Endothelial Nitric Oxide Synthase Function in Pig Lung after Chronic Pulmonary Artery Obstruction

Fadel, Élie; Mazmanian, Guy-Michel; Baudet, Bruno; Detruit, Hélène; Verhoye, Jean‐Philippe; Cron, J; Fattal, Soly; Dartevelle, Philippe; Hervé, Philippe

doi:10.1164/ajrccm.162.4.2001010

Cited by 24 publications

(26 citation statements)

References 22 publications

(21 reference statements)

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“…In this study, we succeeded in replicating high-flow-induced vasculopathy with PA remodeling in the unobstructed right upper lobe 7 and postobstructive vasculopathy combining PA remodeling and bronchial artery hypertrophy in the chronically obstructed right lower lobe and left lung. 9 More importantly, the combination of the postobstructive and overflow vasculopathies resulted in PH with right heart remodeling, as shown by hemodynamic, echocardiographic, and morphological studies. The ET-1 pathway is known to be involved in many causes of PH.…”

Section: Discussionmentioning

confidence: 95%

Piglet Model of Chronic Pulmonary Hypertension

et al. 2013

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None of the animal models have been able to reproduce all aspects of CTEPH because of the rapid resolution of the thrombi in the pulmonary vasculature. The aim of this study was to develop an easily reproducible large-animal model of chronic pulmonary hypertension (PH) related to the development of a postobstructive and overflow vasculopathy. Chronic PH was induced in 5 piglets by ligation of the left pulmonary artery (PA) through a midline sternotomy followed by weekly transcatheter embolization of the right lower-lobe arteries. Sham-operated piglets (n = 5) served as controls. Hemodynamics, RV function, lung morphometry, and endothelin-1 (ET-1) pathway gene expression (ET-1 and its receptors ETA and ETB) were assessed after 5 weeks in the obstructed (left lung and right lower lobe) and unobstructed (right upper lobe) territories. All animals developed chronic PH within 5 weeks. Compared to controls, chronic-PH animals had higher mean PA pressure (28.5 ± 1.7 vs. 11.6 ± 1.8 mmHg, P = 0.0001) and total pulmonary resistance (784 ± 160 vs. 378 ± 51 dyn s −1 cm −5 , P = 0.05). Echocardiography showed RV enlargement, RV wall thickening (56 ± 5 vs. 30 ± 4 mm, P = 0.0003), decreased tricuspid annular plane systolic excursion (11.3 ± 0.9 vs. 14.4 ± 0.4 mm, P = 0.01), and paradoxical septal motion.In obstructed territories, morphometry demonstrated increases in the number of bronchial arteries per bronchus (8.7 ± 0.9 vs. 2 ± 0.17, P < 0.0001) and in distal PA media thickness (60% ± 2.8% vs. 29% ± 0.9%, P < 0.0001), consistent with postobstructive vasculopathy. Distal PA media thickness was increased in unobstructed territories (70% ± 2.4% vs. 29% ± 0.9%, P < 0.0001). ET-1 was overexpressed in unobstructed territories, compared to controls and obstructed territories. In conclusion, the large-animal model described here is reproducible and led to the development of PH in a relatively short time frame.

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Section: Discussionmentioning

confidence: 95%

Piglet Model of Chronic Pulmonary Hypertension

et al. 2013

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“…These alterations have been reproduced in the postobstructive pulmonary vascular bed of animal models by ligation of one pulmonary artery [12]. This postobstructive pulmonary vasculopathy includes development of precapillary bronchial-to-pulmonary vascular anastomoses, pulmonary arterial remodelling and abnormal pulmonary artery vascular reactivity with dysfunction of the pulmonary endothelium [13]. In these animal models the contralateral lung remains normal.…”

