pulmonary hypertension associated with idiopathic...

Review ArticlePulmonary Hypertension Associated with IdiopathicPulmonary Fibrosis Current and Future Perspectives

Scott D Collum1 Javier Amione-Guerra23 Ana S Cruz-Solbes23

Amara DiFrancesco1 Adriana M Hernandez1 Ankit Hanmandlu1 Keith Youker23

Ashrith Guha23 and Harry Karmouty-Quintana1

1Department of Biochemistry and Molecular Biology University of Texas Medical School at Houston Houston TX 77030 USA2Methodist DeBakey Heart and Vascular Center The Methodist Hospital Houston TX 77030 USA3Methodist JC Walter Jr Transplant Center The Methodist Hospital Houston TX 77030 USA

Correspondence should be addressed to Harry Karmouty-Quintana harrykarmoutyuthtmcedu

Received 18 November 2016 Accepted 19 January 2017 Published 13 February 2017

Academic Editor Elie El Agha

Copyright copy 2017 Scott D Collum et alThis is an open access article distributed under theCreative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Pulmonary hypertension (PH) is commonly present in patients with chronic lung diseases such as Chronic Obstructive PulmonaryDisease (COPD) or Idiopathic Pulmonary Fibrosis (IPF) where it is classified as Group III PH by the World Health Organization(WHO) PH has been identified to be present in as much as 40 of patients with COPD or IPF and it is considered as one of theprincipal predictors of mortality in patients with COPD or IPF However despite the prevalence and fatal consequences of PH inthe setting of chronic lung diseases there are limited therapies available for patients with Group III PH with lung transplantationremaining as the most viable option This highlights our need to enhance our understanding of the molecular mechanisms thatlead to the development of Group III PH In this review we have chosen to focus on the current understating of PH in IPF wewill revisit the main mediators that have been shown to play a role in the development of the disease We will also discuss theexperimental models available to study PH associated with lung fibrosis and address the role of the right ventricle in IPF Finallywe will summarize the current available treatment options for Group III PH outside of lung transplantation

1 Prevalence of PH in IPF

Chronic lung diseases including Chronic Obstructive Pul-monary Disease (COPD) and Idiopathic Pulmonary Fibrosis(IPF) represent the third leading cause of death in the US[1] Despite reductions in mortality in cancer and cardiovas-cular disease mortality rates for chronic lung diseases haveremained unaffected over the last decade [2] An importantcomplication of chronic lung diseases that is strongly linkedto the mortality is the presence of pulmonary hypertension(PH) [3 4]

PH is defined by a mean pulmonary arterial pressure(mPAP) of ge25mmHg and a pulmonary artery wedge pres-sure (PAWP) of le15mmHg and elevated pulmonary vascularresistance (PVR) gt 3 wood units (WU) [5] The patho-logic process in PH is characterized by extensive vascular

remodeling including enhanced proliferation of pulmonaryartery smoothmuscle cells (PASMC)This leads to narrowingand obliteration of the vessel lumen resulting in increasedvascular tone Similarly due to the increased pressure load inthe pulmonary vasculature the right ventricle (RV) tries tocompensate resulting in remodeling hypertrophy dysfunc-tion and eventually right-sided heart failure and death [6ndash8]PH is subdivided into 5 comprehensive subsets of PH GroupIndashGroup V PH Group I PH includes Pulmonary ArterialHypertension (PAH) of idiopathic or heritable origin wherethe lung vasculature is affected but not the lung parenchymaGroup II PH is associated with left heart disease GroupIII PH is associated with chronic lung diseases affecting thelung parenchyma and hypoxemia Group IV PH is chronicthromboembolic pulmonary hypertension (CTEPH) finallyGroup V PH includes PH from unclear and multifactorial

HindawiCanadian Respiratory JournalVolume 2017 Article ID 1430350 12 pageshttpsdoiorg10115520171430350

2 Canadian Respiratory Journal

mechanisms [9] This review will focus on Group III PHGroup III PH is associated with chronic lung diseases such asChronicObstructive PulmonaryDisease (COPD) and IPF [34] In this review article we will focus on PH associated withIPF IPF is a parenchymal disease of the lung manifested bychronic cough exertional dyspnea and often leading to acuterespiratory failure [10] The prevalence of IPF is estimated tobe in the range of 14ndash43 per 100000 persons with the rangedependent upon the criteria applied [11 12] It important tomention that IPF is a fatal disease that affects millions ofpeople worldwide yet the funding for chronic respiratorydiseases desperately lags behind its societal burden [2]

The prevalence of PH amongst IPF patients is depen-dent upon the severity of IPF In the early stages or wheninitially diagnosed PH affects lt 10 of IPF patients [4 13]However as IPF advances the incidence of PH increasesmarkedly One study of patients awaiting lung transplantand thus in an advanced stage of IPF reported an incidenceof 32 [14] Subsequent studies have largely supported orincreased this percentage to be between 32 and 50 [1215] However it is important to mention that the symptomsfor PH and IPF are very similar (shortness of breath andexertional dyspnea) and as such it is conceivable for PHto be underdiagnosed in patients with IPF Furthermoretypically the mPAP of patients with IPF is significantly lowerthan patients with Group I PH [16ndash19] Despite this thepresence of PH in IPF is strongly linked to the increasedmortality [12 14] and efforts aimed at treating PH in IPF mayprovide much needed therapies to diminish the mortalityof IPF

2 Epigenetics of PH Associated with IPF

The role of epigenetics in the development of IPF is anintense area of research [20ndash23] Similarly there is a vastliterature that has looked at epigenetic changes in Group IPH namely PAH [24ndash26] These studies have focused onIPF or PAH with little or no research into Group III PHand in particular to PH associated with IPF Thus there is astrong need for enhanced research in this niche as increasedknowledge regarding epigenetic changes in patients with IPFand PH is necessary not only to develop new therapies butalso to enable personalized care for patients with IPF afflictedwith PH Important lessons that can be applied to IPF andPH are how microRNAs (miRNAs) through transcriptionaland translational regulation have the capacity to influencetarget genes in the development of PAH [25] From the fieldof IPF DNA methylation by DNA methyltransferases hasbeen shown to impact myofibroblast differentiation throughregulation of 120572SMA expression in developmental IPF [27]Importantly environmental factors such as cigarette smokehave been implicated inmanipulating themethylome and themethylation patterns of specific promoters in genes that areinvolved in IPF [28 29] Although these mechanisms havenot explicitly been identified in PH associated with IPF it isconceivable that similar processes may be unique in patientsin IPF and PH that can provide insight into the pathogenesisof PH in the setting of IPF in addition to providing uniquetherapeutic avenues for Group III PH

3 Mediators of PH in IPF

The general consensus regarding the pathogenesis of PH inIPFwas that the development of PHwas a complication of theunrelenting fibroproliferative injury in IPF and that treatingthe underlying lung fibrosis would also treat PH Althoughmany animal models have indeed shown that treating lungfibrosis results in attenuation of hallmarks of PH currenttherapies for IPF are unable to reverse the fibroproliferativedamage in IPF This observation and adverse independentimpact of PH in these patients highlight the need to developtherapies that directly impact PH in IPF In order to achievethis aim we must understand the pathogenesis of PH in IPFAlthough chronic hypoxia has been deemed integral in thedevelopment of Group III PH as a whole the downstreammechanisms that lead to PH in IPF are not fully under-stood Many diverse mediators including endothelin 1 (ET-1) transforming growth factor- (TGF-)120573 prostaglandin (PG)E2 bone morphogenetic protein receptor type 2 (BMPR2)adenosine signaling hyaluronan and IL-6 have been shownto play important roles in both the progression of fibrosisand the development of PH However how these mediatorsmay contribute independently to the pathogenesis of PH inthe context of lung fibrosis is not fully understood Figure 1summarizes some of the key mediators in PH associated withIPF

ET-1 is a strong vasoconstrictor that has been implicatedin both Group I PH and pulmonary fibrosis ET-1 was foundto be produced in the vascular endothelium of patients withboth PH and lung fibrosis but not in normal lung or inthose patients solely with fibrosis [30] This increase in ET-1 levels was also seen in the plasma of patients with GroupI PH and was correlated with increased mPAP [31] ET-1expression is also elevated in the airway epitheliumof patientswith IPF [32] ET-1 acts in several pathways canonically itbinds two ET receptors on vascular smooth muscle cellsactivating calcium signaling and vasoconstriction ET-1 canalso stimulate proliferation as well as growth factor andextracellular matrix production [33ndash36] The endothelinreceptor antagonists bosentan and macitentan have beenshown to reduce both the fibroproliferative injury and PH inthe rat bleomycin model of pulmonary fibrosis with PH [37]This also correlated with an increased exercise capacity [38]

A potential activator of ET-1 the RhoA pathway anddownstream effectors Rho-kinases I and II (ROCKs) havebeen associatedwith the development of PH in several animalmodels including bleomycin hypoxia and monocrotaline[39ndash43] In fact treatment of the mouse bleomycin model ofpulmonary fibrosis and PH with fasudil a selective ROCKinhibitor not only reduced the PH hallmarks of vascularremodeling and right ventricle systolic pressure but alsoreduced lung fibrosis [40] ROCKs are involved in manypathways involved in the development of PH and fibrosisincluding proliferation survival migration and contraction[44] Interestingly inhibition of the RhoAROCK pathway iseffective in those animal models that are resistant to inhalednitric oxide (NO) treatment a phenomenon that is commonin patients with PH associated with IPF that do not respondto NO treatment [45] This pathway has also been shown to

