scholarly journals Pulmonary ischemia induces lung remodeling and angiogenesis

2006 ◽  
Vol 100 (2) ◽  
pp. 587-593 ◽  
Author(s):  
Elizabeth M. Wagner ◽  
Irina Petrache ◽  
Brian Schofield ◽  
Wayne Mitzner
Keyword(s):  
Left Lung ◽  
Lung Parenchyma ◽  
Left Pulmonary Artery ◽  
Nuclear Antigen ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Visceral Pleura ◽  
Artery Ligation ◽  
Dividing Cells ◽  
Apoptotic Activity ◽  
Pulmonary Ischemia

Cellular remodeling during angiogenesis in the lung is poorly described. Furthermore, it is the systemic vasculature of the lung and surrounding the lung that is proangiogenic when the pulmonary circulation becomes impaired. In a mouse model of chronic pulmonary thromboembolism, after left pulmonary artery ligation (LPAL), the intercostal vasculature, in proximity to the ischemic lung, proliferates and invades the lung ( 12 ). In the present study, we performed a detailed investigation of the kinetics of remodeling using histological sections of the left lung of C57Bl/6J mice after LPAL (4 h to 20 days) or after sham surgery. New vessels were seen within the thickened visceral pleura 4 days after LPAL predominantly in the upper portion of the left lung. Connections between new vessels within the pleura and pulmonary capillaries were clearly discerned by 7 days after LPAL. The visceral pleura and the lung parenchyma showed intense tissue remodeling, as evidenced by markedly elevated levels of both proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells. Rapidly dividing cells were predominantly macrophages and type II pneumocytes. The increased apoptotic activity was further quantified by caspase-3 activity, which showed a sixfold increase relative to naive lungs, by 24 h after LPAL. Because sham surgeries had little effect on measured parameters, we conclude that both thoracic wound healing and pulmonary ischemia are required for systemic neovascularization.

scholarly journals Inhibition of CXCR2 attenuates bronchial angiogenesis in the ischemic rat lung

2008 ◽  
Vol 104 (5) ◽  
pp. 1470-1475 ◽  
Author(s):  
Adlah Sukkar ◽  
John Jenkins ◽  
Jesús Sánchez ◽  
Elizabeth M. Wagner
Keyword(s):  
Blood Flow ◽  
Time Course ◽  
Main Bronchus ◽  
Left Lung ◽  
Neutralizing Antibody ◽  
Left Pulmonary Artery ◽  
Rat Lung ◽  
Artery Ligation ◽  
Bronchial Arteries ◽  
Pulmonary Ischemia

Under conditions of chronic pulmonary ischemia, the bronchial circulation undergoes massive proliferation. However, little is known regarding the mechanisms that promote neovascularization. An expanding body of literature implicates the glutamic acid-leucine-arginine (ELR+) CXC chemokines and their G protein-coupled receptor, CXCR2, as key proangiogenic components in the lung. We used a rat model of chronic pulmonary ischemia induced by left pulmonary artery ligation (LPAL) to study bronchial angiogenesis. Using a methacrylate mixture, we cast the systemic vasculature of the rat lung at weekly intervals after LPAL. Twenty-one days after LPAL, numerous large, tortuous bronchial arteries were observed surrounding the left main bronchus that penetrated the left lung parenchyma. In stark contrast, the right lung was essentially devoid of vessels. We quantified bronchial neovascularization using 15-μm radiolabeled microspheres to measure systemic blood flow to the left lung ( n = 12 rats). Results showed that by 21 days after LPAL, bronchial blood flow to the ischemic left lung had increased >10-fold compared with controls 2 days after LPAL ( P < 0.01). Focusing on the predominant rat CXC chemokine that signals through CXCR2, we measured increased levels of cytokine-induced neutrophil chemoattractant-3 protein expression in left lung homogenates early (4 and 24 h; n = 10 rats) after LPAL relative to paired right lung controls ( P < 0.01). Treatment with a neutralizing antibody to CXCR2 resulted in a significant decrease in neovascularization 21 days after LPAL ( n = 9 rats; P < 0.01). Our results confirm the time course of bronchial angiogenesis in the rat and suggest the importance of CXC chemokines in promoting systemic neovascularization in the lung.

