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Pathologic changes in pulmonary artery postoperatively (hematoxylin-eosin stain, 3200). A, Sham operation group; B, grade I to II intimal thickening and medial hypertrophy of arterioles; C, grade III advanced medial thickening and severe narrowing or occlusions of arterioles; and D, grade IV-VI plexiform lesions of arterioles.
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We sought to explore and create a reliable, convenient, and economic hyperkinetic pulmonary artery hypertension (PAH) model and confirm the exact time of establishing a reversible or irreversible model to serve as a platform for future studies.
We used a common carotid artery and jugular vein shunt with an anastomosis and cuff to create a hyperkine...
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Context 1
... 3 months, the rabbit lung microvascular vessel in the CJSA and CJSC groups demonstrated uniform intimal thickening and medial hypertrophy, with degeneration, swelling, hyperplasia, and fibrosis of nonmuscular arterial endothelial cells. Furthermore, these groups had developed smooth muscle tissue and hyperplasia of the elastic collagen fibers (grade I-II) in the tunica media (Figure 7, B). Moreover, a severe narrowing or occlusion of the lumen was frequently found in the CJSC (4 of 22) and CJSA (11 of 32) groups (grade III; Figure 7, C). ...
Context 2
... these groups had developed smooth muscle tissue and hyperplasia of the elastic collagen fibers (grade I-II) in the tunica media (Figure 7, B). Moreover, a severe narrowing or occlusion of the lumen was frequently found in the CJSC (4 of 22) and CJSA (11 of 32) groups (grade III; Figure 7, C). By 3 months, 2 of 12 in the CJSC group and 4 of 20 in the CJSA group demonstrated plexiform lesions in the lung microvascular vessels (grade IV-VI), which marked an irreversible pathologic change ( Figure 7, D), consistent with the irreversible changes that occur in human PAH. ...
Context 3
... a severe narrowing or occlusion of the lumen was frequently found in the CJSC (4 of 22) and CJSA (11 of 32) groups (grade III; Figure 7, C). By 3 months, 2 of 12 in the CJSC group and 4 of 20 in the CJSA group demonstrated plexiform lesions in the lung microvascular vessels (grade IV-VI), which marked an irreversible pathologic change ( Figure 7, D), consistent with the irreversible changes that occur in human PAH. However, no such pathologic changes were seen before 3 months in either group. ...
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... At baseline, pulmonary artery pressure (sPAP, dPAP and mPAP) was at levels similar to those reported in other studies in rabbits. 24,25 In this study, we assessed PAP at two different Vt (9 and 15 ml/Kg) aiming to simulate the clinical scenario in humans where low or high Vt may produce different levels of stress in the pulmonary vasculature. 26,27 In normocapic conditions, the increase of Vt from 9 to 15 ml/Kg affected plateau airway (Figure 2(b)) and pulmonary (Table 2) pressure with no statistically significant effect on static compliance (Figure 2(a)). ...
Permissive hypercapnia is commonly used in mechanically ventilated patients to avoid lung injury but its effect on pulmonary artery pressure (PAP) is still unclear, particularly in combination with tidal volume (Vt). Therefore, an in vivo study was performed on adult rabbits ventilated with low (9 ml/Kg, LVt group) or high (15 ml/Kg, HVt group) tidal volume (Vt) and alterations in PAP were estimated. Both groups of animals initially were ventilated with FiO2 0.3 (Normocapnia-1) followed by inhalation of enriched CO2 gas mixture (FiCO2 0.10) to develop hypercapnia (Hypercapnia-1). After 30 min of hypercapnia, animals were re-ventilated with FiO2 0.3 to develop normocapnia (Normocapnia-2) again and then with FiCO2 0.10 to develop hypercapnia (Hypercapnia-2). Systolic, diastolic and mean PAP were assessed with a catheter in the pulmonary artery. In HP-1 and HP-2, PaCO2 increased (p < 0.0001) in both LVt and HVt animals compared to baseline values. pH decreased to ≈7.2 in HP-1 and ≈7.1 in HP -2. In normocapnia, the rise in Vt from 9 to 15 ml/Kg induced an increase in static compliance (Cstat), plateau airway pressure (Pplat) and PAP. Hypercapnia increased PAP in either LVt or HVt animals without significant effect on Cstat or Pplat. A two-way ANOVA revealed that there was not a statistically significant interaction between the effects of hypercapnia and tidal volume on mPAP (p = 0.76). In conclusion, increased Vt per se induced an increase in Cstat, Pplat and PAP in normocapnia. Hypercapnia increased PAP in rabbits ventilated with low or high Vt but this effect was not long-lasting.