Canadian Respiratory Journal 3

ET1

ETRs

ERAS

RhoAROCK1

ECM

Endothelial cell

Smooth muscle cell

Macrophage

Hyaluronan

Collagen

BMPR2

ADORA2B

SODHIFVHL

PGE2proliferation

NO

TGF120573

Remodeling

NOS

Figure 1 Cellular processes and mediators involved in the pathogenesis of PH associated with lung fibrosis

play a role in Group I PH where ROCK inhibitors appear tohave therapeutic value [46 47] PDE5A inhibitors also canattenuate fibrosis associated PH both in patients and in themurine bleomycin model this attenuation proceeds throughthe reduction of ROS and the RhoAROCK pathway [48 49]

TGF-120573 is one of the most potent profibrotic cytokinesduring disease states such as IPF or PH TGF-120573 signalingcan induce proliferation of vascular smooth muscle cellsand increased production of extracellular matrix (ECM)components [50 51] TGF-120573 signaling proceeds throughtwo pathways canonically through Smad7 to activate theSmad23 and Smad4 binding to activate transcription and aSmad independent pathway that proceeds through the p38MAPK and JNK [52 53] Several processes can cause abnor-mal TGF-120573 signaling 5-lipoxygenase can shunt precursors ofPGE2 an antifibrogenic factor causing reduced expressionwhile cellular damage to epithelial cells can also reduce theproduction of PGE2 [54]This reduction of PGE2 can lead toincreased TGF-120573 production [55] A second pathway that canresult in TGF-120573 signaling is the loss of signaling through thebone morphogenetic protein receptor 2 (BMPR2) BMPR2 isa member of the TGF-120573 superfamily and has a major rolein suppressing TGF-120573 signaling in normal tissues BMPR2signaling activates Smad158 activationwhich directly acts toinhibit Smad23 signaling thus reducing the downstreameffects of TGF-120573 activation [56] BMPR2 levels are inverselycorrelated with mPAP in patients with IPF and reduced

BMPR2 expression can cause fibroproliferation [57] Expres-sion of mutated BMPR2 in an experimental model of lungfibrosis and PH shows increased PH compared to wild typemice [58] These studies show that reduced BMPR2 maycontribute to both fibrosis and PH through excessive TGF-120573signaling

Another role that TGF-120573 may play in Group III PH isthrough promoting endothelial to mesenchymal transition(EndMT) [59 60] EndMT includes a change in cell shapeloss of contact inhibition and an increase in motility relatedto increased ECM production This transition in addition toendothelial cell injury can contribute to fibrosis and couldalso explain the reduced effectiveness of endothelin receptorantagonist a group of oral vasodilators including macitentanand bosentan that show little effectiveness in Group III PH[61]

Interestingly expression of mutant BMPR2 in miceresulted in increased hypoxia inducible factor (HIF)1A sta-bilization allowing for activation of HIF inducible transcripts[58] The HIF pathway has been shown to play an importantrole in the progression of several chronic lung diseasesincluding IPF In the bleomycin model of lung fibrosistransgenic mice with HIF deleted in the vascular endothelialcells were protected from PH while still developing fibrosisAberrant HIF signaling can promote PASMC and perme-ability contributing to PH progression [62] HIF signaling innormoxic conditions is suppressed by the tumor suppressor


von Hippel-Lindau (VHL) [63] Patients carrying a VHLmutation have many symptoms including cancerous andnoncancerous tumors but also PH In transgenic mice with amutatedVHL protein hallmarks of PH and lung fibrosis havebeen documented This suggest a mechanistic link betweenHIF signaling and PH in IPF [64]

While hypoxia plays a role in the development of IPFand PH reactive oxygen species can also contribute to thedevelopment of these diseases Superoxide dismutase (SOD)is an enzyme that catalyzes the transition of a superoxideanion to oxygen or hydrogen peroxide relieving the oxidativepotential of this species It has been shown in the TGF-120573overexpression rat model of pulmonary fibrosis that overex-pression of extracellular SOD (EC-SOD) is protective againstthe fibrosis caused by the excess TGF-120573 signaling whichcan be activated by ROS [65] Although strictly not in amodel of lung fibrosis and PH the depletion of EC-SODleads to increased vascular remodeling in bleomycin-inducedbronchopulmonary dysplasia (BPD) where features of PHare evident [66] Also the specific KO of EC-SOD in PASMCshows increased PH in the hypoxia model mouse model ofPH [67] Taken together these findings support the role ofEC-SOD in both IPF and PH

Similar to the role of EC-SOD in the rat bleomycinmodelof BPD and PH inhibition of tissue necrosis factor (TNF-120572)signaling by both pharmaceutical intervention and exposureto 7 CO

2caused reduced PH symptoms and reduced

lung injury indicating a role of TNF-120572 signaling in diseasedevelopment [68] Additionally thiol-redox alterations havebeen shown to be induced during in vitro exposure of lungvascular endothelial cells to bleomycin These changes areaccompanied by morphological and physiological changesalong with increased ROS associated with vascular remodel-ing during pulmonary fibrosis that are abrogated by treatmentwith thiol-redox protective reagents [69] Linking TGF-120573and ET-1 signaling and these oxidative stress pathways isthe nitric oxide synthase pathway Nitric oxide synthase(NOS) produces NO which is a vasodilator inhibits smoothmuscle proliferation protects against ROS and is reduced inPH Tetrahydrobiopterin (BH4) is a cofactor of NOS and isfound to be reduced in the pulmonary arteries of patientswith IPF and rescue of BH4 in the bleomycin model of ratpulmonary fibrosis and PH attenuated vascular remodeling[70] Additionally in vitro experiments in human pulmonaryartery endothelial cells showed that increased BH4 inhibitedendothelial to mesenchymal transition mirroring the role inthe rat lung Inhibition of arginase an enzyme that producesa precursor of collagen and limits nitric oxide productioncan also reduce fibrosis and PH in the neonatal rat bleomycinmodel [71]

HIF-1A has been identified as a transcriptional regu-lator of the A2B Adenosine Receptor (ADORA2B) [72]ADORA2B is activated by adenosine an extracellular signal-ing molecule that is produced by cell injury and promotestissue repair but can promote disease progression in chronicdisease states [73] ADORA2B has been shown to play anactive role in lung fibrosis [74 75] In the context of PHactivation of this receptor has been shown to modulate thedevelopment of PH by mediating the release of hyaluronan

[76ndash78] from the PASMC and macrophages Hyaluronan isa component of the lung extracellular matrix that has beenimplicated in the development of PH [79ndash81] Activation ofADORA2B also results in increased IL-6 which is a strongmediator of Group I PH both by reducing BMPR2 andvascular endothelial growth factor receptor II (VEGFR2)[74 82 83] In fact ADORA2B receptor levels in patientswith IPF directly correlated with mPAP indicating a role inthe progression of PH in IPF patients [84] In the bleomycinmodel of fibrosis and PH pharmacological blockage of theADORA2B and genetic deletion of the receptor both returnspulmonary pressures to normal and reduces fibrosis Thisreduction in disease state is also accompanied by reducedlevels of IL-6 and ET-1 [76 78]

An important driver of fibrosis is aberrant inflammationdriven by IL-6 [85] This role of IL-6 signaling is seen inthe bleomycin model of pulmonary fibrosis This pathwayis also upregulated in human PH patients In fact there isa direct correlation between IL-6 and increased pulmonarypressures pulmonary artery remodeling and RV remodeling[83 86]These parallel roles of IL-6 in fibrosis and PH suggesta common role of increased pulmonary inflammation in thefibrosis and PH in Group III PH

Together these mechanisms of development of PH inIPF show that this disease progresses through complicatedsignaling pathways that often interact and overlap Whileeach mechanism offers unique potential for therapeuticintervention this large web can complicate the study ofdisease progression in patients

4 The Right Ventricle (RV) in IPF

An essential consequence of the development of PH is itsadverse impact on the right ventricle (RV)The right ventricle(RV) is a low-pressure chamber that pumps blood to a low-pressure pulmonary circuit It pumps the same stroke volumeas its counterpart the left ventricle (LV) with approximately25 of the stroke work because of the low resistance andpressure of the pulmonary vasculature [94] According to thelaw of Laplace pressure and radius have a direct relationshipwith afterload [95] Therefore the initial adaptive responseto pressure overload is RV hypertrophy [96ndash98] Afterwardsthe RV dilates in response to this pressure despite reducedfractional shortening [94] Eventually it becomes unable tocompensate and right ventricular failure occurs [99] while LVfunction remains preserved [100]

The term ldquocor pulmonalerdquo refers to an RV alteration(structure andor function) resulting from lung disease aslong as it is not secondary to LV dysfunction [101 102] Inchronic cor pulmonale RVH is a direct result of chronichypoxic pulmonary vasoconstriction and PH leading toincreased RV work and stress [103] Additionally in IPFfibrosis and loss of lung parenchyma also contribute to PHand RV hypertrophy by obliterating pulmonary vascularbeds [104 105] and by limiting cardiac filling secondary torelative stiffness of intrathoracic structures [106 107] PH isa severe complication of IPF that significantly contributes tomorbidity and mortality [108] and it has been hypothesizedthat it is actually the RV failure component that drives the


mortality in these patients [109] This highlights the need towiden our understanding of the pathogenesis of RV failure inIPF Little is known about the exact incidence and prevalenceof cor pulmonale in IPF because right-heart catheterization(RHC) the gold standard for a definitive diagnosis [110]is an invasive procedure and these patients are consideredhigh risk [96] As such most of the data regarding RHChemodynamic information in IPF was obtained at the time oflung-transplant evaluations [111] and results may be skewedby selection bias since lung transplant is reserved for end-stage disease only