scholarly journals Increased hyaluronan fragmentation during pulmonary ischemia

2011 ◽  
Vol 301 (5) ◽  
pp. L782-L788 ◽  
Author(s):  
Lindsey Eldridge ◽  
Aigul Moldobaeva ◽  
Elizabeth M. Wagner
Keyword(s):  
Left Lung ◽  
Left Pulmonary Artery ◽  
Tube Formation ◽  
Mouse Lung ◽  
Artery Ligation ◽  
Fourfold Increase ◽  
Ha Synthase ◽  
Pulmonary Ischemia

Hyaluronan (HA), a glycosaminoglycan critical to the lung extracellular matrix, has been shown to dissociate into low-molecular-weight (LMW) HA fragments following exposure to injurious stimuli. In the present study we questioned whether lung HA changed during ischemia and whether changes had an effect on subsequent angiogenesis. After left pulmonary artery ligation (LPAL) in mice, we analyzed left lung homogenates immediately after the onset of ischemia (0 h) and intermittently for 14 days. The relative expression of HA synthase (HAS)1, HAS2, and HAS3 was determined by real-time RT-PCR, total HA in the lung was measured by an ELISA-like assay, gel electrophoresis was performed to determine changes in HA size distribution, and the activity of hyaluronidases was determined by zymography. A 50% increase in total HA was measured 16 h after the onset of ischemia and remained elevated for up to 7 days. Furthermore, a fourfold increase in LMW HA fragments (495–30 kDa) was observed by 4 h after LPAL. Both HAS1 and HAS2 showed increased expression 4–16 h after LPAL, yet no changes were seen in hyaluronidase activity. These results suggest that both HA fragmentation and activation of HA synthesis contribute to increased HA levels during lung ischemia. Delivery of LMW HA fragments in an in vitro tube formation assay or directly to the ischemic mouse lung in vivo both resulted in increased angiogenesis. We conclude that ischemic injury results in matrix fragmentation, which leads to stimulation of neovascularization.

Effects of pulmonary ischemia on lung morphology

2007 ◽  
Vol 293 (1) ◽  
pp. L254-L258 ◽  
Author(s):  
Michael J. Fields ◽  
John M. Bishai ◽  
Wayne Mitzner ◽  
Elizabeth M. Wagner
Keyword(s):  
Left Lung ◽  
Left Pulmonary Artery ◽  
Systemic Circulation ◽  
Lung Mechanics ◽  
Functional Responses ◽  
Artery Ligation ◽  
Tissue Ischemia ◽  
Pulmonary Capillaries ◽  
Alveolar Tissue ◽  
Pulmonary Ischemia

Pulmonary ischemia resulting from chronic pulmonary embolism leads to proliferation of the systemic circulation within and surrounding the lung. However, it is not clear how well alveolar tissue is sustained during the time of complete pulmonary ischemia. In the present study, we investigated how pulmonary ischemia after left pulmonary artery ligation (LPAL) would alter lung mechanical properties and morphology. In this established mouse model of lung angiogenesis after chronic LPAL ( 10 ), we evaluated lung function and structure before (3 days) and after (14 days) a functional systemic circulation to the left lung is established. Age-matched naïve and sham-operated C57Bl/6 mice and mice undergoing chronic LPAL were studied. Left and right lung pressure-volume relationships were determined. Next, lungs were inflated in situ with warmed agarose (25–30 cmH2O) and fixed, and mean chord lengths (MCL) of histological sections were quantified. MCL of naïve mice averaged 43.9 ± 1.8 μm. No significant changes in MCL were observed at either time point after LPAL. Left lung volumes and specific compliances were significantly reduced 3 days after LPAL. However, by 14 days after LPAL, lung pressure-volume relationships were not different from controls. These results suggest that severe pulmonary ischemia causes changes in lung mechanics early after LPAL that are reversed by the time a new systemic vasculature is known to perfuse pulmonary capillaries. The LPAL model thus affords a unique opportunity to study lung functional responses to tissue ischemia and subsequent recovery.