... 3) Alternatively, autologous mesenchymal stem-cell transplantation has been shown to reduce PAH established by shunting, 4) and hHIF-1 gene transfection in endothelial progenitor cells may reduce hyperkinetic PAH and reverse pulmonary vascular remodeling. 5,6) A few studies have identified inflammation as a possible mechanism involved in the development of PAH. 7,8) Several perivascular inflammatory cells including macrophages, dendritic cells, T and B lymphocytes, and mast cells have been observed in pathological sections of patients with PAH. ...
... The PAH model was created by anastomosis of the common carotid and jugular veins. 6) After measuring pulmonary pressure, we selected 30 successful modeling rats (systolic pulmonary arterial pressure [SPAP] = 34.53 ± 2.66 mmHg). ...
... Four weeks after EP treatment, intravenous injection of pentobarbital sodium (30 mg/kg) was administered to anesthetize rats. Catheterization (as described in our preliminary research 6,12) ) was performed to collect hemodynamic data. The parameters were recorded three times per animal, and the average pressure was noted. ...
Purpose: Pulmonary arterial hypertension (PAH) is a formidable disease with no effective treatment at present. With the goal of developing potential therapies, we attempted to determine whether ethyl pyruvate (EP) could alleviate PAH and its mechanism.
Methods: Pulmonary smooth muscle cells were cultured in conventional low-oxygen environments, and cellular proliferation was monitored after treatment with either EP or phosphate-balanced solution (PBS). Expression of high mobility group protein B1 (HMGB1) and receptor for advanced glycation end-products (RAGE) protein were detected by western blot. After hyperkinetic PAH rat models were treated with EP, hemodynamic data were collected. Right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Expression of HMGB1 and RAGE protein was also detected.
Results: In vitro, proliferative activity increased in low-oxygen environments, but was inhibited by EP treatment. Furthermore, Western blotting showed the decreased expression of HMGB1 and RAGE protein after EP treatment. In vivo, pulmonary artery pressures were attenuated with EP. Right ventricular hypertrophy and pulmonary vascular remodeling were also reversed. Additionally, the expression levels of HMGB1 and RAGE were reduced in lung tissues.
Conclusions: EP can alleviate PAH by suppressing the proliferation of pulmonary artery smooth muscle cells via inhibition of HMGB1/RAGE expression.
... 13 The strain came to Penn State Hershey in 1988 from the National Cancer Institute. 37 Rabbits have been used as an induced experimental model for a wide variety of pulmonary conditions, including hypertension, 29 tuberculosis, 36 and aspiration pneumonia. 51 Rabbits have also been proposed as a model for aging research. ...
Spontaneous age-related lesions of laboratory rabbits are not well documented in the contemporary scientific literature. A retrospective study of diagnostic necropsies of 36 rabbits >2 years of age found a number of common lung lesions. Fibromuscular intimal hyperplasia affected medium and to a lesser extent large pulmonary arteries and was present to a variable extent in all 36 rabbits >2 years of age. The lesions were characterized by fragmentation and/or reduplication of the internal elastic lamina (IEL), proliferation of smoothelin+/alpha-smooth muscle actin (α-SMA)+/vimentin− smooth muscle cells and fewer smoothelin−/α-SMA+/vimentin+ myofibroblasts, and intimal deposition of collagen without thrombosis, embolism, or evidence of pulmonary hypertension. Pulmonary emphysema, present in 30/36 rabbits, was characterized by the loss of alveolar septa; most affected rabbits did not have clinical signs of respiratory disease. In 8/13 rabbits of the inbred EIII/JC audiogenic strain, we identified a unique syndrome of granulomatous pneumonia containing hyaline brown to gray, globular to ring-like acellular material that was Alcian blue and periodic acid-Schiff positive. The material was immunoreactive for surfactant protein-A and had the ultrastructural appearance of multilamellar vesicles, suggesting a genetic defect in surfactant metabolism. Additionally, we found small benign primary lung tumors (fibropapillomas, 5 rabbits) not previously described. Other findings included heterotopic bone (5 rabbits), subacute to chronic suppurative bronchopneumonia, pyogranulomatous pneumonia with plant material, and pulmonary artifacts from barbiturate euthanasia solution.
