethepotentialther- for PHandCLD. there isaneedfornewtherapeuticapproaches observed 10yearsago, sis remainsequal,orevenhigher,thanthat mortality followingadecompensationincirrho- based onover100,000casesshowedthat30-day effective treatmentforPH,arecentanalysis the extendeduseofthesedrugsasmost 1-adrenergic properties. 4 stronglysuggesting 3 Despite permissions sagepub.com/journals- Article reuseguidelines: © TheAuthor(s),2018. 1756284818811294 https://doi.org/10.1177/1756284818811294 DOI: 10.1177/ https://doi.org/10.1177/1756284818811294 2018, Vol.11:1–19 Ther AdvGastroenterol Bern, Switzerland Research, Universityof Department ofBiomedical Sergi Guixé-Muntet Institute, Barcelona,Spain Biomedical Research Laboratory, IDIBAPS Hepatic Hemodynamic Iglesias Anabel Fernández- Marina Vilaseca [email protected] Spain 4th floor,08036Barcelona, CIBEREHD, Rosselló149, Research Institute, IDIBAPS Biomedical Hemodynamic Laboratory, Barcelona Hepatic Research Group, Liver VascularBiology Jordi Gracia-Sancho Correspondence to: Review

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Figure 1. Schematic representation of different therapeutic approaches for portal hypertension focused on their liver vasomodulation effect. Drugs in bold denote currently ongoing RCT and known mechanisms of action are indicated in parenthesis. APAP, acetaminophen; COX, cyclooxygenase; ECA, enzyme converter of angiotensin; ERβ, estrogen beta; FXR, farnesoid X receptor; OCA, obeticholic acid; 5-MTHF, 5 methylfolate; eNOS, endothelial nitric oxide synthase; ET, endothelin receptor; GTP, triphosphate; cGMP, cyclic ; KLF2, Kruppel-like factor 2; NO, nitric oxide; sGC, soluble guanylate cyclase; L-arg, L-arginine; LTC, leukotriene; MAS, Mas receptor; PDE, phosphodiesterase; NCX, NO-donor compound derived from ursodeoxycholic acid; JNK, Jun N-terminal kinases; PLA2, phospholipase A2; RhoK, Rho kinase; RAA, renin–angiotensin–aldosterone; RCT, randomized controlled trial; TXA2, thromboxane A2.

Vasoprotective strategies Inhibition of vasoconstriction. One of the most CLD is characterized by persistent injury of the potent vasoconstrictors that contributes to micro- liver due to different etiologies, including alco- vascular dysfunction in CLD is endothelin. This holic and nonalcoholic steatohepatitis (NASH) or molecule is synthesized by the activated endothe- viral infections. This in turn leads to alterations of lium and acts as a ligand for the endothelin recep- the hepatic microvasculature, which in combina- tors (ET) on hepatic stellate cells (HSCs), which tion with fibrosis constitute the main components are the final effectors of vasoconstriction. Indeed,

of increased IHVR. This scenario of vascular the use of antagonists targeting ET (either ETA, alterations has led to the assessment of different ETB or both) showed improvements in the hepatic vasoprotective strategies for the treatment of sinusoid and in liver fibrosis in preclinical models5,6 intrahepatic-derived PH, mainly vasomodulators, and decreased PP in a small clinical study.7 How- anticoagulants and antiangiogenic approaches. ever, its possible beneficial effects were not fur- ther validated in human randomized-controlled trials (RCTs).8,9 Currently ongoing human RCTs Vasomodulators evaluating the unspecific antagonist macitentan10 One of the causes of the abovementioned micro- and ambrisentan11 will provide essential informa- vascular alterations during CLD is a shift/altera- tion to support or discard this therapeutic strat- tion in the synthesis of vasoactive molecules in the egy in cirrhosis and PH. liver, where vasoconstrictors prevail over vasodi- lators. Thus, several vasomodulator strategies Urotensin is another vasoconstrictor playing a aimed at enhancing intrahepatic vasodilation and role in PH, known to correlate with HVPG normalizing excessive vasoconstriction have been levels.12 Similar to ET, blockage of the urotensin recently proposed (Figure 1). II receptor with the antagonist palosuran decreases

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Figure 2. Schematic representation of different therapeutic approaches for portal hypertension based on their effect on apoptosis, oxidative stress or inflammation as main features of chronic liver damage. Known mechanisms of action are indicated in parenthesis.

ASK1, apoptosis signal-regulating kinase; CeO2, cerium oxide; EET, epoxyeicosatrienoic acids; GLP-1R, glucagon-like peptide 1 receptor; JAK2, janus kinase 2; NADPH, nicotinamide dinucleotide phosphate; NO, nitric oxide; rMn, Recombinant Manganese; ROS, reactive oxygen species; SOD, superoxide dismutase.