scholarly journals Role of IL-6 in systemic angiogenesis of the lung

2005 ◽  
Vol 99 (3) ◽  
pp. 861-866 ◽  
Author(s):  
Jessica Y. McClintock ◽  
Elizabeth M. Wagner
Keyword(s):  
Cardiac Output ◽  
Left Lung ◽  
Fold Increase ◽  
Left Pulmonary Artery ◽  
Artery Ligation ◽  
Vessel Growth ◽  
Pulmonary Ischemia ◽  
Cell Profile ◽  
Multifunctional Cytokine

The multifunctional cytokine interleukin (IL)-6 has been shown to modulate inflammation and angiogenesis. In a mouse model of lung angiogenesis induced by chronic left pulmonary artery ligation (LPAL), we previously showed increased expression of IL-6 mRNA in lung homogenates 4 h after the onset of pulmonary ischemia ( 31 ). To determine whether IL-6 influences both new vessel growth and inflammatory cell influx, we studied wild-type (WT) and IL-6-deficient C57Bl/6J (KO) mice after LPAL (4 h and 1, 7, 14 days). We measured IL-6 protein of the lung by ELISA, the lavage cell profile of the left lung, and new systemic vessel growth with radiolabeled microspheres (14 days after LPAL) in WT and KO mice. We confirmed a 2.4-fold increase in IL-6 protein in the left lung of WT mice compared with right lung 4 h after LPAL. A significant increase in lavaged neutrophils (7.5% of total cells) was observed only in WT mice 4 h after LPAL. New vessel growth was significantly attenuated in KO relative to WT (0.7 vs. 1.9% cardiac output). In an additional series, treatment of WT mice with anti-neutrophil antibody demonstrated a reduction in lavaged neutrophils 4 h after LPAL; however, IL-6 protein remained elevated and neovascularization to the left lung (2.3% cardiac output) was not altered. These results demonstrate that IL-6 plays an important modulatory role in lung angiogenesis, but the changes are not dependent on trapped neutrophils.

scholarly journals Lung and vascular function during chronic severe pulmonary ischemia

2011 ◽  
Vol 110 (2) ◽  
pp. 538-544 ◽  
Author(s):  
Elizabeth M. Wagner ◽  
John Jenkins ◽  
Maria Grazia Perino ◽  
Adlah Sukkar ◽  
Wayne Mitzner
Keyword(s):  
Pulmonary Artery ◽  
Vascular Permeability ◽  
Lung Tissue ◽  
Lung Volume ◽  
Left Lung ◽  
Left Pulmonary Artery ◽  
Lung Pathology ◽  
Diffusing Capacity ◽  
Artery Ligation ◽  
Pulmonary Ischemia

Bronchial vascular angiogenesis takes place in a variety of lung inflammatory conditions such as asthma, cystic fibrosis, lung cancer, and chronic pulmonary thromboembolic disease. However, it is unclear whether neovascularization is predominantly appropriate and preserves lung tissue or whether it contributes further to lung pathology through edema formation and inflammation. In the present study we examined airway and lung parenchymal function 14 days after left pulmonary artery ligation. In rats as well as higher mammals, severe pulmonary ischemia results in bronchial vascular proliferation. Using labeled microspheres, we demonstrated an 18-fold increase in systemic blood flow to the ischemic left lung. Additionally, vascular remodeling extended to the tracheal venules, which showed an average 28% increase in venular diameter. Despite this increase in vascularity, airways resistance was not altered nor was methacholine responsiveness. Since these measurements include the entire lung, we suggest that the normal right lung, which represented 78% of the total lung, obscured the ability to detect a change. When functional indexes such as diffusing capacity, in situ lung volume, and vascular permeability of the left lung could be separated from right lung, significant changes were observed. Thus when comparing average left lung values of rats 14 days after left pulmonary artery ligation to left lungs of rats undergoing sham surgery, diffusing capacity of the left lung decreased by 72%, left lung volume decreased by 38%, and the vascular permeability to protein increased by 58%. No significant differences in inflammatory cell recruitment were observed, suggesting that acute ischemic inflammation had resolved. We conclude that despite the preservation of lung tissue, the proliferating bronchial neovasculature may contribute to a sustained decrement in pulmonary function.