Efforts have been made to identify RV dysfunction usingnoninvasive imaging methods in patients with IPF Echocar-diography on these patients is technically challenging becausesuboptimal images are frequently encountered [96 112] andconventional techniques of RV longitudinal function suchas tricuspid annular plane systolic excursion (TAPSE) aparameter of global RV function and tissue Doppler systolicpeak velocity are prone to error and may not adequatelyreflect RV dysfunction [113] However RV LV ratio [111] maybe useful in predicting mortality in these patients and RVglobal longitudinal strain may directly correlate to FVCand RHC-obtained mPAP as well as independently predict-ing functional capacity during 6-minute walking distance(6MWD) tests [114] In the normal population MRI is thebest method for measuring RV dimensions and functionhowever data is still inconclusive regarding use of MRI inpatients with IPF RHC is currently the definitive diagnostictool for RV dysfunction in IPF [110]

Clinically cor pulmonale is a challenging diagnosis sincethe signs and symptoms are insensitive and nonspecific [96115] and distinguishing chronic lung disease from associatedPH and RV failure can be difficult Dyspnea peripheraledema elevated jugular venous pressure and hepatomegalymay arise from new RV failure or progression of theunderlying lung disease or a combination of both [105 116]In addition physical exam may be of limited value in thesepatients since classical signs of RV failure (precordial heaveaccentuated pulmonic component of S2murmur of tricuspidregurgitation and right-sided gallop) may be masked by IPFpathophysiology [105]

To complement the clinical diagnosis of cor pulmonale inIPF patients EKG findings (rightward P-wave axis deviationan S1S2S3pattern S

1Q3pattern and right bundle branch

block [117]) have a high specificity but very low sensitivity[96 118] On the other hand 6MWD correlated better withRV failure per echochardiography [119] Additionally brainnatriuretic peptide (BNP) seems to be a promising markerfor PH and RV failure in IPF since elevated levels in serumare both a marker for PH presence in this cohort [120] and anindependent predictor of prognosis [121 122]

Mortality related to cor pulmonale is also difficult toassess chronic lung disease is responsible for 100000 deathsper year in the USA [123] however the role of PH and Right-Heart Failure is not specified [96] Cor pulmonale is thesecond cause of death of pulmonary hypertension worldwide[115] however most of it is driven by COPD Survival in PHindependent of the cause is directly related to the capacity

of the RV to adapt to the elevated pulmonary vascular load[124]

In addition to the cardiac consequences of increased pul-monary pressures treatment for IPF may negatively impactcardiac function Nintedanib caused cardiac events in 97ndash103 of patients 03ndash06 of them are fatal [125] and athree-drug combination (prednisone azathioprine and N-acetylcysteine) also showed cardiac adverse events in 39of patients [126] however pirfenidone demonstrated a safecardiac profile [127ndash129] Details of cardiac events were notspecified Taken together these observations highlight ourlimited understating of the pathogenic RV in IPF and howcurrent therapies for IPF may impact the heart providingfurther rationale to invest in research aimed at uncoveringunique mechanisms of RV failure in IPF

5 Experimental Models of PH and CLD

An important difficulty in studying the development of PHin IPF is the lack of animal models that exhibit both lungfibrosis and PH Although there are several experimentalmodels of lung fibrosis [87 88]m not all of them are knownto exhibit markers of PH such as increased right ventriclesystolic pressure (RVSP) vascular remodeling or elevatedFulton indices as a marker of right ventricle hypertrophy(RVH) In this reviewwewill summarize themodels that havebeen shown to present with features of both fibrosis and PHThe most common model of lung fibrosis uses the exposureof mice to the anticancer agent bleomycin (BLM) Typicallyin this model BLM is intratracheally instilled leading to thedevelopment of fibrosis by day 14 [88] Alternatively in thismodel BLM is chronically administered intraperitoneally for4 weeks resulting in the development of fibrosis [74 89]In both models researchers have identified hallmarks of PHincluding elevated RVSP RVH and vascular remodeling[40 58 76 90] Another model of lung fibrosis and PHis the VHL200W mice which are remarkable in that themutation of the von Hippel-Lindau (VHL) tumor suppressorprotein at codon 200 (R200W) leads to PH and lung fibrosisin mice [64] However these mice have been seldom usedto study PH associated with lung fibrosis Another geneticmouse model of Group III PH is the adenosine deaminase-deficient (Adaminusminus)miceThesemice are unable to break downadenosine and as a result they develop features of chroniclung disease such as lung fibrosis and airspace enlargement[91] with hallmarks of PH [77] Another model of fibrosis isfus-related antigen 2 (Fra-2) transgenicmicemodel [92] Fra-2 is a phosphorylated protein which results in lung fibrosisand lung inflammation The Fra-2 transgenic mice do notsurvive after 17 weeks of age due to respiratory distressThesemice present with fibrotic lesions in addition tomarkedvascular remodeling akin to those observed in other modelsof lung fibrosis and PH Unfortunately RVSP levels or RVHwere not performed in these mice thus despite markedvascular remodeling whether increased pressures are presentis not known An additional model is the transforminggrowth factor Beta I (TGF-1205731) expressing a kinase-deficienthuman type II TGF120573 receptor (T120573RIIdeltaK) is selectivelyexpressed in fibroblast in a transgenic mice model used to


study lung fibrosis [93] Remarkably exposure to these miceto chronic hypoxia results in vascular remodeling increasedRVSP RVH and fibrotic injury positioning this model asa solid alternative to the bleomycin exposure models Insummary there are limitedmodels of PHassociatedwith lungfibrosis which hampers our ability to identify mechanismsthat are unique to the development of PH in lung fibrosis

6 Present and Future Therapies for PH in IPF

Currently there is no specific therapy for PH associated withlung diseases Treatment of the underlying disease should beoptimized to reduce disease progression Current ESCERSguidelines recommend that hypoxemic patients with lungdisease and pulmonary hypertension should be started onlong-term O

2therapy [130]

Several studies have analyzed the role of existing GroupI PH therapies and their impact on patients with PH inthe setting of IPF In an earlier study with a small sam-ple size and different causes of pulmonary fibrosis it wasshown that inhaled prostacyclin caused a marked reductionof pulmonary pressures without affecting arterial pressureand lung diffusion [131] Both intravenous prostaglandinsand calcium channel blockers caused a significant drop ofsystemic pressures

The use of sildenafil was also compared in a randomizedcontrolled open label trial of 16 patients with PH associatedwith IPF that received inhaled NO (10ndash20 ppm) and wererandomized to receive either intravenous epoprostenol ororal sildenafil NO reduced PVR by 22 epoprostenol by37 and sildenafil by 33 However epoprostenol increasedVQmismatch and decreased arterial oxygenation while NOand sildenafil maintained VQ matching [48] In a largerrandomized controlled trial STEP-IPF trial 180 patientsreceived either sildenafil or placebo for 12 weeks on a secondperiod of 12 weeks all the placebo patients were crossed overto the sildenafil arm There was no difference in the primaryoutcome (defined as an increase in 6MWDbygt20) betweenthe two groups (10 of patients in the sildenafil group versus7 in the placebo119901 = 039) therewas however improvementin the shortness of breath and quality of life questionnaires aswell as small differences in arterial oxygenation and DLCOAs in the previous study there were no significant side effects[132]

Currently there are 3 endothelin receptor antagonists(ERAs) approved for the treatment of Group I PH (bosentanambrisentan and macitentan) The role of ERAs in patientswith PH associated with IPF has been studied in severalrandomized control trials all of which have shown no benefitfrom the use of these agents in patients with PH and IPFIn the BUILD-1 (Bosentan Use in Interstitial Lung Disease)trial the safety and efficacy of the nonselective endothelinantagonist bosentan were studied In this double-blindmulticenter RCT of 158 patients bosentan had no superioritywhen compared to placebo to meet either the primary(6MWD at 1 year) or the secondary endpoint (time to deathor disease progression) of the study [133]The ARTEMIS-IPFtrial which included IPF patients with and without PHtreated with the selective endothelin agonist ambrisentan

was terminated early after an interim analysis of 492 patientsdemonstrated an increase in the disease progression in thetreatment arm compared to placebo Furthermore patientstreated with ambrisentan were more likely to develop res-piratory hospitalizations when the analysis was limited tothose patients with IPF and concomitant PH results weresimilar [13] Similarly the BPHIT study was a 16-weekmulticenter double-blind RCT of patients diagnosed withfibrotic idiopathic pneumonia (including IPF andnonspecificinterstitial pneumonia) and pulmonary hypertension treatedwith either bosentan or placebo In this study the primaryendpoint was a fall of 20 in the PVRi as in previous studiesthere was no difference between both groups (asymp28 for botharms) even when IPF-PH patients were analyzed alone [61]

Riociguat a stimulator of the soluble guanylate cyclaseis a novel treatment for both Group I PH [134] and GroupIV PH [135] (Patent-1 and CHEST-1 trials) Riociguat has alsobeen studied in patients with fibrotic lung disease and PH Ina pilot trial byHoeper et al riociguat improved PVR CO and6MWD[136] However a Phase II studywas terminated by itsData Monitoring Committee due to an apparent increased inthe risk for death and other serious adverse events (PH-IIPNCT02138825)

One of the most recently approved medications for treat-ment of IPF in the United States is nintedanib a nonselectiveinhibitor of tyrosine kinases the INPULSIS-1 and INPULSIS-2 trials showed an improvement in FVC however the impacton pulmonary pressures was not studied [137]