PP in experimental models.13 Nevertheless, there a hormone system that controls blood pressure are no current studies on cirrhotic patients in and fluid balance, playing also an important role order to validate the translatability of these results regulating hepatic hemodynamics. Importantly, to the bedside. angiotensin II is a potent vasoconstrictor peptide with hepatic effects that favors the development Eicosanoids represent another important family of of PH.23 Several strategies have been developed vasoconstrictors derived from the conversion of to reduce its effects on the liver: angiotensin- arachidonic acid. Indeed, cyclooxygenase (COX)- converting-enzyme inhibitors (captopril) and derived prostanoids (a subclass of eicosanoids) are angiotensin receptor blockers (losartan, cande- overexpressed in the cirrhotic liver.14,15 In this sartan, irbesartan) have been tested in preclini- regard, several drugs have been used to chroni- cal and clinical settings and showed beneficial cally inhibit either their synthesis (i.e. by COX effects on reducing PH but mainly in compen- inhibition with nitroflurbiprofen16 or celecoxib17,18) sated patients with Child A cirrhosis.24 Given or to block their receptor (e.g. thromboxane A2 the potential of these drugs, some strategies receptor with terutroban19). Although these strat- aimed at focusing on the RAA system down- egies decreased PP in preclinical models of cirrho- stream pathway. Indeed, the Janus kinase inhibi- sis, there is only one ongoing RCT with the tor AG490 showed a PP-lowering effect additive thromboxane receptor antagonist ifetroban.20 to propranolol in preclinical models,25–27 while Similar strategies aimed at reducing arachidonic the Rho-kinase inhibitors Y-2763228 and fasudil29 acid metabolites focused on inhibiting epoxyge- showed comparable beneficial effects. Indeed, nases using MS-PPOH21 and cysteinyl leukot- RhoA modulation using ferulate30 or dia- rienes with montelukast.22 rylpropionitrile31 showed beneficial effects in preclinical PH, and interestingly, pointed out the In addition to the increased synthesis of vasocon- relevance of the latter (which is an estrogen- strictors, the cirrhotic liver is also hypersensitive receptor β agonist) in postmenopausal women. to these molecules. Thus, research aimed to On the other hand, the receptor Mas also repre- inhibit the effect of not only hepatic vasoconstric- sents an alternative downstream target of the tors, but also systemic ones. In this regard, the RAA pathway. Its activation showed promising renin–angiotensin–aldosterone (RAA) system is effects in experimental models of cirrhosis, also