Unintended Pulmonary Artery Ligation during PDA Ligation

2016 ◽  
Vol 19 (4) ◽  
pp. 187 ◽  
Author(s):  
Dohun Kim ◽  
Si-Wook Kim ◽  
Hong-Ju Shin ◽  
Jong-Myeon Hong ◽  
Ji Hyuk Lee ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Ductus Arteriosus ◽  
Left Lung ◽  
Left Pulmonary Artery ◽  
Chest Ct ◽  
Mechanical Ventilator ◽  
Artery Ligation ◽  
Ventilator Support ◽  
Surgical Ligation ◽  
Emergent Operation

A 10-day-old boy was transferred to our hospital due to tachypnea. Patent ductus arteriosus (PDA), 4.8 mm in diameter, with small ASD was diagnosed on echocardiography. Surgical ligation of the ductus was performed after failure of three cycles of ibuprofen. However, the ductus remained open on routine postoperative echocardiography on the second postoperative day, and chest CT revealed inadvertent ligation of the left pulmonary artery (LPA) rather than the PDA. Emergent operation successfully reopened the clipped LPA and ligated the ductus on the same (second postoperative) day.<br />Mechanical ventilator support was weaned on postoperative day 21, and the baby was discharged on postoperative day 47 with a normal left lung shadow.

scholarly journals Role of ROS in ischemia-induced lung angiogenesis

2010 ◽  
Vol 299 (4) ◽  
pp. L535-L541 ◽  
Author(s):  
Julie Nijmeh ◽  
Aigul Moldobaeva ◽  
Elizabeth M. Wagner
Keyword(s):  
Pulmonary Artery ◽  
Left Lung ◽  
Left Pulmonary Artery ◽  
Wild Type ◽  
Systemic Blood Flow ◽  
Artery Ligation ◽  
Underlying Mechanisms ◽  
Pulmonary Artery Obstruction ◽  
Artery Obstruction

Pulmonary artery obstruction and subsequent lung ischemia have been shown to induce systemic angiogenesis despite preservation of normoxia. The underlying mechanisms, however, remain poorly understood. In a mouse model of lung ischemia induced by left pulmonary artery ligation (LPAL), we showed previously, the formation of a new systemic vasculature to the ischemic lung. We hypothesize that LPAL in the mouse increases reactive oxygen species (ROS) production, and these molecules play an initiating role in subsequent lung neovascularization. We used oxidant-sensitive dyes (DHE and H2DCF-DA) to quantify ROS and measured the antioxidant-reduced glutathione (GSH) and its oxidized form (GSSG) as indicators of ROS levels after LPAL. The magnitude of systemic neovascularization was determined by measuring systemic blood flow to the left lung with radiolabeled microspheres 14 days after LPAL. An increase in ROS was observed early (30 min: 55% increase in H2DCF-DA) after LPAL, with a return to baseline by 24 h. GSH/GSSG was decreased (∼50%) 4 h after LPAL, suggesting earlier ROS upregulation. Mice treated with the antioxidant N-acetylcysteine showed attenuated angiogenesis (62% of wild-type LPAL), and mice lacking Nrf2, a transcription factor important for antioxidant synthesis, resulted in increased neovascularization (207% of wild-type LPAL). Overall, GSH/GSSG was inversely associated with the magnitude of neovascularization. These results demonstrate that LPAL induces an early and transient ROS upregulation, and ROS appear to play a role in promoting ischemia-induced angiogenesis.