Section: Pathophysiological Mechanismsmentioning

confidence: 99%

Chronic thromboembolic pulmonary hypertension

Dartevelle¹,

Fadel²,

Mussot³

et al. 2004

European Respiratory Journal

435

350

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Pulmonary arterial hypertension is a severe disease that has been ignored for a long time. However, over the past 20 yrs chest physicians, cardiologists and thoracic surgeons have shown increasing interest in this disease because of the development of new therapies, that have improved both the outcome and quality of life of patients, including pulmonary transplantation and prostacyclin therapy.Chronic thromboembolic pulmonary arterial hypertension (CTEPH) can be cured surgically through a complex surgical procedure: the pulmonary thromboendarterectomy. Pulmonary thromboendarterectomy is performed under hypothermia and total circulatory arrest.Due to clinically evident acute-pulmonary embolism episodes being absent in w50% of patients, the diagnosis of CTEPH can be difficult. Lung scintiscan showing segmental mismatched perfusion defects is the best diagnostic tool to detect CTEPH.Pulmonary angiography confirms the diagnosis and determines the feasability of endarterectomy according to the location of the disease, proximal versus distal. The technique of angiography must be perfect with the whole arterial tree captured on the same picture for each lung. The lesions must start at the level of the pulmonary artery trunk, or at the level of the lobar arteries, in order to find a plan for the endarterectomy.When the haemodynamic gravity corresponds to the degree of obliteration, pulmonary thromboendarterectomy can be performed with minimal perioperative mortality, providing definitive, excellent functional results in almost all cases. Pulmonary arterial hypertension is a severe disease that has been historically neglected. Over the past 20 yrs, chest physicians, cardiologists and thoracic surgeons have shown increasing interest in this disease because of the development of new therapies that have improved the outcome and quality of life of patients. Available options now include prostacyclin therapy, pulmonary endarterectomy and pulmonary transplantation.Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by obstruction of the large pulmonary arteries by acute and recurrent pulmonary emboli, and organisation of these blood clots. This disease, initially considered to be rare, is being diagnosed more and more frequently. A possible reason for this is the availability of successful medical and surgical treatment. The development of centres specialising in the diagnosis and treatment of pulmonary hypertension, and more consistent follow-up procedures for patients presenting with acute pulmonary emboli may also contribute to the ongoing increase in the number of patients diagnosed and treated for CTEPH. Pathogenesis or natural history of pulmonary emboliHaemodynamic failure and death occurs in 20-40% of patients within 1 h of acute pulmonary emboli [1]. Among survivors, the natural evolution, in most cases, is resorption of blood clots by local fibrinolysis with complete restoration of

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“…In addition to bronchial circulation hypertrophy, post-obstructive vasculopathy is characterised by pulmonary artery abnormalities including increased media thickness [30], impaired vasoreactivity [31], impaired endothelial nitric-oxide-synthase function [30], and increased reactivity to endothelin (ET)-1 [32] leading to increased resistance after reperfusion [33].…”

Section: Models Replicating Pulmonary Artery Obstructionmentioning

confidence: 99%

Chronic thromboembolic pulmonary hypertension: animal models

Mercier

Fadel

2013

Eur Respir J

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Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening disease due to pulmonary artery obstruction by persistent organised clots related to one or more episodes of acute pulmonary embolism. To date, the pathogenesis of CTEPH remains unexplained. Pulmonary endarterectomy removes obstruction from pulmonary vessels and can cure patients. However, some unreachable distal pulmonary obstruction and/or associated distal pulmonary vasculopathy could induce persistent pulmonary hypertension, the main postoperative complication.The pathophysiology of CTEPH is not fully understood and improving knowledge of this disease could improve our future surgical and medical management. Many attempts, conducted over several decades, have failed to reproduce this chronic disease in animals. However, several animal models have provided insights into the pathophysiology and pathogenesis of CTEPH. Here, we review all the animal models that have improved the comprehension of CTEPH and hold promise for further investigations. This short review analyses strengths and weaknesses of all animal models available to study the pathophysiology of CTEPH. , chronic thromboembolic pulmonary hypertension (CTEPH) is a type-4 subtype of pulmonary hypertension (PH), in which pulmonary endarterectomy (PEA) [2] is effective in preventing death by right ventricle (RV) failure. CTEPH is due to obstruction of pulmonary arteries by persistent organised clots formed during one or more episodes of acute pulmonary embolism. The reason for clot persistence is unknown and the pathogenesis of CTEPH remains unexplained. To date, the lack of risk factors predicting the evolution from acute pulmonary embolism to CTEPH does not allow the development of preventive care and/or screening programmes.The increase in pulmonary vascular resistance is believed to result from a combination of proximal pulmonary artery obstruction and distal pulmonary vasculopathy [3,4], which have to be quantified before PEA to estimate risks and predict surgical success. However, the mechanisms underlying lesion development in the obstructed and unobstructed peripheral vascular beds remain unknown. Hence, medical management of inoperable CTEPH or operable CTEPH with an important distal vasculopathy remains troublesome because of a lack of efficient therapy.To elucidate the pathophysiology of CTEPH, considerable effort has been expended in attempting to develop reliable animal models. Acute pulmonary embolism is easily produced in several animal species. In contrast, the induction of a disease replicating all the components of human CTEPH has proved challenging. These

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Endothelial Nitric Oxide Synthase Function in Pig Lung after Chronic Pulmonary Artery Obstruction

Cited by 24 publications

References 22 publications

Piglet Model of Chronic Pulmonary Hypertension

Piglet Model of Chronic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension: animal models

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