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reducing PP and liver fibrosis.32 Nevertheless, downstream mediator. When sGC is activated by another study blocking the Mas receptor with NO, it induces the formation of the intermediate A779 led to the same decrease in PP,33 leaving the cyclic guanosine monophosphate (cGMP), which Mas receptor role in a paradigm. confers potent vasodilation. In this regard, the stimulation of the nonoxidized form of sGC or the Vasopressin, also named antidiuretic hormone, is a oxidized and free-sGC form may represent novel hormone that contributes to the regulation of water approaches for activating cGMP production and and electrolyte homeostasis and constricts arteri- subsequently ameliorate the vasoconstrictor envi- oles, increasing vascular resistance and blood pres- ronment. In fact, a recent study using the nonoxi- sure. The blockage of vasopressin using conivaptan dized and free-sGC stimulator riociguat showed has been recently tested in an RCT and showed no improved liver fibrosis and PP in cirrhotic ani- beneficial effects on PP.34 Indeed, previous data mals.44 However, no studies have evaluated the support the concept that vaptans may not only be potential of activators of the oxidized form of sGC ineffective but also have negative secondary effects for the treatment of PH. Considering that oxida- in terms of morbidity and mortality in patients with tive stress plays a key role in cirrhosis and PH, and cirrhosis.35,36 Partial vasopressin agonists in the that sGC activators are able to generate cGMP mesentery may have better projection. Indeed, a even in these detrimental conditions,45 their use- recent study demonstrated beneficial effects of FE fulness as a therapeutic option for PH deserves fur- 204038 reducing PP in cirrhotic rats,37 and a ther investigation. recently started RCT evaluates the compound FE 204205 in cirrhotic patients with PH.38 In addition to sGC strategies, there are other approaches aimed at potentiating the effects of Promotion of vasodilation. Nitric oxide (NO) is a cGMP by preventing its degradation by phospho- potent vasodilator synthesized by the NO syn- diesterase-5 (PDE-5). Indeed, different PDE-5 thase (NOS) that regulates vascular tone and inhibitors showed lowering effects on PP in cir- inflammation; however, it becomes markedly rhotic patients.46–48 deregulated in the cirrhotic liver. Several thera- peutic approaches focused at increasing its levels, Transcriptional modulators. In addition to specific either by enhancing NO production (NOS- modulators of vasoactive molecules, other strate- dependent strategies), or by providing NO as an gies rely on the modulation of transcription factors exogenous source or decreasing NO degradation that regulate the expression of many of these pro- (NOS-independent strategies). teins. For example, farnesoid X receptor (FXR) is a bile-acid-responsive transcription factor highly Delivering NO to precise cellular locations, like expressed in the liver that controls the expression the liver sinusoid, represents a challenge. of many genes involved in metabolic regulation, However, nanoparticle delivery has lately become hepatic fibrosis, vascular homeostasis and inflam- an important and emerging field. In fact, recent mation, and thus it has been considered a promis- studies using NO-releasing nanoparticles coated ing therapeutic target in CLD. Obeticholic acid with vitamin A, which is mainly stored in HSCs (OCA), a semisynthetic FXR agonist, has been in the liver, reduced PP in a preclinical cirrhotic tested in preclinical models of cirrhosis showing model.39 Similar effects were observed when NO beneficial effects on PH by reducing the IHVR.49 synthesis was enhanced: the NOS cofactor tet- Indeed, different ongoing clinical trials are investi- rahydrobiopterin (sapropterin) and the NOS gating its effects in advanced CLD,50–52 including transcription enhancer (AVE 9488) decreased PP patients with NASH cirrhosis.53,54 This drug, how- in cirrhotic animal models,40,41 nevertheless no ever, has raised some cases of overdose-related tox- benefits were observed in an RCT evaluating the icity in patients with severe or even mild liver first.42 In this same strategy, a currently ongoing dysfunction, so its dosage needs to be carefully RCT will describe the effectiveness of serelaxin, a adjusted.55 In addition to OCA, new nonsteroidal drug that has been used for the treatment of acute FXR agonists have been developed to evade heart failure due its capability to activate the enterohepatic recirculation. These drugs (e.g. relaxin receptor and NOS.43 PX201606, GS-9674), have been tested in animals with CLD showing increased endothelial NOS The soluble guanylate cyclase (sGC) is the only expression, reduced inflammatory response and known receptor for NO and represents its improved liver injury.56,57 The effects of these newly

4 journals.sagepub.com/home/tag M Vilaseca, S Guixé-Muntet et al. formulated compounds on advanced CLD and Vascular endothelial growth factor (VEGF) is the PH require further investigation. main proangiogenic factor promoting neovascu- larization in the mesentery and contributes to the On the other hand, statins are lipid-lowering development of increased splanchnic vasodila- drugs that have shown strong hepatosinusoidal tion. Therefore, different studies have focused on protective effects in preclinical models of CLD, blocking VEGF receptors (VEGFr) to decrease ultimately leading to PP decrease.58–60 Underlying splanchnic circulation and improve PP. Initially, mechanisms of statins mostly rely on their capa- monoclonal antibodies and specific inhibitors of bility to induce the expression of the transcription VEGFr2 were used in PH animals showing factor Kruppel-like factor 2 that leads to liver improvement in portosystemic collateral vessel sinusoidal endothelial cell (LSEC) phenotype formation but showing no effect on PP.81,82 amelioration, HSC deactivation, and global Subsequent preclinical studies investigated oral improvement in hepatic injury.61–66 Encouraged tyrosine kinase inhibitors that block VEGFr2, by the preclinical results, several clinical studies such as sorafenib,83,84 brivanib84,85 and have tested statins in PH-cirrhotic patients. regorafenib86 and showed improved PP and sys- Recent analyses have shown that statins are asso- temic shunting in cirrhotic and noncirrhotic rats ciated with decreased risk of decompensation, with PH. Indeed, tyrosine kinase inhibitors have death and hepatocellular carcinoma develop- also been shown to decrease liver fibrosis.87 ment.67,68 Moreover, simvastatin has shown ben- These beneficial preclinical results were con- eficial effects when administered alone69 or firmed in a small clinical trial where sorafenib combined with beta blockers.70 Future and ongo- significantly improved PH in patients with liver ing RCTs will extend our knowledge regarding cirrhosis and hepatocellular carcinoma.88 the use of statins for the treatment of PH.71 Apart from VEGF, other molecules such as pig- ment epithelium-derived factor (PEDF) or vasohi- Anticoagulants bin-1 have been shown as potent endogenous It is widely accepted that cirrhotic patients have inhibitors of angiogenesis. In fact, overexpression an imbalance in anti- and procoagulant factors, by adenovirus of PEDF or vashoihin-1 resulted in leading to both increased risk of bleedings and decreased mesenteric angiogenesis, portosystemic microthrombosis in the liver, which may in turn shunting, PH and liver fibrosis.89,90 Nevertheless, increase liver hypoxia and inflammation.72 no current RCTs are being performed following Therefore, different anticoagulants have been this approach. It is important to highlight that angi- lately tested in the setting of CLD with success in ogenesis is not only deleterious but also required the prevention of hepatic fibrosis.73 Indeed, the for repairmen of hepatic tissue during liver fibrosis direct antithrombin enoxaparin has been shown resolution, therefore total angiogenesis blockade to reduce PP and liver fibrosis in experimental may not be a realistic therapeutic approach. CLD,74 confirming at the bench side its clinical benefits on cirrhosis decompensation and sur- vival.75 A different anticoagulant strategy is the Cell death, oxidative stress and direct inhibitor of factor Xa rivaroxaban, which inflammation has been shown to reduce liver microthrombosis, HSC activation and PP in experimental models of Prevention of cell death cirrhosis.76 Moreover, it is currently being tested The main factor in the progression of cirrhosis is in RCTs on patients with cirrhosis77 or with por- chronic liver injury. This is a scenario of persis- tal-vein thrombosis.78 Additional, ongoing RCTs tent cell death (due to different etiologies), will provide more data on the use of anticoagu- which leads to excessive inflammation and asso- lants for CLD-patients.79 ciated cytotoxicity, and oxidative stress. This sequence of events has led to the hypothesis that pharmacological inhibition of cell death may Antiangiogenics represent a therapeutic option for the treatment Angiogenesis is an important feature in the devel- of PH and CLD (Figure 2). opment of PH, being triggered by hypoxia and inflammation which are present during hepatic Emricasan is an orally active pan-caspase inhibitor fibrogenesis.80 that has proven promising potential in the setting