Another agent pirfenidone an antifibrotic agent thatinhibits TGF-b mediated collagen synthesis has also beenapproved by the FDA for treatment of IPF after the ASCENDtrial demonstrated a reduced disease progressionHowever aswith nintedanib the impact of pulmonary pressures was notaddressed [127]

Dysregulation of multiple pathways leads to the devel-opment of IPF and PH Targeting multiple pathways withcombination therapy is an attractive idea for the treatmentof this condition However very few studies have been doneto analyze the safety and efficacy of this treatment strategyin this specific patient population The safety and pharma-cokinetics of nintedanib and pirfenidone combination werestudied in 50 patients there were no serious side effects andthere was a trend towards a lower exposure of nintedanibwhen added to pirfenidone however if the patients had ornot pulmonary hypertension was not specified in the study[138] In a small case control study of patients with advancedIPF and PH receiving pirfenidone only or pirfenidone plussildenafil there was a trend towards a preserved DLCO andno difference in side effects [139] A Phase IIb randomizedcontrolled trial to evaluate the efficacy and safety of pir-fenidone and sildenafil combination is currently recruitingpatients (NCT02951429) Results from this trial could providefuture directions regarding combination therapy in this verysick patient population

Overall there are no effective PH-specific treatmentsin patients with IPF-PH And as some large trials havedemonstrated pulmonary vasodilators have the potential riskof increasing the VQ mismatch which could result in aworsening hypoxemia and disease progression A different


approach to the treatment of IPF-PH should be consideredin future research studies

The role of stem cells has not been studied in patients withPH associated with IPF However there have been preclinicalstudies analyzing the role of stemmesenchymal cell deliveryin experimental models of lung fibrosis [140ndash143] or PH[144ndash146] but not both Encouragingly delivery of stem cellshas been shown to appear to be safe in patients with eitherIPF [147] or PAH [148] If regenerative therapies are ableto restore endothelial function and reduce the inflammatoryand profibrotic process this modality of treatment could be apotential strategy in patients with PH associated with IPF

In conclusion research in PH associated with IPF can beconsidered an emerging field where further investigation isdesperately required in order to develop novel therapies thatare able to effectively target PH in IPF Presently therapies forPH in IPF are far from ideal and the fact thatmany treatmentsaimed at Group I PH show disappointing results in clinicaltrials for patients with IPF and PH highlights differentialmechanisms of disease that must be uncovered Intrinsicallylinked to PH is RV failure in IPF that is also strongly linked tomortality yet it also remains underinvestigated with limitedtreatment options PH in IPF has often been regarded asa complication of IPF and due to its lower mPAP valuescompared to other presentations of PH it has not receivedmuch attention and the assumption was that diminishingthe extent of fibroproliferative injury would also attenuatePH hallmarks However our inability to effectively reversefibrotic deposition in patients in IPF in addition to the factthat PH and RV failure are strongly linked to mortalityshould stimulate therapies that target RV failure and PHtherapeutically and perhaps prophylactically too

Competing Interests

The authors declare that they have no competing interests

Acknowledgments

This study was funded by 2013 Intelligence Award AmericanHeart Association Scientist Development Grant 14SDG1855003 and 2015UTHealth PulmonaryCenter of ExcellenceDiscovery Award (to Harry Karmouty-Quintana)

References

[1] CDC National Center for Health StatisticsmdashLeading Causes ofDeath September 2016 httpwwwcdcgovnchsfastatslead-ing-causes-of-deathhtm

[2] The Lancet Respiratory Medicine ldquoLung disease left out in thecoldrdquoThe Lancet Respiratory Medicine vol 4 no 7 p 527 2016

[3] A Chaouat R Naeije and EWeitzenblum ldquoPulmonary hyper-tension in COPDrdquo European Respiratory Journal vol 32 no 5pp 1371ndash1385 2008

[4] J R Klinger ldquoGroup III pulmonary hypertension pulmonaryhypertension associated with lung disease epidemiologypathophysiology and treatmentsrdquo Cardiology Clinics vol 34no 3 pp 413ndash433 2016

[5] M M Hoeper H J Bogaard R Condliffe et al ldquoDefinitionsand diagnosis of pulmonary hypertensionrdquo Journal of theAmerican College of Cardiology vol 62 no 25 pp D42ndashD502013

[6] S Hansdottir D J Groskreutz and B K Gehlbach ldquoWHOrsquos insecond a practical review of world health organization group2 pulmonary hypertensionrdquo Chest vol 144 no 2 pp 638ndash6502013

[7] H D Poor R Girgis and S M Studer ldquoWorld HealthOrganization Group III pulmonary hypertensionrdquo Progress inCardiovascular Diseases vol 55 no 2 pp 119ndash127 2012

[8] C E Ventetuolo and J R Klinger ldquoWHO Group 1 pulmonaryarterial hypertension current and investigative therapiesrdquoProgress in Cardiovascular Diseases vol 55 no 2 pp 89ndash1032012

[9] G Simonneau I M Robbins M Beghetti et al ldquoUpdatedclinical classification of pulmonary hypertensionrdquo Journal of theAmerican College of Cardiology vol 54 no 1 pp S43ndashS54 2009

[10] A Agrawal I Verma V Shah A Agarwal and R R SikachildquoCardiac manifestations of idiopathic pulmonary fibrosisrdquoIntractable amp Rare Diseases Research vol 5 no 2 pp 70ndash752016

[11] G Raghu D Weycker J Edelsberg W Z Bradford andG Oster ldquoIncidence and prevalence of idiopathic pulmonaryfibrosisrdquo American Journal of Respiratory and Critical CareMedicine vol 174 no 7 pp 810ndash816 2006

[12] N M Patel D J Lederer A C Borczuk and S M KawutldquoPulmonary hypertension in idiopathic pulmonary fibrosisrdquoChest vol 132 no 3 pp 998ndash1006 2007

[13] G Raghu J Behr K K Brown et al ldquoTreatment of idiopathicpulmonary fibrosis with ambrisentan A parallel RandomizedTrialrdquo Annals of Internal Medicine vol 158 no 9 pp 641ndash6492013

[14] C J Lettieri S D Nathan S D Barnett S Ahmad and A FShorr ldquoPrevalence and outcomes of pulmonary arterial hyper-tension in advanced idiopathic pulmonary fibrosisrdquo Chest vol129 no 3 pp 746ndash752 2006

[15] A F Shorr J L Wainright C S Cors C J Lettieri and S DNathan ldquoPulmonary hypertension in patients with pulmonaryfibrosis awaiting lung transplantrdquo European Respiratory Journalvol 30 no 4 pp 715ndash721 2007

[16] R A Dweik S Rounds S C Erzurum et al ldquoAn officialAmericanThoracic Society statement pulmonary hypertensionphenotypesrdquo American Journal of Respiratory and Critical CareMedicine vol 189 no 3 pp 345ndash355 2014

[17] RDMachado L Southgate C A Eichstaedt et al ldquoPulmonaryarterial hypertension a current perspective on established andemerging molecular genetic defectsrdquoHuman Mutation vol 36no 12 pp 1113ndash1127 2015

[18] K B Martin J R Klinger and S I S Rounds ldquoPulmonaryarterial hypertension new insights and new hoperdquo Respirologyvol 11 no 1 pp 6ndash17 2006

[19] A OrsquoBrien and S Rounds ldquoPulmonary hypertension updaterdquoComprehensive Therapy vol 26 no 3 pp 190ndash196 2000

[20] B A Helling and I V Yang ldquoEpigenetics in lung fibrosisfrom pathobiology to treatment perspectiverdquo Current Opinionin Pulmonary Medicine vol 21 no 5 pp 454ndash462 2015

[21] A Tzouvelekis and N Kaminski ldquoEpigenetics in idiopathicpulmonary fibrosisrdquo Biochemistry and Cell Biology vol 93 no2 pp 159ndash170 2015


[22] I V Yang ldquoEpigenomics of idiopathic pulmonary fibrosisrdquoEpigenomics vol 4 no 2 pp 195ndash203 2012

[23] I V Yang and D A Schwartz ldquoEpigenetics of idiopathicpulmonary fibrosisrdquo Translational Research vol 165 no 1 pp48ndash60 2015

[24] J H Huston and J J Ryan ldquoThe emerging role of epigeneticsin pulmonary arterial hypertension an important avenue forclinical trials (2015 Grover Conference Series)rdquo PulmonaryCirculation vol 6 no 3 pp 274ndash284 2016

[25] J Kim A Lee J Choi et al ldquoEpigenetic modulation as atherapeutic approach for pulmonary arterial hypertensionrdquoExperimental amp Molecular Medicine vol 47 no 7 article noe175 2015

[26] X-F Xu F Cheng and L-Z Du ldquoEpigenetic regulation ofpulmonary arterial hypertensionrdquo Hypertension Research vol34 no 9 pp 981ndash986 2011

[27] BHuMGharaee-Kermani ZWu and SH Phan ldquoEpigeneticregulation of myofibroblast differentiation by DNA methyla-tionrdquoThe American Journal of Pathology vol 177 no 1 pp 21ndash28 2010

[28] R A Philibert R A Sears L S Powers et al ldquoCoordinatedDNA methylation and gene expression changes in smokeralveolar macrophages specific effects on VEGF receptor 1expressionrdquo Journal of Leukocyte Biology vol 92 no 3 pp 621ndash631 2012

