A Pulmonary Hypertension Model Induced by Continuous Pulmonary Air Embolization

Zhou, Xuguo; Wang, Dongfang; Castro, Claudia Y.; Hawkins, Hal K.; Lynch, James E.; Liu, Xiaojun; Zwischenberger, Joseph B.

doi:10.1016/j.jss.2011.04.030

Cited by 11 publications

(9 citation statements)

References 18 publications

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“…PH has been created in small animal models, including mice and rats, with hypoxia, 2–5 monocrotaline, 6–14 genetic modifications, 9,40–42 and surgical shunts 16 One of the limitations of these models is the difficulty with chronic hemodynamic and tissue monitoring. Larger animal models, including, pigs, sheep, dogs, macaques, calves, and apes, have also been created with hypoxia, 43–50 monocrotaline, 51–53 infectious agents, 15 air infusions, 54 carotid to jugular vein anastomoses, 55 ligation of pulmonary veins, 56 systemic to pulmonary arterial shunts, surgical pulmonary artery ligation, and microsphere infusions. 18,19,22,57–63 They have added significantly to the understanding of PH.…”

Section: Discussionmentioning

confidence: 99%

Challenges in the development of chronic pulmonary hypertension models in large animals

Rothman

Wiencek

Davidson³

et al. 2017

Pulm. circ.

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Pulmonary hypertension (PH) results in significant morbidity and mortality. Chronic PH animal models may advance the study of PH’s mechanisms, evolution, and therapy. In this report, we describe the challenges and successes in developing three models of chronic PH in large animals: two models (one canine and one swine) utilized repeated infusions of ceramic microspheres into the pulmonary vascular bed, and the third model employed a surgical aorto-pulmonary shunt. In the canine model, seven dogs underwent microsphere infusions that resulted in progressive elevation of pulmonary arterial pressure over a few months. In this model, pulmonary endoarterial tissue was obtained for histology. In the aorto-pulmonary shunt swine model, 17 pigs developed systemic level pulmonary pressures after 2–3 months. In this model, pulmonary endoarterial tissue was sequentially obtained to assess for changes in gene and microRNA expression. In the swine microsphere infusion model, three pigs developed only a modest chronic increase in pulmonary arterial pressure, despite repeated infusions of microspheres (up to 40 in one animal). The main purpose of this model was for vasodilator testing, which was performed successfully immediately after acute microsphere infusions. Chronic PH in large animal models can be successfully created; however, a model’s characteristics need to match the investigational goals.

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Section: Discussionmentioning

confidence: 99%

Challenges in the development of chronic pulmonary hypertension models in large animals

Rothman

Wiencek

Davidson³

et al. 2017

Pulm. circ.

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“…There have been other studies that utilized recurrent embolization techniques to create a PH model in large animals ( Table 3 ) [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 15 , 16 ]. These studies have a number of notable differences between them, including the embolic material (e.g., dextran beads, ceramic beads, air), number of procedures required to create the model (e.g., continuous/daily, weekly, biweekly), and the experimental conditions (e.g., mechanical ventilation, pO 2 , anesthesia) under which the cardiopulmonary hemodynamics were assessed.…”

Section: Discussionmentioning

confidence: 99%

“…When considering the effect of recurrent pulmonary artery embolization on mPA pressure and PVR index, the greatest observed relative change (> 2-fold vs. baseline or controls) in these variables was achieved only in studies where hemodynamic assessments were made following a short (≤ 7 days) recovery period after the last embolization procedure. This finding appears to be independent of animal species, embolization material, or ventilation [ 8 , 9 , 15 ]. In the current study, we added a proximal embolization procedure together with repeat distal embolization to create the chronic PH model.…”

Section: Discussionmentioning

confidence: 99%

Combination Proximal Pulmonary Artery Coiling and Distal Embolization Induces Chronic Elevations in Pulmonary Artery Pressure in Swine

et al. 2015

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Pulmonary hypertension (PH) is associated with aberrant vascular remodeling and right ventricular (RV) dysfunction that contribute to early mortality. Large animal models that recapitulate human PH are essential for mechanistic studies and evaluating novel therapies; however, these models are not readily accessible to the field owing to the need for advanced surgical techniques or hypoxia. In this study, we present a novel swine model that develops cardiopulmonary hemodynamics and structural changes characteristic of chronic PH. This percutaneous model was created in swine (n=6) by combining distal embolization of dextran beads with selective coiling of the lobar pulmonary arteries (2 procedures per lung over 4 weeks). As controls, findings from this model were compared with those from a standard weekly distal embolization model (n=6) and sham animals (n=4). Survival with the combined embolization model was 100%. At 8 weeks after the index procedure, combined embolization procedure animals had increased mean pulmonary artery pressure (mPA) and pulmonary vascular resistance (PVR) compared to the controls with no effect on left heart or systemic pressures. RV remodeling and RV dysfunction were also present with a decrease in the RV ejection fraction, increase in the myocardial performance index, impaired longitudinal function, as well as cardiomyocyte hypertrophy, and interstitial fibrosis, which were not present in the controls. Pulmonary vascular remodeling occurred in both embolization models, although only the combination embolization model had a decrease in pulmonary capacitance. Taken together, these cardiopulmonary hemodynamic and structural findings identify the novel combination embolization swine model as a valuable tool for future studies of chronic PH.

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“…A porcine model for pulmonary hypertension has been shown to recreate the pathology from continuous small amounts of air over an 8-week period. The increased air decreases the amount of perfusion present while causing inflammation to the surrounding tissues 19 .…”

Section: Key Learning Points/opportunitiesmentioning

confidence: 99%

Method of Isolated <em>Ex Vivo</em> Lung Perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program

Nelson

Bobba

Eren

et al. 2015

JoVE

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The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. As this technology expands and improves, the ability to potentially evaluate and improve the quality of substandard lungs prior to transplant is a critical need. In order to more rigorously evaluate these approaches, a reproducible animal model needs to be established that would allow for testing of improved techniques and management of the donated lungs as well as to the lung-transplant recipient. In addition, an EVLP animal model of associated pathologies, e.g., ventilation induced lung injury (VILI), would provide a novel method to evaluate treatments for these pathologies. Here, we describe the development of a rat EVLP lung program and refinements to this method that allow for a reproducible model for future expansion. We also describe the application of this EVLP system to model VILI in rat lungs. The goal is to provide the research community with key information and "pearls of wisdom"/techniques that arose from trial and error and are critical to establishing an EVLP system that is robust and reproducible.

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A Pulmonary Hypertension Model Induced by Continuous Pulmonary Air Embolization

Cited by 11 publications

References 18 publications

Challenges in the development of chronic pulmonary hypertension models in large animals

Challenges in the development of chronic pulmonary hypertension models in large animals

Combination Proximal Pulmonary Artery Coiling and Distal Embolization Induces Chronic Elevations in Pulmonary Artery Pressure in Swine

Method of Isolated <em>Ex Vivo</em> Lung Perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program

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