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of CLD. Indeed, a preclinical study presented as activity or by transcriptional/post-transcriptional

a meeting abstract describes that CCl4-cirrhotic modulation of other enzymes. However, cirrhotic rats receiving emricasan displayed improved PP livers are known to produce reduced levels of and IHVR compared with vehicle-treated rats, in antioxidants compared with control livers, thus addition to improved liver function and microcir- further aggravating the increased oxidative stress culation, and these effects were accompanied by in this setting.100,101 For this reason, several stud- improved LSEC and HSC phenotype and ies aimed to develop pharmacological antioxi- reduced inflammation.91 More recently, another dant-enhancing strategies for CLD. One of these study in bile-duct-ligated (BDL) mice reported is mitoquinone, a mitochondria-targeted antioxi- similar effects of this caspase inhibitor.92 At the dant with oral administration approved for human bedside, emricasan did not show positive effects use. This drug has already proved positive effects in acute-on-chronic liver failure.93 However, a in preventing oxidative damage in models of liver proof-of-concept clinical study suggests that diseases such as NASH or ischemia/reperfu- emricasan ameliorates PP in patients with com- sion.102,103 In a recent study, treatment with mito- pensated cirrhosis and severe PH.94 The comple- quinone reduced PP and IHVR in two different 95 tion of a bigger ongoing clinical trial may preclinical models of CLD [CCl4 and thioaceta- confirm these promising results in the near future. mide (TAA)] by reducing oxidative stress and fibrosis.101 Importantly, these antifibrotic effects These findings are in agreement with other stud- were also validated in precision-cut liver slices ies assessing the use of caspase inhibitors in from human tissue, suggesting potential applica- chronic liver diseases, such as NASH (reviewed bility in clinical practice. Moreover, a recent elsewhere96). Of note, inhibition of the apoptosis abstract reports similar effects of this drug in the signal-regulating kinase 1 is another potential BDL rat model.104 candidate strategy in CLD, as it has shown sig- nificant results in reducing the fibrosis stage of Apocynin is a natural antioxidant of vegetal origin NASH patients.97 which has a specific inhibitory effect on NADPH oxidase and thus has been studied for its antioxi- Despite the exciting results, there is still contro- dant properties.105–107 In this regard, a recent versy on the role of cell-death modulation in study assessed the effects of apocynin in a model CLD. Indeed, a recent study suggests that the use of mild fibrosis.108 Although authors described of caspase inhibitors would not avoid cell death, amelioration of markers of liver damage, oxida- as hepatocytes may still die from necrosis.98 On tive stress, inflammation and fibrosis, these effects the other hand, some vasoprotective drugs modu- were not observed in a previous study using ani- late hepatic fibrosis at least in part due to selective mals with advanced CLD probably due to a pro- apoptosis of HSCs,65 while other studies suggest gressive reduction in NADPH oxidase activity that treatment with low doses of an apoptotic during cirrhosis development.109 This advocates agent (gliotoxin) may achieve similar effects with- for the use of NADPH oxidase inhibitors during out affecting hepatocyte viability.99 progression but not at advanced stages of CLD. Indeed, a study using a new generation of Future studies will clarify the usefulness of cell- NADPH oxidase inhibitor demonstrated anti- death inhibition in a context where the injury is inflammatory and hepatoprotective effects in a not present anymore, such as the regression of preclinical model of NASH without significant CLD after the removal of the hepatic injury. fibrosis,110 altogether encouraging future studies to ascertain which would be the appropriate ther- apeutic window for this strategy in cirrhosis. Antioxidants During liver damage, increased inflammation, In addition to their protective effects against oxida- mitochondrial damage and enzymatic alterations tive stress, antioxidants may also play an important [i.e. and nicotinamide adenine dinucle- role in ameliorating microvascular dysfunction, as otide phosphate (NADPH) oxidases] induce oxi- they prevent the scavenging of NO by the superox- − 100 dative stress. Antioxidants are molecules that ide anion (O2 ). In this direction, back in 2006, compensate this oxidative stress by promoting the Hernández-Guerra and collegues assessed whether conversion of reactive oxygen species (ROS) into acute administration of ascorbic acid would pre- less reactive molecules, either by direct enzymatic vent the increase in HVPG associated with the