[29] E S Wan W Qiu A Baccarelli et al ldquoCigarette smokingbehaviors and time since quitting are associated with differ-ential DNA methylation across the human genomerdquo HumanMolecular Genetics vol 21 no 13 pp 3073ndash3082 2012

[30] A Giaid M Yanagisawa D Langleben et al ldquoExpression ofendothelin-1 in the lungs of patients with pulmonary hyper-tensionrdquo New England Journal of Medicine vol 328 no 24 pp1732ndash1739 1993

[31] C E Ventetuolo S M Kawut and D J Lederer ldquoPlasmaendothelin-1 and vascular endothelial growth factor levels andtheir relationship to hemodynamics in idiopathic pulmonaryfibrosisrdquo Respiration vol 84 no 4 pp 299ndash305 2012

[32] A Giaid R P Michel D Stewart M Sheppard Q Hamid andB Corrin ldquoExpression of endothelin-1 in lungs of patients withcryptogenic fibrosing alveolitisrdquo The Lancet vol 341 no 8860pp 1550ndash1554 1993

[33] D M Pollock T L Keith and R F Highsmith ldquoEndothelinreceptors and calcium signalingrdquo FASEB Journal vol 9 no 12pp 1196ndash1204 1995

[34] A Matsuura W Yamochi K-I Hirata S Kawashima and MYokoyama ldquoStimulatory interaction between vascular endothe-lial growth factor and endothelin-1 on each gene expressionrdquoHypertension vol 32 no 1 pp 89ndash95 1998

[35] G F Alberts K A Peifley A Johns J F Kleha and J AWinkles ldquoConstitutive endothelin-1 overexpression promotessmoothmuscle cell proliferation via an external autocrine looprdquoJournal of Biological Chemistry vol 269 no 13 pp 10112ndash101181994

[36] M Marini S Carpi A Bellini F Patalano and S Mat-toli ldquoEndothelin-1 induces increased fibronectin expression inhuman bronchial epithelial cellsrdquo Biochemical and BiophysicalResearch Communications vol 220 no 3 pp 896ndash899 1996

[37] M Iglarz A Bossu D Wanner et al ldquoComparison of phar-macological activity of macitentan and bosentan in preclinicalmodels of systemic and pulmonary hypertensionrdquo Life sciencesvol 118 no 2 pp 333ndash339 2014

[38] S Schroll M Arzt D Sebah M Nuchterlein F Blumberg andM Pfeifer ldquoImprovement of bleomycin-induced pulmonaryhypertension and pulmonary fibrosis by the endothelin recep-tor antagonist Bosentanrdquo Respiratory Physiology and Neurobiol-ogy vol 170 no 1 pp 32ndash36 2010

[39] Z Wang N Jin S Ganguli D R Swartz L Li and RA Rhoades ldquoRho-kinase activation is involved in hypoxia-induced pulmonary vasoconstrictionrdquo American Journal ofRespiratory Cell and Molecular Biology vol 25 no 5 pp 628ndash635 2001

[40] Y Bei T Hua-Huy S Duong-Quy et al ldquoLong-term treatmentwith fasudil improves bleomycin-induced pulmonary fibrosisand pulmonary hypertension via inhibition of Smad23 phos-phorylationrdquo Pulmonary Pharmacology and Therapeutics vol26 no 6 pp 635ndash643 2013

[41] NHomma TNagaoka V Karoor et al ldquoInvolvement of RhoARho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized ratsby dehydroepiandrosteronerdquo American Journal of Physiology -Lung Cellular and Molecular Physiology vol 295 no 1 pp L71ndashL78 2008

[42] J Gien N Tseng G Seedorf K Kuhn and S H AbmanldquoEndothelin-1mdashRho kinase interactions impair lung structureand cause pulmonary hypertension after bleomycin exposurein neonatal rat pupsrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 311 no 6 pp L1090ndashL1100 2016

[43] A H Lee R Dhaliwal C Kantores et al ldquoRho-Kinase inhibitorprevents bleomycin-induced injury in neonatal rats indepen-dent of effects on lung inflammationrdquo American Journal ofRespiratory Cell and Molecular Biology vol 50 no 1 pp 61ndash732014

[44] G Loirand P Guerin and P Pacaud ldquoRho kinases in cardiovas-cular physiology and pathophysiologyrdquo Circulation Researchvol 98 no 3 pp 322ndash334 2006

[45] P J McNamara P Murthy C Kantores et al ldquoAcute vasodilatoreffects of Rho-kinase inhibitors in neonatal rats with pulmonaryhypertension unresponsive to nitric oxiderdquoAmerican Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 294no 2 pp L205ndashL213 2008

[46] H Fujita Y Fukumoto K Saji et al ldquoAcute vasodilator effects ofinhaled fasudil a specific Rho-kinase inhibitor in patients withpulmonary arterial hypertensionrdquoHeart and Vessels vol 25 no2 pp 144ndash149 2010

[47] K Ishikura N Yamada M Ito et al ldquoBeneficial acute effectsof Rho-kinase inhibitor in patients with pulmonary arterialhypertensionrdquo Circulation Journal vol 70 no 2 pp 174ndash1782006

[48] H A Ghofrani R Wiedemann F Rose et al ldquoSildenafil fortreatment of lung fibrosis and pulmonary hypertension arandomised controlled trialrdquoThe Lancet vol 360 no 9337 pp895ndash900 2002

[49] A R Hemnes A Zaiman and H C Champion ldquoPDE5Ainhibition attenuates bleomycin-induced pulmonary fibrosisand pulmonary hypertension through inhibition of ROS gen-eration and RhoARho kinase activationrdquo American Journal ofPhysiology - Lung Cellular and Molecular Physiology vol 294no 1 pp L24ndashL33 2008

[50] R Khan A Agrotis and A Bobik ldquoUnderstanding the role oftransforming growth factor-1205731 in intimal thickening after vas-cular injuryrdquo Cardiovascular Research vol 74 no 2 pp 223ndash234 2007


[51] S Nakerakanti and M Trojanowska ldquoThe role of TGF-120573receptors in fibrosisrdquo Open Rheumatology Journal vol 6 no 1pp 156ndash162 2012

[52] A Moustakas and C-H Heldin ldquoNon-Smad TGF-120573 signalsrdquoJournal of Cell Science vol 118 no 16 pp 3573ndash3584 2005

[53] A Agrotis N Kalinina and A Bobik ldquoTransforming growthfactor-120573 cell signaling and cardiovascular disordersrdquo CurrentVascular Pharmacology vol 3 no 1 pp 55ndash61 2005

[54] J Wilborn L J Crofford M O Burdick S L Kunkel RM Strieter and M Peters- Golden ldquoCultured lung fibroblastsisolated from patients with idiopathic pulmonary fibrosis havea diminished capacity to synthesize prostaglandin E2 and toexpress cyclooxygenase-2rdquo Journal of Clinical Investigation vol95 no 4 pp 1861ndash1868 1995

[55] R J McAnulty N A Hernandez-Rodrıguez S E Mutsaers RK Coker and G J Laurent ldquoIndomethacin suppresses the anti-proliferative effects of transforming growth factor-120573 isoformson fibroblast cell culturesrdquo Biochemical Journal vol 321 no 3pp 639ndash643 1997

[56] L Gilboa A Nohe T Geissendorfer W Sebald Y I Henisand P Knaus ldquoBonemorphogenetic protein receptor complexeson the surface of live cells a new oligomerization mode forserinethreonine kinase receptorsrdquoMolecular Biology of the Cellvol 11 no 3 pp 1023ndash1035 2000

[57] N-Y Chen S D Collum F Luo et al ldquoMacrophage bone mor-phogenic protein receptor 2 depletion in idiopathic pulmonaryfibrosis and Group III pulmonary hypertensionrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 311 no 2 pp L238ndashL254 2016

[58] A J Bryant L J Robinson C S Moore et al ldquoExpressionof mutant bone morphogenetic protein receptor II worsenspulmonary hypertension secondary to pulmonary fibrosisrdquoPulmonary Circulation vol 5 pp 681ndash690 2015

[59] B C Cooley J Nevado J Mellad et al ldquoTGF-120573 signaling medi-ates endothelial-to-mesenchymal transition (EndMT) duringvein graft remodelingrdquo Science Translational Medicine vol 6no 227 Article ID 227ra34 2014

[60] N Hashimoto S H Phan K Imaizumi et al ldquoEndothelial-mesenchymal transition in bleomycin-induced pulmonaryfibrosisrdquo American Journal of Respiratory Cell and MolecularBiology vol 43 no 2 pp 161ndash172 2010

[61] T J Corte G J Keir K Dimopoulos et al ldquoBosentan inpulmonary hypertension associated with fibrotic idiopathicinterstitial pneumoniardquo American Journal of Respiratory andCritical Care Medicine vol 190 no 2 pp 208ndash217 2014

[62] A J Bryant R P Carrick M E McConaha et al ldquoEndothe-lial hif signaling regulates pulmonary fibrosis-associated pul-monary hypertensionrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 310 no 3 pp L249ndashL262 2016

[63] K Iwai K Yamanaka T Kamura et al ldquoIdentification of the vonHippel-Lindau tumor-suppressor protein as part of an active E3ubiquitin ligase complexrdquo Proceedings of the National Academyof Sciences of the United States of America vol 96 no 22 pp12436ndash12441 1999

[64] M M Hickey T Richardson T Wang et al ldquoThe von Hippel-Lindau Chuvash mutation promotes pulmonary hypertensionand fibrosis in micerdquo Journal of Clinical Investigation vol 120no 3 pp 827ndash839 2010