... Previous animal models of PPH using monocrotaline have been criticized for not leading to successful therapies because the changes in the pulmonary arteries did not translate to those seen in humans. 7,8 However, a recently described model of surgically induced PH in the rat via a shunt from the left common carotid to left jugular vein produced changes of medial hypertrophy and intimal proliferation, which may lead to improved therapy because adequate reagents will be more likely to be available for testing. 7 Ranchoux et al 6 administered CP in three different animal models (mouse, rat, and rabbit), in which they reproduced morphological characteristics of PVOD similar to humans. ...
... 7,8 However, a recently described model of surgically induced PH in the rat via a shunt from the left common carotid to left jugular vein produced changes of medial hypertrophy and intimal proliferation, which may lead to improved therapy because adequate reagents will be more likely to be available for testing. 7 Ranchoux et al 6 administered CP in three different animal models (mouse, rat, and rabbit), in which they reproduced morphological characteristics of PVOD similar to humans. They used these three models due to recognized morphological differences of pulmonary veins between rodents and rabbits whereby rodents have muscularized pulmonary veins whereas rabbits have thin fibrous vein walls that more closely resemble human pulmonary veins. ...
... 8,9 However, early studies to establish an A-V shunt via the carotid artery-jugular vein-induced PAH model were primarily conducted in rats 10 and rabbits. 11,12 The cardiovascular systems in pigs have anatomical properties similar to humans compared with the previously described animal models. 13 Moreover, large animal models of PAH, like those established in minipigs, are more convenient for hemodynamic measurements, including cardiac catheter and echocardiography measurements. ...
... Recently, success of A-V shunt-induced PAH has been reported in small animals, including rats 10 and rabbits. 11 Although these models are easy to establish, models in these small animals are often intolerant of repeated invasive hemodynamic measurements, and more importantly, the anatomic characteristics of these small animals are not similar to humans, which limits the translatable value. Minipigs have similar anatomic features of the human cardiovascular system. ...
The continuous changes in pulmonary hemodynamic properties and right ventricular (RV) function in pulmonary arterial hypertension (PAH) have not been fully characterized in large animal model of PAH induced by a carotid artery-jugular vein shunt. A minipig model of PAH was induced by a surgical anastomosis between the left common carotid artery and the left jugular vein. The model was validated by catheter examination and pathologic analyses, and the hemodynamic features and right-ventricle functional characteristics of the model were continuously observed by Doppler echocardiography. Of the 45 minipigs who received the surgery, 27 survived and were validated as models of PAH, reflected by mean pulmonary artery pressure ≥25 mmHg, and typical pathologic changes of pulmonary arterial remodeling and RV fibrosis. Non-invasive indices of pulmonary hemodynamics (pulmonary artery accelerating time and its ratio to RV ventricular ejection time) were temporarily increased, then reduced later, similar to changes in tricuspid annular displacement. The Tei index of the RV was elevated, indicating a progressive impairment in RV function. Surgical anastomosis between carotid artery and jugular vein in a minipig is effective to establish PAH, and non-invasive hemodynamic and right-ventricle functional indices measured by Doppler echocardiography may be used as early indicators of PAH.
© 2015 by the Society for Experimental Biology and Medicine.
... Previous animal models of PPH using monocrotaline have been criticized for not leading to successful therapies because the changes in the pulmonary arteries did not translate to those seen in humans. 7,8 However, a recently described model of surgically induced PH in the rat via a shunt from the left common carotid to left jugular vein produced changes of medial hypertrophy and intimal proliferation, which may lead to improved therapy because adequate reagents will be more likely to be available for testing. 7 Ranchoux et al 6 administered CP in three different animal models (mouse, rat, and rabbit), in which they reproduced morphological characteristics of PVOD similar to humans. ...