6 journals.sagepub.com/home/tag M Vilaseca, S Guixé-Muntet et al. defective ability of the cirrhotic endothelium to hemodynamic amelioration in the partial portal- accommodate the postprandial increase in portal vein ligation model,26 while combination with blood flow. Indeed, patients receiving vitamin C NSBB achieved additive effects.27 displayed lower HVPG after a meal compared with placebo, suggesting improved microvascular func- Epoxyeicosatrienoic acids (EETs) are products of tion.111 Interestingly, a more recent publication the arachidonic acid metabolism with anti-inflam- demonstrated that consumption of dark chocolate matory properties.125 These molecules are further had similar effects on the postprandial increase of metabolized by the soluble epoxide hydrolase HVPG.112 Since then, several studies have (sEH), thus inhibition of this enzyme represents a addressed the role of antioxidant therapy in the good strategy in maintaining or increasing EET improvement of NO bioavailability. In this regard, levels. Indeed, the anti-inflammatory effects of the modulation of the activity of the antioxidant the sEH inhibitor t-TUCB have been recently enzyme superoxide dismutase (SOD) has proven validated in steatotic livers.126 In addition to these promising effects in animal models of CLD.113,114 effects, EETs have also been described to show In a study from 2011, administration of tempol, a vasoactive properties,127 thus suggesting addi- SOD analog, improved the IHVR of cirrhotic rats tional potential in liver vascular diseases. Indeed, in an NO-dependent manner.114 Similarly, a more recent studies reported that t-TUCB treatment recent study assessed the administration of a ameliorates PH in CCl4-cirrhotic rats, altogether recombinant form of human manganese SOD in improving fibrogenesis and endothelial dysfunc- two different animal models of CLD resulting in tion128,129 while additionally ameliorating extrahe- improved liver hemodynamics, as well as reduced patic circulation.130 Although inflammatory oxidative stress and liver fibrosis.115 Resveratrol is markers were also downregulated by this inhibi- an antioxidant found in the skin of grapes that acti- tor, whether the hemodynamic effects were addi- vates the histone deacetylase Sirt1, which regulates tive or directly mediated by inflammation was not several vasoprotective pathways leading to NO assessed. Despite these promising reports, there is overexpression.116 Recent studies have reported some controversy regarding the role of EETs in hepatic antifibrotic effects of resveratrol in models cirrhosis, as another study reported opposite of mild liver injury linked to its antioxidant proper- effects in the splanchnic territory.21 ties117–119 while its administration to rats with severe PH reduced PP and hepatic fibrosis, and In addition to conventional anti-inflammatory ameliorated hepatic microvascular dysfunction.120 pharmacological strategies, engineered nanopar- ticles represent an alternative therapeutic option with targetable delivery. Cerium oxide nanoparti- Strategies targeting inflammation cles have been shown to behave as anti-inflamma- Anti-inflammatory strategies. Rapamycin is an tory agents, with no exception in the liver. Indeed, immunosuppressor that negatively regulates the these nanoparticles prevented macrophage infil- mammalian target of rapamycin (mTOR) com- tration and overexpression of hepatic inflamma- plexes, which play a central role in the regulation tory genes, causing a reduction in oxidative stress of many of the cellular pathways including prolif- and improving PP in rats with mild PH.131 eration, inflammation, apoptosis and autophagy. In the field of CLD, rapamycin has shown the Antidiabetic drugs. As expected from drugs aimed ability to reduce the PP in rats with PH due to its at normalizing glucose levels, antidiabetic treat- intrahepatic121,122 and extrahepatic effects.123,124 ments usually target glucose and lipid transport, as well as metabolism. However, these drugs have The Janus kinase 2 protein (JAK2) is involved in also been reported to have vasoprotective effects the toll-like receptor (TLR) signaling in response associated with NO bioavailability, inflammation to lipopolysaccharide, and upregulates profibrotic and oxidative stress.132–134 In consequence, these and inflammatory genes. As commented above, beneficial effects have been assessed in CLD. One AG490 is a specific inhibitor of JAK2 but it can such pharmacological strategy is use of liraglu- also regulate the TLR signaling pathway. Recently, tide. This glucagon-like peptide 1 (GLP-1) ana- its potent antifibrotic and anti-inflammatory effects log has shown the ability to ameliorate PH and were proven in livers of BDL-cirrhotic rats, liver microvascular function in cirrhotic animals partially normalizing PH. Furthermore, the by reducing HSC activation and the levels of same study reported additional extrahepatic inflammatory markers independently of the

