Severe pulmonary hypertensive diseases: a perspective

Voelkel, Norbert F.; Tuder, Rubin M.

doi:10.1183/09031936.99.14612469

Cited by 24 publications

(20 citation statements)

References 21 publications

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“…Indeed, this combined review of the pathology and pathobiology of PH seeks to show their complementarities. We forecast that the pathogenetic insights will allow one to further reclassify the disease as angioproliferative [120] or myofibroblastic (as in idiopathic pulmonary fibrosis), neoplastic-like, or a reaction to injury, with clear implications to biomarker discovery, disease-tailored therapies, genetic association studies, etc. Based solely on the advances in the past 10 years, there is the potential to refine the diagnostic tools using genomics of peripheral blood cells of PH patients [121] and also to breakdown the apparently unifying pathology of severe PH using genomics applied to lung tissue [122].…”

Section: Discussionmentioning

confidence: 99%

Pathology of Pulmonary Hypertension

Tuder

Marecki

Richter

et al. 2013

Clinics in Chest Medicine

220

107

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Section: Discussionmentioning

confidence: 99%

Pathology of Pulmonary Hypertension

Tuder

Marecki

Richter

et al. 2013

Clinics in Chest Medicine

220

107

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“…Severe PH can present with unique tumorlets of hyperproliferating ECs that obliterate mediumsized precapillary arteries, forming structures known as plexiform lesions that express angiogenic and inflammatory factors including members of the VEGF and TGF-␤ families (54,56,59). Recently, imatinib, an effective agent in chronic myelogenous leukemia with PDGFR and c-Kit inhibitory activity, showed a significant survival effect in a conventional monocrotaline-induced rodent model of PH (48) and objective evidence of clinical improvement in two advanced PH patients (15,41).…”

Section: Discussionmentioning

confidence: 99%

“…The degree of infiltration and remodeling was quantified with the Heath-Edwards grading system (Fig. 4), which incorporates EC and smooth muscle cell (SMC) derangement based on H & E staining as previously described (59). This revealed a significantly higher average histological grade of remodeling per animal in the hypoxia/SU-5416-exposed rats, with complete attenuation of vascular remodeling (average grade of 0) in rats receiving sorafenib treatment.…”

Section: Effect Of Sorafenib On Vascular Morphology In Rodent Phmentioning

confidence: 99%

“…PULMONARY ARTERIAL HYPERTENSION (PH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) with a mean pressure of Ͼ25 mmHg at rest or 30 mmHg during exercise (43), with severe PH exhibiting PAP values Ͼ50 mmHg (2,59). Severe PH manifests as both an acute and a chronic presentation, with chronic PH leading to progressive right ventricular (RV) systolic pressure overload and ventricular dilatation, resulting in gradual RV dysfunction, heart failure, and death (21).…”

mentioning

confidence: 99%

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Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Moreno‐Vinasco

Gomberg‐Maitland

Maitland

et al. 2008

Physiological Genomics

100

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Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 33: 278 -291, 2008. First published February 26, 2008 doi:10.1152/physiolgenomics.00169.2007.-Pulmonary hypertension (PH) and cancer pathology share growth factor-and MAPK stressmediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1-3, PDGF receptor (PDGFR)-␤, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxiaexposed control animals, four groups were maintained at 10% inspired O 2 fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/ sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]-and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change Ͼ1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target. microarrays; SU-5416; bioinformatics PULMONARY ARTERIAL HYPERTENSION (PH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) with a mean pressure of Ͼ25 mmHg at rest or 30 mmHg during exercise (43), with severe PH exhibiting PAP values Ͼ50 mmHg (2, 59). Severe PH manifests as both an acute and a chronic presentation, with chronic PH leading to progressive right ventricular (RV) systolic pressure overload and ventricular dilatation, resulting in gradual RV dysfunction, heart failure, and death (21). Idiopathic PH has an estimated annual incidence of 1-2 per million (1) with mutations of the bone morphogenetic protein receptor type 2 gene (BMPR2) identified in ϳ50% of cases of familial PH (7). However, because only 20% of persons with a BMPR2 mutation develop PH (32), external stimuli, coupled with a susceptible genetic profile,...

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“…These lesions contain a disorganized monoclonal EC proliferation in a stroma of myofibroblasts (28,29). These so-called plexiform or complex vascular lesions are characterized by apoptosis-resistant (30)(31)(32)(33)(34)(35), phenotypically altered EC (36)(37)(38)(39)(40)(41).…”

Section: Smc and Ec In The Many Forms Of Pahmentioning

confidence: 99%

Reversible or Irreversible Remodeling in Pulmonary Arterial Hypertension

Sakao¹,

Tatsumi²,

Voelkel³

2010

Am J Respir Cell Mol Biol

151

120

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Vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC). Successful treatment of experimental PAH with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor offers the perspective of ''reverse remodeling'' (i.e., the regression of established pulmonary vascular lesions). Here we ask the question: which forms of pulmonary vascular remodeling are reversible and can such remodeling caused by angiogenic proliferation of EC be reversed? It is important to emphasize that the report showing reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor showed only a reduction of the pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack the feature of clustered proliferated EC in the lumen of pulmonary arteries. The regression of vascular muscularization is an important manifestation, whereby proliferative adult SMC convert back to a nonproliferative state. In contrast, in vitro experiments assessing the contribution of EC to the development of PAH demonstrated that phenotypically altered EC generated as a consequence of a vascular endothelial growth factor receptor blockade did not reverse to normal EC. Whereas it is suggested that the proliferative state of SMC may be reversible, it remains unknown whether phenotypically altered EC can switch back to a normal monolayer-forming EC. This article reviews the pathogenetic concepts of severe PAH and explains the many forms in PAH with reversible or irreversible remodeling.Keywords: remodeling; PAH; endothelial cell; smooth muscle cell Pulmonary vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance and reduced compliance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC) resulting in the obstruction of blood flow in the resistance pulmonary arteries (1, 2). In a recent Perspective article, Rai and coworkers (3) characterized severe PAH as a quasi-neoplastic, angioproliferative disorder, and this concept provides a new framework for antiproliferative, antiangiogenic therapy in severe PAH.Successful treatment with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor of experimental pulmonary hypertension offers the prospect of ''reverse remodeling'' (i.e., the regression of established pulmonary vascular lesions) (4).This review asks the question: which forms of pulmonary vascular remodeling are reversible and can the remodeling caused by the angiogenic proliferation of EC be reversed (5-8)? It is important to emphasize that the report showing a reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor (4) showed only the reduction of pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack ...

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Severe pulmonary hypertensive diseases: a perspective

Cited by 24 publications

References 21 publications

Pathology of Pulmonary Hypertension

Pathology of Pulmonary Hypertension

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Reversible or Irreversible Remodeling in Pulmonary Arterial Hypertension

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