[65] Y Cui J Robertson S Maharaj et al ldquoOxidative stress con-tributes to the induction and persistence of TGF-1205731 induced

pulmonary fibrosisrdquo International Journal of Biochemistry andCell Biology vol 43 no 8 pp 1122ndash1133 2011

[66] C Delaney R H Wright J-R Tang et al ldquoLack of EC-SODworsens alveolar and vascular development in a neonatalmousemodel of bleomycin-induced bronchopulmonary dysplasia andpulmonary hypertensionrdquo Pediatric Research vol 78 no 6 pp634ndash640 2015

[67] E Nozik-Grayck C Woods J M Taylor et al ldquoSelective deple-tion of vascular EC-SOD augments chronic hypoxic pulmonaryhypertensionrdquo American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 307 no 11 pp L868ndashL876 2014

[68] A C P Sewing C Kantores J Ivanovska et al ldquoThera-peutic hypercapnia prevents bleomycin-induced pulmonaryhypertension in neonatal rats by limiting macrophage-derivedtumor necrosis factor-120572rdquoAmerican Journal of PhysiologymdashLungCellular and Molecular Physiology vol 303 no 1 pp L75ndashL872012

[69] R B Patel S R Kotha L A Sauers et al ldquoThiol-redox antiox-idants protect against lung vascular endothelial cytoskeletalalterations caused by pulmonary fibrosis inducer bleomycincomparison between classical thiol-protectant N-acetyl-l-cysteine and novel thiol antioxidantNN1015840-bis-2-mercaptoethylisophthalamiderdquo Toxicology Mechanisms and Methods vol 22no 5 pp 383ndash396 2012

[70] P Almudever J Milara A De Diego et al ldquoRole of tetrahydro-biopterin in pulmonary vascular remodelling associated withpulmonary fibrosisrdquoThorax vol 68 no 10 pp 938ndash948 2013

[71] H Grasemann R Dhaliwal J Ivanovska et al ldquoArginaseinhibition prevents bleomycin-induced pulmonary hyperten-sion vascular remodeling and collagen deposition in neonatalrat lungsrdquo American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 308 no 6 pp L503ndashL510 2015

[72] T Eckle E M Kewley K S Brodsky et al ldquoIdentification ofhypoxia-inducible factor HIF-1A as transcriptional regulator ofthe A2B adenosine receptor during acute lung injuryrdquo Journalof Immunology vol 192 no 3 pp 1249ndash1256 2014

[73] Y Zhou D J Schneider and M R Blackburn ldquoAdenosinesignaling and the regulation of chronic lung diseaserdquo Pharma-cology andTherapeutics vol 123 no 1 pp 105ndash116 2009

[74] Y Zhou D J Schneider E Morschl et al ldquoDistinct roles forthe A2B adenosine receptor in acute and chronic stages ofbleomycin-induced lung injuryrdquo Journal of Immunology vol186 no 2 pp 1097ndash1106 2011

[75] Y Zhou J N Murthy D Zeng L Belardinelli andM R Black-burn ldquoAlterations in adenosine metabolism and signalingin patients with chronic obstructive pulmonary disease andidiopathic pulmonary fibrosisrdquo PLoS ONE vol 5 no 2 ArticleID e9224 2010

[76] H Karmouty-Quintana H Zhong L Acero et al ldquoThe A2Badenosine receptor modulates pulmonary hypertension associ-ated with interstitial lung diseaserdquo FASEB Journal vol 26 no 6pp 2546ndash2557 2012

[77] H Karmouty-Quintana T Weng L J Garcia-Morales et alldquoAdenosine A2B receptor and hyaluronanmodulate pulmonaryhypertension associated with Chronic obstructive pulmonarydiseaserdquo American Journal of Respiratory Cell and MolecularBiology vol 49 no 6 pp 1038ndash1047 2013

[78] H Karmouty-Quintana K Philip L F Acero et al ldquoDeletionof ADORA2B from myeloid cells dampens lung fibrosis andpulmonary hypertensionrdquo FASEB Journal vol 29 no 1 pp 50ndash60 2015


[79] N Kalay D Elcik H Canatan et al ldquoElevated plasma hyaluro-nan levels in pulmonary hypertensionrdquo Tohoku Journal ofExperimental Medicine vol 230 no 1 pp 7ndash11 2013

[80] M Aytekin and R A Dweik ldquoLow-molecular-mass of hyaluro-nan was detected in PASMCs from the patients with idio-pathic pulmonary arterial hypertensionrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 300no 1 article L148 2011

[81] M Aytekin S A A Comhair C De LaMotte et al ldquoHigh levelsof hyaluronan in idiopathic pulmonary arterial hypertensionrdquoAmerican Journal of Physiology - Lung Cellular and MolecularPhysiology vol 295 no 5 pp L789ndashL799 2008

[82] M Brock M Trenkmann R E Gay et al ldquoInterleukin-6modulates the expression of the bone morphogenic proteinreceptor type II through a novel STAT3-microRNAcluster 1792pathwayrdquo Circulation Research vol 104 no 10 pp 1184ndash11912009

[83] M K Steiner O L Syrkina N Kolliputi E J Mark C AHales and A B Waxman ldquoInterleukin-6 overexpressioninduces pulmonary hypertensionrdquo Circulation Research vol104 no 2 pp 236ndash244 2009

[84] L J Garcia-Morales N-Y Chen T Weng et al ldquoAlteredhypoxic-adenosine axis and metabolism in group III pul-monary hypertensionrdquoAmerican Journal of Respiratory Cell andMolecular Biology vol 54 no 4 pp 574ndash583 2016

[85] T Le Thanh-Thuy H Karmouty-Quintana E Melicoff et alldquoBlockade of IL-6 trans signaling attenuates pulmonary fibro-sisrdquo Journal of Immunology vol 193 no 7 pp 3755ndash3768 2014

[86] L Savale L Tu D Rideau et al ldquoImpact of interleukin-6 onhypoxia-induced pulmonary hypertension and lung inflamma-tion in micerdquo Respiratory Research vol 10 article no 6 2009

[87] A L Degryse and W E Lawson ldquoProgress toward improvinganimal models for idiopathic pulmonary fibrosisrdquo The Ameri-can Journal of the Medical Sciences vol 341 no 6 pp 444ndash4492011

[88] B B Moore W E Lawson T D Oury T H Sisson K Raghav-endran and C M Hogaboam ldquoAnimal models of fibrotic lungdiseaserdquo American Journal of Respiratory Cell and MolecularBiology vol 49 no 2 pp 167ndash179 2013

[89] C P Baran JMOpalek SMcMaken et al ldquoImportant roles formacrophage colony-stimulating factor CC chemokine ligand 2andmononuclear phagocytes in the pathogenesis of pulmonaryfibrosisrdquo American Journal of Respiratory and Critical CareMedicine vol 176 no 1 pp 78ndash89 2007

[90] Z Van Rheen C Fattman S Domarski et al ldquoLung extracel-lular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodelingrdquoAmerican Journal of Respiratory Cell andMolecular Biology vol44 no 4 pp 500ndash508 2011

[91] J L Chunn J G Molina T Mi Y Xia R E Kellems andM R Blackburn ldquoAdenosine-dependent pulmonary fibrosis inadenosine deaminase-deficient micerdquo Journal of Immunologyvol 175 no 3 pp 1937ndash1946 2005

[92] R Eferl P Hasselblatt M Rath et al ldquoDevelopment of pul-monary fibrosis through a pathway involving the transcriptionfactor Fra-2AP-1rdquo Proceedings of the National Academy ofSciences of the United States of America vol 105 no 30 pp10525ndash10530 2008

[93] E C Derrett-Smith A Dooley A J Gilbane et al ldquoEndothelialinjury in a transforming growth factor 120573-dependent mouse

model of scleroderma induces pulmonary arterial hyperten-sionrdquo Arthritis and Rheumatism vol 65 no 11 pp 2928ndash29392013

[94] N F Voelkel R A Quaife L A Leinwand et al ldquoRight ventric-ular function and failure report of a National Heart Lungand Blood Institute working group on cellular and molecularmechanisms of right heart failurerdquo Circulation vol 114 no 17pp 1883ndash1891 2006

[95] T Moriarty ldquoThe law of Laplace Its limitations as a relation fordiastolic pressure volume or wall stress of the left ventriclerdquoCirculation Research vol 46 no 3 pp 321ndash331 1980

[96] E Weitzenblum ldquoChronic cor pulmonalerdquoHeart vol 89 no 2pp 225ndash230 2003

[97] T Kuehne S Yilmaz P Steendijk et al ldquoMagnetic resonanceimaging analysis of right ventricular pressure-volume loopsin vivo validation and clinical application in patients withpulmonary hypertensionrdquoCirculation vol 110 no 14 pp 2010ndash2016 2004

[98] C A Dias R S Assad L F Caneo et al ldquoReversible pulmonarytrunk banding II An experimental model for rapid pulmonaryventricular hypertrophyrdquo Journal of Thoracic and Cardiovascu-lar Surgery vol 124 no 5 pp 999ndash1006 2002

[99] D S Schulman and R A Matthay ldquoThe right ventricle inpulmonary diseaserdquoCardiology Clinics vol 10 no 1 pp 111ndash1351992

[100] A Zangiabadi C G De Pasquale and D Sajkov ldquoPulmonaryhypertension and right heart dysfunction in chronic lungdiseaserdquo BioMed Research International vol 2014 Article ID739674 13 pages 2014

[101] R H Behnke S G Blount J D Bristow et al ldquoPrimaryprevention of pulmonary heart diseaserdquo Journal of the AmericanOsteopathic Association vol 69 no 11 pp 1139ndash1146 1970