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GLP-1 receptor.135 In this same study, the effects patients compared with the placebo group.149 of liraglutide were validated in different human Bifidobacterium pseudocatenulatum CECT7765 sup- models in vitro, thus shortening the gap between plementation had similar anti-inflammatory fea- the preclinical study and clinical trials. Indeed, tures. On one hand, liver or blood macrophages liraglutide has shown antifibrotic effects also in isolated from cirrhotic animals and patients (respec- NASH patients,136 thus representing a promising tively) switched to an anti-inflammatory M2 phe- drug with high probabilities of success as a treat- notype when treated in vitro with B. ment for PH and CLD. Similarly, the antidiabetic pseudocatenulatum150 while on the other hand, oral drug metformin has shown improvement in liver administration of the bifidobacteria to BDL- hemodynamic and fibrosis, which were accompa- cirrhotic rats improved their hepatic hemodynamic nied by a reduction in inflammation and oxidative parameters, liver damage and markers of inflam- stress.137 Interestingly, the observed hemody- mation in vivo.151 namic effects were complementary to the effects of NSBB. Lastly, fenofibrate, another antidiabetic These findings suggest that not only direct admin- drug with described positive vascular effects, also istration of bacteria but also diets that modify the improved PP in cirrhotic rats in addition to gut microbiota could have therapeutic value in hepatic fibrosis and microvascular function.138 CLD and PH. Indeed, a recent clinical trial reported that cohorts of healthy controls and An additional strategy to these drugs is the use of patients with cirrhosis have different microbiota antibodies that specifically block the interaction populations, that microbiota diversity negatively between metabolic hormones and their ligands. correlates with the degree of cirrhosis, and that Leptin, the satiety hormone, is overexpressed in cirrhotic patients with diets that ensure higher obese people, who may suffer from leptin resist- microbiota diversity had lower risk of hospitaliza- ance. Furthermore, this hormone has been impli- tion.152 Dietary goods associated with microbiota cated in fibrosis and is highly expressed in cirrhotic diversity included fermented milk products, cof- patients, probably due to inflammation.139,140 fee, tea, dark chocolate and vegetables, while con- Interestingly, the use of a competitive antibody sumption of carbonated drinks (including against leptin receptor proved to be effective in caffeinated ones) was predictor of poor diversity. ameliorating PP and IHVR in cirrhotic rats, sug- Interestingly, most of the microbiota-beneficial gesting that leptin is not only a marker in CLD but products are rich in polyphenols (antioxidants), is also a targetable effector.141 thus holding a potential combined effect to that.