... 7,8 However, a recently described model of surgically induced PH in the rat via a shunt from the left common carotid to left jugular vein produced changes of medial hypertrophy and intimal proliferation, which may lead to improved therapy because adequate reagents will be more likely to be available for testing. 7 Ranchoux et al 6 administered CP in three different animal models (mouse, rat, and rabbit), in which they reproduced morphological characteristics of PVOD similar to humans. They used these three models due to recognized morphological differences of pulmonary veins between rodents and rabbits whereby rodents have muscularized pulmonary veins whereas rabbits have thin fibrous vein walls that more closely resemble human pulmonary veins. ...
This commentary highlights the article by Ranchoux and Günther, showing a cause-and-effect link between alkylating agents and pulmonary veno-occlusive disease.
Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Hyperkinetic pulmonary arterial hypertension (PAH) is a common complication in congenital heart disease, and affects operations, indications, and prognoses for patients. Gene-based stem cell transplantation is an alternative treatment that can attenuate PAH.
Hyperkinetic PAH rabbit models were successfully established, using common carotid artery and jugular vein anastomosis. Endothelial progenitor cells (EPCs) were isolated from the bone marrow, cultured, and transfected with human hypoxia inducible factor-1 alpha (hHIF-1α), using lentiviruses. Two weeks after the transfected EPCs were transplanted into the rabbits, catheterization was applied to collect hemodynamic data. The hypertrophy of the right ventricle and pulmonary vascular remodeling were evaluated by measuring the right ventricle hypertrophy index, the medial wall thickness, and the medial wall area. Western blot and immunohistochemistry analyses were used to detect the expression of hHIF-1α in the pulmonary small arteries.
Two weeks after transplantation, systolic pulmonary arterial pressure and mean pulmonary arterial pressure were both attenuated. The hypertrophy of the right ventricle, and pulmonary vascular remodeling were reversed. Expression of hHIF-1α in the hHIF-1α-transfected EPCs that had been transplanted was high, and the number of pulmonary small arteries had increased. In addition, combined HIF-1α and homogeneous EPC therapy was more effective at attenuating PAH and increasing the density of pulmonary small arteries, compared with EPC transplantation alone.
Both the therapy with HIF-1α-transfected EPCs, and EPC transplantation, attenuated shunt flow-induced PAH, by means of an angiogenic effect. The former therapeutic method was more effective.
Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
Objective:
To investigate the effect of sequential and timely transfection of the recombinant human hepatocyte growth factor (hHGF) gene and human monocyte chemotactic protein-1 (hMCP-1) gene on hyperkinetic pulmonary artery hypertension in a rabbit model.
Methods:
The rabbits with pulmonary artery hypertension were randomly separated into 5 groups: control; hHGF; hMCP-1; hHGF/hMCP-1 simultaneous transfection; and hHGF/hMCP-1 sequential, timely transfection. Two weeks after the transfection, real-time polymerase chain reaction and immunohistochemistry examination were used to detect the expression of hHGF and hMCP-1. Four weeks later, the hemodynamic parameters were measured, and immunohistochemical and immunofluorescence staining were performed, to investigate microvascular density and arterialization.
Results:
The final adenovirus coding with enhanced green fluorescent protein-hMCP-1 virus was 3 × 10(10) plaque-forming units/mL, and the purity of adenovirus coding with hHGF was 1.31. Three days after the transfection, enhance green fluorescent protein hMCP-1 green fluorescence was detected in the lung tissues and increased to its peak point in 1 week. Two weeks later, hHGF and hMCP-1 were expressed in all transfection groups. By the end of 4 weeks, the mean pulmonary artery pressure in the hHGF/hMCP-1 sequential and timely transfection group was lower than that in the other groups. Confirmed by immunohistochemical and immunofluorescence staining, the microvascular and arteriolar density in the lung tissues of the sequential and timely hHGF/hMCP-1 transfection group were higher than that in the other groups.
Conclusions:
Expression of hHGF and hMCP-1 were found in rabbit lung after gene transfection via an airway approach. By increasing the pulmonary microvascular density and promoting arterializations, sequential and timely hHGF/hMCP-1 transfection ameliorates the shunt flow-induced pulmonary artery hypertension.