[102] M S Niederman and R A Matthay ldquoCardiovascular functionin secondary pulmonary hypertensionrdquo Heart and Lung Jour-nal of Acute and Critical Care vol 15 no 4 pp 341ndash351 1986

[103] M M Budev A C Arroliga H P Wiedemann and R AMatthay ldquoCor pulmonale an overviewrdquo Seminars in Respiratoryand Critical Care Medicine vol 24 no 3 pp 233ndash244 2003

[104] E Weitzenblum M Ehrhart J Rasaholinjanahary and CHirth ldquoPulmonary hemodynamics in idiopathic pulmonaryfibrosis and other interstitial pulmonary diseasesrdquo Respirationvol 44 no 2 pp 118ndash127 1983

[105] T M Kolb and P M Hassoun ldquoRight ventricular dysfunctionin chronic lung diseaserdquo Cardiology Clinics vol 30 no 2 pp243ndash256 2012

[106] K Sietsema ldquoCardiovascular limitations in chronic pulmonarydiseaserdquoMedicine and Science in Sports and Exercise vol 33 no7 pp S656ndashS661 2001

[107] C C W Hsia ldquoCardiopulmonary limitations to exercise inrestrictive lung diseaserdquo Medicine and Science in Sports andExercise vol 31 no 1 pp S28ndashS32 1999

[108] S D Nathan P W Noble and R M Tuder ldquoIdiopathicpulmonary fibrosis and pulmonary hypertension connectingthe dotsrdquo American Journal of Respiratory and Critical CareMedicine vol 175 no 9 pp 875ndash880 2007

[109] M L Handoko F S De Man C P Allaart W J Paulus NWesterhof and A Vonk-Noordegraaf ldquoPerspectives on noveltherapeutic strategies for right heart failure in pulmonaryarterial hypertension lessons from the left heartrdquo EuropeanRespiratory Review vol 19 no 115 pp 72ndash82 2010


[110] M McGoon D Gutterman V Steen et al ldquoScreening earlydetection and diagnosis of pulmonary arterial hypertensionACCP evidence-based clinical practice guidelinesrdquo Chest vol126 no 1 pp 14Sndash34S 2004

[111] B N Rivera-Lebron P R Forfia M Kreider J C Lee J HHolmes and S M Kawut ldquoEchocardiographic and hemody-namic predictors of mortality in idiopathic pulmonary fibrosisrdquoChest vol 144 no 2 pp 564ndash570 2013

[112] S M Arcasoy J D Christie V A Ferrari et al ldquoEchocardio-graphic assessment of pulmonary hypertension in patients withadvanced lung diseaserdquo American Journal of Respiratory andCritical Care Medicine vol 167 no 5 pp 735ndash740 2003

[113] A DrsquoAndrea A Stanziola M DrsquoAlto et al ldquoRight ventricularstrain an independent predictor of survival in idiopathicpulmonary fibrosisrdquo International Journal of Cardiology vol222 pp 908ndash910 2016

[114] A DrsquoAndrea A Stanziola E Di Palma et al ldquoRight ventricularstructure and function in idiopathic pulmonary fibrosis withor without pulmonary hypertensionrdquo Echocardiography vol 33no 1 pp 57ndash65 2016

[115] W Macnee ldquoPathophysiology of cor pulmonale in chronicobstructive pulmonary disease part twordquo American Journal ofRespiratory and Critical Care Medicine vol 150 no 4 pp 1158ndash1168 1994

[116] M M Hoeper S Andreas A Bastian et al ldquoPulmonary hyper-tension due to chronic lung disease updated recommendationsof the cologne consensus conference 2011rdquo International Journalof Cardiology vol 154 no 1 pp S45ndashS53 2011

[117] R A Incalzi L Fuso M De Rosa et al ldquoElectrocardiographicsigns of chronic cor pulmonale a negative prognostic findingin chronic obstructive pulmonary diseaserdquo Circulation vol 99no 12 pp 1600ndash1605 1999

[118] B Burrows L J Kettel A H Niden M Rabinowitz and CF Diener ldquoPatterns of cardiovascular dysfunction in chronicobstructive lung diseaserdquoNew England Journal of Medicine vol286 no 17 pp 912ndash918 1972

[119] GGiannakoulas TDKaramitsosG Pitsiou andH I Karvou-nis ldquoRight ventricular dysfunction and functional limitation inidiopathic pulmonary fibrosisrdquo European Respiratory Journalvol 31 no 1 pp 219ndash220 2008

[120] H H Leuchte C Neurohr R Baumgartner et al ldquoBrainnatriuretic peptide and exercise capacity in lung fibrosis andpulmonary hypertensionrdquo American Journal of Respiratory andCritical Care Medicine vol 170 no 4 pp 360ndash365 2004

[121] J W Song J-K Song and D S Kim ldquoEchocardiography andbrain natriuretic peptide as prognostic indicators in idiopathicpulmonary fibrosisrdquo Respiratory Medicine vol 103 no 2 pp180ndash186 2009

[122] H H Leuchte R A Baumgartner M El Nounou et al ldquoBrainnatriuretic peptide is a prognostic parameter in chronic lungdiseaserdquo American Journal of Respiratory and Critical CareMedicine vol 173 no 7 pp 744ndash750 2006

[123] R A Pauwels A S Buist P M A Calverley C R Jenkinsand S S Hurd ldquoGlobal strategy for the diagnosis managementand prevention of chronic obstructive pulmonary diseaseNHLBIWHO global initiative for chronic obstructive lungdisease (GOLD) workshop summaryrdquo American Journal ofRespiratory and Critical Care Medicine vol 163 no 5 pp 1256ndash1276 2001

[124] A SachdevH RVillarraga R P Frantz et al ldquoRight ventricularstrain for prediction of survival in patients with pulmonaryarterial hypertensionrdquo Chest vol 139 no 6 pp 1299ndash1309 2011

[125] L Richeldi U Costabel M Selman et al ldquoEfficacy of a tyrosinekinase inhibitor in idiopathic pulmonary fibrosisrdquoNew EnglandJournal of Medicine vol 365 no 12 pp 1079ndash1087 2011

[126] Idiopathic Pulmonary Fibrosis Clinical Research Network GRaghu K J Anstrom T E King Jr J A Lasky and F JMartinez ldquoPrednisone azathioprine and N-acetylcysteine forpulmonary fibrosisrdquoThe New England Journal of Medicine vol366 no 21 pp 1968ndash1977 2012

[127] T E King Jr W Z Bradford S Castro-Bernardini et alldquoA phase 3 trial of pirfenidone in patients with idiopathicpulmonary fibrosisrdquoNew England Journal of Medicine vol 370no 22 pp 2083ndash2092 2014

[128] P W Noble C Albera W Z Bradford et al ldquoPirfenidone inpatients with idiopathic pulmonary fibrosis (CAPACITY) tworandomised trialsrdquoThe Lancet vol 377 no 9779 pp 1760ndash17692011

[129] U Costabel C Albera W Z Bradford et al ldquoAnalysis of lungfunction and survival in RECAP an open-label extension studyof pirfenidone in patients with idiopathic pulmonary fibrosisrdquoSarcoidosis Vasculitis and Diffuse Lung Diseases vol 31 no 3pp 198ndash205 2014

[130] E M T Lau Y Tamura M D McGoon and O Sitbon ldquoThe2015 ESCERS Guidelines for the diagnosis and treatment ofpulmonary hypertension a practical chronicle of progressrdquoTheEuropean Respiratory Journal vol 46 no 4 pp 879ndash882 2015

[131] H Olschewski H A Ghofrani D Walmrath et al ldquoInhaledprostacyclin and iloprost in severe pulmonary hypertensionsecondary to lung fibrosisrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 160 no 2 pp 600ndash607 1999

[132] D A Zisman M Schwarz K J Anstrom H R Collard KR Flaherty and G W Hunninghake ldquoA controlled trial ofsildenafil in advanced idiopathic pulmonary fibrosisrdquoThe NewEngland Journal of Medicine vol 363 pp 620ndash628 2010

[133] T E King Jr J Behr KK Brown et al ldquoBUILD-1 a randomizedplacebo-controlled trial of bosentan in idiopathic pulmonaryfibrosisrdquo American Journal of Respiratory and Critical CareMedicine vol 177 no 1 pp 75ndash81 2008

[134] H-A Ghofrani N Galie F Grimminger et al ldquoRiociguatfor the treatment of pulmonary arterial hypertensionrdquo NewEngland Journal of Medicine vol 369 no 4 pp 330ndash340 2013

[135] H-A Ghofrani A M DrsquoArmini F Grimminger et al ldquoRio-ciguat for the treatment of chronic thromboembolic pulmonaryhypertensionrdquoNew England Journal of Medicine vol 369 no 4pp 319ndash329 2013

[136] M M Hoeper M Halank H Wilkens et al ldquoRiociguat forinterstitial lung disease and pulmonary hypertension a pilottrialrdquo European Respiratory Journal vol 41 no 4 pp 853ndash8602013

[137] L Richeldi R M Du Bois G Raghu et al ldquoEfficacy and safetyof nintedanib in idiopathic pulmonary fibrosisrdquo New EnglandJournal of Medicine vol 370 no 22 pp 2071ndash2082 2014

[138] T Ogura H Taniguchi A Azuma et al ldquoSafety and phar-macokinetics of nintedanib and pirfenidone in idiopathic pul-monary fibrosisrdquo European Respiratory Journal vol 45 no 5pp 1382ndash1392 2015