Microbiota modulators. Intestinal bacteria are known to modulate splanchnic flow and thus par- Strategies targeting fibrogenesis ticipate in the PH-derived hyperdynamic syn- As stated above, it is well known that chronic liver drome. In addition, during cirrhosis, increased damage in combination with paracrine signaling gut permeability allows translocation of bacteria from the activated endothelium lead to the activa- or their products into the bloodstream, causing tion of HSCs, promoting fibrogenesis.63,153 general and hepatic inflammation.142,143 For this reason, different clinical trials have assessed the Although most of the vasoprotective strategies use of antibiotics (rifaximin,144–146 norfloxacin147) described above ultimately lead to significant ame- as prophylactic intervention against general infec- lioration in fibrosis, there are a few pharmacologi- tions in decompensated cirrhotic patients, which cal approaches that directly target the process of overall improved their outcome. fiber formation/stabilization. One of these is simtu- zumab, a monoclonal antibody against lysyl oxi- However, recent research suggests that the compo- dase homologue 2 (LOXL2). LOXL2 is a protein sition of the microbiota population may also play a that participates in the cross-linking of collagens role in gut permeability and, interestingly, in liver and elastin. This protein is highly expressed in hemodynamics. In this regard, oral administration fibrotic livers (unlike control livers) and its inhibi- of the probiotic VSL#3 (a mix of four Lactobacillus tion with antibodies has shown positive results in species) prevented the increase in the systemic lev- preventing and reducing liver fibrosis in preclinical els of inflammatory cytokines and vasodilators in a models.154 Despite these promising results, simtu- rat model of BDL cirrhosis148 and ameliorated liver zumab proved to be ineffective in a recent phase II function and pro-inflammatory markers in cirrhotic RCT in NASH-cirrhotic patients,155 highlighting

8 journals.sagepub.com/home/tag M Vilaseca, S Guixé-Muntet et al. the controversy that is often found in the transla- chorionic plate-derived MSC transplantation in 166 tion of some therapies from the laboratory to the CCl4-injured rats and the amelioration in fibro- clinic. sis and cirrhosis progression in fibrotic rodents receiving human amniotic membrane-derived mesenchymal167 or epithelial stem cells168 has Cell therapy been reported. In addition, transplantation of The lack of pharmacologic therapeutic options to human amniotic MSCs in TAA-induced cirrhotic ameliorate PH and cirrhosis has prompted the use mice was able to restore the hepatic function and of regenerative therapies or cell-derived interven- improve liver fibrosis;169 importantly, this study tions. In 2006, Terai and colleagues performed suggested the PDSCs transplantation as a better the first clinical trial studying the autologous bone therapeutic option in comparison with adipose marrow cell infusion (ABMi) in decompensated tissue-derived MSCs. cirrhotic patients, showing a decrease in Child- Pugh score as well as better liver function.156 Regarding the effects of stem cells on PH and Latterly, infusion of mesenchymal stem cells hepatic microcirculation, much less is known. (MSCs) from bone marrow or from umbilical Brückner and colleagues suggested that transplan- cord to patients with liver cirrhosis demonstrated tation of hepatocyte-like cells in vitro differentiated amelioration in hepatic fibrosis and function with from rat adipose tissue MSCs into CCl4-cirrhotic increased serum albumin levels and with a good rats led to an amelioration in PH after 3 weeks of safety profile.157 However, the last investigations treatment without changes in liver dysfunction or in the field are focused on less invasive therapies fibrosis.170 However, an ongoing preclinical study using induced pluripotent stem cells (iPS).158 iPS presented as a meeting abstract has shown the ben- have been proposed as a new therapeutic option to eficial effects of transplantation of human amniotic replace damaged hepatocytes by healthy hepato- stem cells (mesenchymal or epithelial) in CCl4- cyte-like cells in CLD.159 Nevertheless, hepato- induced cirrhotic rats with PH, improving HSC cyte-like cells induced by reprogramming methods and LSEC phenotype, inflammation and liver remain immature without the specific hepatocyte function, resulting in an amelioration in PH and characteristics such as detoxification or produc- microvascular dysfunction.171 tion of albumin and urea.160 Along this theme, transplantation of human fetal hepatocytes161 was The promising results of cell therapy in preclini- evaluated in patients with end-stage CLD; cal models of CLD and PH support future and although the small population size of the study ongoing clinical trials using this strategy. was an important limitation for obtaining a robust conclusion, model for end-stage liver disease (MELD) score and portosystemic encephalopathy Lifestyle and dietary interventions episodes were ameliorated in transplanted The basis of most of the abovementioned strate- patients. Even though several clinical trials evalu- gies is to improve deregulated processes in CLD ating stem cell therapies in CLD are still ongo- (vasoconstriction, oxidative stress, etc.) with ing,162–164 none of them specifically performs drugs or other molecules that specifically target HVPG measurements; therefore, these RCTs will these molecular pathways. Alternatively, wider not provide new results about the effect of stem effects on these pathological processes can also be cells in PH. achieved by modification in lifestyle; mainly diet and exercise. On the other hand, preclinical studies have evalu- ated the effectiveness of cell-derived therapy ame- liorating hepatic fibrosis, inflammation and liver Dietary approaches hemodynamics using different sources and The effects of certain diet components (dark potency of stem cells in fibrotic and cirrhotic chocolate, coffee/tea, fermented milk) on gut rodents. Specifically, human placenta-derived microbiota and its implications in CLD have been stem cells (PDSCs) are considered a promising described above.112,152,172 In summary, consump- therapeutic option for their proliferation and dif- tion of these products ensures a proper diversity in ferentiation capacities, as well as their low immu- the gut microbiota while some of them also pos- nogenicity potential.165 In this sense, the sess antioxidant properties, thus ameliorating liver anti-inflammatory and regenerative effects of damage and hemodynamics in CLD. In addition

