Formation Of Plexiform Lesions In Experimental Severe Pulmonary Arterial Hypertension

Abe, Kohtaro; Toba, Michie; Alzoubi, Abdallah; Ito, Masako; Fagan, Karen A.; Voelkel, Norbert F.; McMurtry, Ivan F.; Oka, Masahiko

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a6336

Cited by 63 publications

(112 citation statements)

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“…102-106 SU-5416 inhibits VEGFR-2, which plays a prosurvival role in endothelial cells and leads to endothelial apoptosis that contributes to the development of PH. [102][103][104][105][106] Constant improvement of the model appears to bring us one step closer to better modeling and understanding of the full complexity of PH.…”

Section: Chronic Hypoxia Modelmentioning

confidence: 99%

A Comprehensive Review: The Evolution of Animal Models in Pulmonary Hypertension Research; Are We there Yet?

et al. 2013

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Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans.

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Section: Chronic Hypoxia Modelmentioning

confidence: 99%

A Comprehensive Review: The Evolution of Animal Models in Pulmonary Hypertension Research; Are We there Yet?

et al. 2013

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“…12 We and others have demonstrated previously that levels of the major NO • metabolite, nitrite (NO 2 − ), are decreased in lung tissue harvested from pulmonary hypertensive rats exposed to chronic hypoxia, which, in turn, is associated with pulmonary vascular remodeling and dysfunction. 13,14 Numerous potential mechanisms exist by which to account for the observation that pulmonary vascular levels of bioavailable NO • are decreased in the setting of chronic hypoxia, including the adverse effects of increased pulmonary vascular oxidant stress on NO • sensing by soluble guanylyl cyclase (which is the chief biological source of cGMP), 15 consumption of NO • by elevated levels of pulmonary vascular reactive oxygen species, 16 or diminished endothelin receptor type B-dependent NO • synthesis, 13 among others. 17 Together, these observations provide biological plausibility to the assertion that restoring cGMP levels in pulmonary vascular tissue through PDE-5i may be an important and as yet underutilized treatment in COPD-PH.…”

Section: Rationale Ph Due To Chronic Obstructive Lung Diseasementioning

confidence: 99%

Study Design and Rationale for Investigating Phosphodiesterase type 5 Inhibition for the Treatment of Pulmonary Hypertension Due to Chronic Obstructive Lung Disease: The TADA‐PHiLD (TADAlafil for Pulmonary Hypertension Associated with Chronic Obstructive Lung Disease) Trial

et al. 2013

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In patients with chronic obstructive pulmonary disease (COPD), moderate or severe pulmonary hypertension (COPD-PH) is associated with increased rates of morbidity and mortality. Despite this, approaches to treatment and the efficacy of phosphodiesterase type 5 inhibition (PDE-5i) in COPD-PH are unresolved. We present the clinical rationale and study design to assess the effect of oral tadalafil on exercise capacity, cardiopulmonary hemodynamics, and clinical outcome measures in COPD-PH patients. Male and female patients 40-85 years old with GOLD stage 2 COPD or higher and pulmonary hypertension diagnosed on the basis of invasive cardiac hemodynamic assessment (mean pulmonary artery pressure [mPAP] >30 mmHg, pulmonary vascular resistance [PVR] >2.5 Wood units, and pulmonary capillary wedge pressure ≤18 mmHg at rest) will be randomized at a 1∶1 ratio to receive placebo or oral PDE-5i with tadalafil (40 mg daily for 12 months). The primary end point is change from baseline in 6-minute walk distance at 12 months. The secondary end points are change from baseline in PVR and mPAP at 6 months and change from baseline in peak volume of oxygen consumption ([Formula: see text]) during exercise at 12 months. Changes in systemic blood pressure and/or oxyhemoglobin saturation (Sao2) at rest and during exercise will function as safety outcome measures. TADA-PHiLD (TADAlafil for Pulmonary Hypertension assocIated with chronic obstructive Lung Disease) is the first sufficiently powered randomized clinical trial testing the effect of PDE-5i on key clinical and drug safety outcome measures in patients with at least moderate PH due to COPD.

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“…2,3,[10][11][12][13][14] Rather, this report aims to present a summary of the findings from a recent poll conducted through the Pulmonary Vascular Research Institute (PVRI). The aim of the poll was to examine the current use of, and phenotyping methods for, animal models for PAH across academia and industry.…”

Section: Introductionmentioning

confidence: 99%

A Report on the Use of Animal Models and Phenotyping Methods in Pulmonary Hypertension Research

Lawrie

2014

Pulm. circ.

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The failure to translate positive results from preclinical studies into new clinical therapies is a major problem throughout medical research. Specifically, in pulmonary hypertension, numerous research studies have shown beneficial effects of new therapies in experimental models, but these have largely failed to translate into clinical benefit in human trials. This is undoubtedly due, at least in part, to inadequacies of the models, but while monogenic animal models will never fully recapitulate human disease, they do still provide the best platform on which to test novel therapeutic agents. In the postgenomic era, there is emphasis on a greater understanding of disease pathogenesis, which has subsequently led to the development of both new targets and new models in which to test them. The evolution of new technologies means that we are now better equipped to phenotype these models, but the level of detail provided varies dramatically throughout the literature. However, subtle variances in experimental methods can make comparing data/findings between research laboratories difficult and are a possible contributing factor to variance between preclinical and clinical data. The aim of this report was to capture information on current practice for use of the growing array of animal models, to help movement toward developing guidelines and standards for the "best" use of animal models of pulmonary hypertension.

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Formation Of Plexiform Lesions In Experimental Severe Pulmonary Arterial Hypertension

Cited by 63 publications

References 0 publications

A Comprehensive Review: The Evolution of Animal Models in Pulmonary Hypertension Research; Are We there Yet?

A Comprehensive Review: The Evolution of Animal Models in Pulmonary Hypertension Research; Are We there Yet?

Study Design and Rationale for Investigating Phosphodiesterase type 5 Inhibition for the Treatment of Pulmonary Hypertension Due to Chronic Obstructive Lung Disease: The TADA‐PHiLD (TADAlafil for Pulmonary Hypertension Associated with Chronic Obstructive Lung Disease) Trial

A Report on the Use of Animal Models and Phenotyping Methods in Pulmonary Hypertension Research

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