[139] P Minnis and J Egan ldquoThe use of pirfenidone in combinationwith sildenafil for advanced idiopathic pulmonary fibrosisrdquo inA38 Diamonds Are Forever But New Treatments for InterstitialLung Disease Canrsquot Wait vol 189 p A1432 American Journal ofRespiratory and Critical Care Medicine 2014

[140] Y-W Lan K-B Choo C-M Chen et al ldquoHypoxia-precon-ditioned mesenchymal stem cells attenuate bleomycin-induced


pulmonary fibrosisrdquo Stem Cell Research andTherapy vol 6 no1 article 97 2015

[141] L A Ortiz F Gambelli C McBride et al ldquoMesenchymal stemcell engraftment in lung is enhanced in response to bleomycinexposure and ameliorates its fibrotic effectsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 100 no 14 pp 8407ndash8411 2003

[142] M Reddy L Fonseca S Gowda B Chougule A Hari and STotey ldquoHuman adipose-derived mesenchymal stem cells atten-uate early stage of bleomycin induced pulmonary fibrosiscomparison with pirfenidonerdquo International Journal of StemCells vol 9 no 2 pp 192ndash206 2016

[143] M Rojas J Xu C R Woods et al ldquoBone marrow-derivedmesenchymal stem cells in repair of the injured lungrdquoAmericanJournal of Respiratory Cell and Molecular Biology vol 33 no 2pp 145ndash152 2005

[144] L Luo T Lin S Zheng et al ldquoAdipose-derived stem cells atten-uate pulmonary arterial hypertension and ameliorate pul-monary arterial remodeling in monocrotaline-induced pul-monary hypertensive ratsrdquoClinical and Experimental Hyperten-sion vol 37 no 3 pp 241ndash248 2015

[145] C M Suen S H J Mei L Kugathasan and D J Stewart ldquoTar-geted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseasesrdquo ComprehensivePhysiology vol 3 no 4 pp 1749ndash1779 2013

[146] Y D Zhao D W Courtman Y Deng L Kugathasan QZhang and D J Stewart ldquoRescue of monocrotaline-inducedpulmonary arterial hypertension using bone marrow-derivedendothelial-like progenitor cells efficacy of combined cell andeNOS gene therapy in established diseaserdquoCirculation Researchvol 96 no 4 pp 442ndash450 2005

[147] A Tzouvelekis V Paspaliaris G Koliakos et al ldquoA prospectivenon-randomized no placebo-controlled phase Ib clinical trialto study the safety of the adipose derived stromal cells-stromalvascular fraction in idiopathic pulmonary fibrosisrdquo Journal ofTranslational Medicine vol 11 no 1 article no 171 2013

[148] X-X Wang F-R Zhang Y-P Shang et al ldquoTransplantationof autologous endothelial progenitor cells may be beneficialin patients with idiopathic pulmonary arterial hypertensiona pilot randomized controlled trialrdquo Journal of the AmericanCollege of Cardiology vol 49 no 14 pp 1566ndash1571 2007

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


mechanisms [9] This review will focus on Group III PHGroup III PH is associated with chronic lung diseases such asChronicObstructive PulmonaryDisease (COPD) and IPF [34] In this review article we will focus on PH associated withIPF IPF is a parenchymal disease of the lung manifested bychronic cough exertional dyspnea and often leading to acuterespiratory failure [10] The prevalence of IPF is estimated tobe in the range of 14ndash43 per 100000 persons with the rangedependent upon the criteria applied [11 12] It important tomention that IPF is a fatal disease that affects millions ofpeople worldwide yet the funding for chronic respiratorydiseases desperately lags behind its societal burden [2]

The prevalence of PH amongst IPF patients is depen-dent upon the severity of IPF In the early stages or wheninitially diagnosed PH affects lt 10 of IPF patients [4 13]However as IPF advances the incidence of PH increasesmarkedly One study of patients awaiting lung transplantand thus in an advanced stage of IPF reported an incidenceof 32 [14] Subsequent studies have largely supported orincreased this percentage to be between 32 and 50 [1215] However it is important to mention that the symptomsfor PH and IPF are very similar (shortness of breath andexertional dyspnea) and as such it is conceivable for PHto be underdiagnosed in patients with IPF Furthermoretypically the mPAP of patients with IPF is significantly lowerthan patients with Group I PH [16ndash19] Despite this thepresence of PH in IPF is strongly linked to the increasedmortality [12 14] and efforts aimed at treating PH in IPF mayprovide much needed therapies to diminish the mortalityof IPF

2 Epigenetics of PH Associated with IPF

The role of epigenetics in the development of IPF is anintense area of research [20ndash23] Similarly there is a vastliterature that has looked at epigenetic changes in Group IPH namely PAH [24ndash26] These studies have focused onIPF or PAH with little or no research into Group III PHand in particular to PH associated with IPF Thus there is astrong need for enhanced research in this niche as increasedknowledge regarding epigenetic changes in patients with IPFand PH is necessary not only to develop new therapies butalso to enable personalized care for patients with IPF afflictedwith PH Important lessons that can be applied to IPF andPH are how microRNAs (miRNAs) through transcriptionaland translational regulation have the capacity to influencetarget genes in the development of PAH [25] From the fieldof IPF DNA methylation by DNA methyltransferases hasbeen shown to impact myofibroblast differentiation throughregulation of 120572SMA expression in developmental IPF [27]Importantly environmental factors such as cigarette smokehave been implicated inmanipulating themethylome and themethylation patterns of specific promoters in genes that areinvolved in IPF [28 29] Although these mechanisms havenot explicitly been identified in PH associated with IPF it isconceivable that similar processes may be unique in patientsin IPF and PH that can provide insight into the pathogenesisof PH in the setting of IPF in addition to providing uniquetherapeutic avenues for Group III PH

3 Mediators of PH in IPF

The general consensus regarding the pathogenesis of PH inIPFwas that the development of PHwas a complication of theunrelenting fibroproliferative injury in IPF and that treatingthe underlying lung fibrosis would also treat PH Althoughmany animal models have indeed shown that treating lungfibrosis results in attenuation of hallmarks of PH currenttherapies for IPF are unable to reverse the fibroproliferativedamage in IPF This observation and adverse independentimpact of PH in these patients highlight the need to developtherapies that directly impact PH in IPF In order to achievethis aim we must understand the pathogenesis of PH in IPFAlthough chronic hypoxia has been deemed integral in thedevelopment of Group III PH as a whole the downstreammechanisms that lead to PH in IPF are not fully under-stood Many diverse mediators including endothelin 1 (ET-1) transforming growth factor- (TGF-)120573 prostaglandin (PG)E2 bone morphogenetic protein receptor type 2 (BMPR2)adenosine signaling hyaluronan and IL-6 have been shownto play important roles in both the progression of fibrosisand the development of PH However how these mediatorsmay contribute independently to the pathogenesis of PH inthe context of lung fibrosis is not fully understood Figure 1summarizes some of the key mediators in PH associated withIPF

ET-1 is a strong vasoconstrictor that has been implicatedin both Group I PH and pulmonary fibrosis ET-1 was foundto be produced in the vascular endothelium of patients withboth PH and lung fibrosis but not in normal lung or inthose patients solely with fibrosis [30] This increase in ET-1 levels was also seen in the plasma of patients with GroupI PH and was correlated with increased mPAP [31] ET-1expression is also elevated in the airway epitheliumof patientswith IPF [32] ET-1 acts in several pathways canonically itbinds two ET receptors on vascular smooth muscle cellsactivating calcium signaling and vasoconstriction ET-1 canalso stimulate proliferation as well as growth factor andextracellular matrix production [33ndash36] The endothelinreceptor antagonists bosentan and macitentan have beenshown to reduce both the fibroproliferative injury and PH inthe rat bleomycin model of pulmonary fibrosis with PH [37]This also correlated with an increased exercise capacity [38]

A potential activator of ET-1 the RhoA pathway anddownstream effectors Rho-kinases I and II (ROCKs) havebeen associatedwith the development of PH in several animalmodels including bleomycin hypoxia and monocrotaline[39ndash43] In fact treatment of the mouse bleomycin model ofpulmonary fibrosis and PH with fasudil a selective ROCKinhibitor not only reduced the PH hallmarks of vascularremodeling and right ventricle systolic pressure but alsoreduced lung fibrosis [40] ROCKs are involved in manypathways involved in the development of PH and fibrosisincluding proliferation survival migration and contraction[44] Interestingly inhibition of the RhoAROCK pathway iseffective in those animal models that are resistant to inhalednitric oxide (NO) treatment a phenomenon that is commonin patients with PH associated with IPF that do not respondto NO treatment [45] This pathway has also been shown to


ET1

ETRs

ERAS

RhoAROCK1

ECM

Endothelial cell

Smooth muscle cell

Macrophage

Hyaluronan

Collagen

BMPR2

ADORA2B

SODHIFVHL

PGE2proliferation

NO

TGF120573

Remodeling

NOS




































2therapy [130]














Competing Interests


Acknowledgments


References


































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















ET1

ETRs

ERAS

RhoAROCK1

ECM

Endothelial cell

Smooth muscle cell

Macrophage

Hyaluronan

Collagen

BMPR2

ADORA2B

SODHIFVHL

PGE2proliferation

NO

TGF120573

Remodeling

NOS




































2therapy [130]














Competing Interests


Acknowledgments


References


































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































2therapy [130]














Competing Interests


Acknowledgments


References


































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Competing Interests


Acknowledgments


References


































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















pulmonary hypertension associated with idiopathic...

Documents