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to these, the following dietary supplementations exercise therapy on cirrhosis and its complica- may have the potential to ameliorate PH. tions has been extensively studied in patients185,186 as well as in preclinical models.187 intake is extended worldwide, either in the form of coffee, tea or carbonated drinks. Independently of its effects on the gut microbiota,173 Conclusion caffeine consumption (in the form of coffee) has The knowledge about the pathophysiology of been associated with reduced liver fibrosis in precir- CLD has improved dramatically in the last few rhotic patients.174 Although there are no reports of years. Consequently, many preclinical studies its effects in PH in humans, prophylactic but also reported novel treatments with promising therapeutic treatment of BDL-cirrhotic rats with improvements in PH and its complications that, caffeine or caffeinated coffee ameliorated PP, liver importantly, act at different levels of the disease inflammation and fibrosis, while also improving the (either improving the microcirculation or the liv- extrahepatic vasculature.175,176 er’s response to damage). Indeed, some of these proposed treatments are currently being tested in Taurine is an amino-sulfonic acid ubiquitously RCTs and could become new options for the expressed in mammals with many pleiotropic treatment of CLD in the near future. effects177 and is also a component of the so- labeled ‘energy drinks’. It has been reported that However, it seems obvious that the rate of success taurine deficiency leads to CLD in preclinical of the preclinical strategies at the bedside is still far models,178 suggesting a protective role in cirrho- from optimal. In this regard, new studies on the sis. Indeed, oral taurine administration has been mechanisms of the disease (still to be fully under- proven to ameliorate PP due to reduction in stood) will provide new insights on novel targeta- fibrosis and systemic vasodilation in a rat model ble molecular pathways and metabolites. of mild cirrhosis179 while more recently, a clinical Nevertheless, we believe that in addition to the trial in a small cohort of patients with clinically important research on drug development and effi- significant PH (HVPG >12 mmHg) also reported cacy, it is time to start wondering why these thera- reduction in PP.180 Thus, consumption of low pies fail in translation. What are the differences carbonated ‘energy drinks’ (which are rich in tau- between preclinical models and current patients rine, and also contain caffeine) may have a posi- that make these therapies ineffective? Should the tive impact in PH. preclinical models integrate important variables present in humans, like comorbidities, epigenetics, Finally, curcumin is a dietary product most com- aging, etc.? Are therapeutic windows different in mon in Asian countries but extended worldwide humans? If so, could we ‘desensitize’ the human that possesses anti-inflammatory, antiangiogenic liver to these therapeutic windows? In our opinion, and antiproliferative properties.181 Indeed, its this second line of research could widen the cur- administration to BDL-cirrhotic rats decreased rent bottleneck in the translation of pharmacologi- hepatic fibrosis and ameliorated liver endothelial cal strategies and reopen the box of failed phenotype while inducing splanchnic vasocon- therapeutic options in search of second chances. striction, which led to a reduction in PP.182 Acknowledgement MV and SG-M contributed equally to this Lifestyle interventions article. In addition to nutritional strategies, nonsedentary lifestyle exerts beneficial effects on CLD compli- Funding cations such as PH. ‘The SportDiet study’ dem- SG-M has a postdoctoral fellowship from the onstrated that moderate exercise in combination Stiftung für Leberkrankheiten and the Asociación with a controlled diet reduced PP and body Española Para el Estudio del Hígado. AF-I has a weight in overweight patients with compensated Sara Borrell contract from the Instituto de Salud cirrhosis and PH.183 Moreover, another RCT Carlos III (CD15/00050). JG-S has received evaluating the effects of exercise and diet inter- continued funding from the Instituto de Salud vention in patients with cirrhosis and PH showed Carlos III (currently, FIS PI17/00012), the an improvement in HVPG determined before Spanish Ministry of Science, Innovation and and postintervention.184 Moreover, the impact of Universities, Centro de Investigación Biomédica

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