Ligation of left pulmonary artery instead of patent ductus arteriosus

2020 ◽  
Vol 30 (12) ◽  
pp. 1943-1945
Author(s):  
Semih Murat Yucel ◽  
Irfan Oguz Sahin
Keyword(s):  
Surgical Treatment ◽  
Pulmonary Artery ◽  
Patent Ductus Arteriosus ◽  
Surgical Complication ◽  
Ductus Arteriosus ◽  
Left Pulmonary Artery ◽  
Artery Ligation ◽  
Surgical Closure ◽  
Post Operative Period ◽  
Patent Ductus

AbstractDuctus arteriosus is an essential component of fetal circulation. Due to occurring changes in the cardiopulmonary system physiology after birth, ductus arteriosus closes. Patent ductus arteriosus can be closed by medical or invasive (percutaneous or surgical) treatment methods. Percutaneous or surgical closure of patent ductus arteriosus can be performed for the cases that medical closure failed. Surgical treatment is often preferred method for closure of patent ductus arteriosus in the neonatal period. The most common surgical complications are pneumothorax, recurrent laryngeal nerve injury, bleeding, and recanalisation. A very rare surgical complication is left pulmonary artery ligation that has been presented in a few cases in the literature. Echocardiography control should be performed in the early post-operative period, especially in patients with clinical suspicion. If reoperation is required, it should never be delayed. We report a newborn patient whose left pulmonary artery ligated accidentally during patent ductus arteriosus closure surgery and surgical correction of this complication at the early post-operative period.

scholarly journals Phloretin Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia in Rats by Regulating the Inflammatory Response, Oxidative Stress and Apoptosis

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 743
Author(s):  
Chao Yu Hsu ◽  
Yi Sheng Lin ◽  
Wei Chun Weng ◽  
Lauren Panny ◽  
Hsiang Lai Chen ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Weight Ratio ◽  
Nuclear Antigen ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Body Weight Ratio ◽  
Proliferative Cell Nuclear Antigen ◽  
Prostate Weight ◽  
Prostatic Enlargement ◽  
Inflammatory Proteins ◽  
Proliferative Cell

The inflammatory process is proposed to be one of the factors to benign prostatic enlargement (BPH), and this is the first study examining the anti-inflammatory ability of phloretin in treating rats with testosterone-induced BPH. BPH would be induced by testosterone (10 mg/kg/day testosterone subcutaneously for 28 days), and the other groups of rats were treated with phloretin 50 mg/kg/day or 100 mg/kg/day orally (phr50 or phr100 group) after induction. Prostate weight and prostate weight to body weight ratio were significantly reduced in the Phr100 group. Reduced dihydrotestosterone without interfering with 5α-reductase was observed in the phr100 group. In inflammatory proteins, reduced IL-6, IL-8, IL-17, NF-κB, and COX-2 were seen in the phr100 group. In reactive oxygen species, malondialdehyde was reduced, and superoxide dismutase and glutathione peroxidase were elevated in the phr100 group. In apoptotic assessment, elevated cleaved caspase-3 was observed in rats of the phr100 group. Enhanced pro-apoptotic Bax and reduced anti-apoptotic Bc1-2 could be seen in the phr100 group. In histological stains, markedly decreased glandular hyperplasia and proliferative cell nuclear antigen were observed with reduced expression in the phr100 group. Meanwhile, positive cells of terminal deoxynucleotidyl transferase dUTP nick end labeling were increased in the phr100 group. In conclusion, the treatment of phloretin 100 mg/kg/day could ameliorate testosterone-induced BPH.

Abstract 12430: Vicious Circle Between Progressive Right Ventricular Dilatation and Pulmonary Regurgitation in Patients After Tetralogy of Fallot Repair? Right Heart Enlargement Promotes Flow Reversal in the Left Pulmonary Artery

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Atsuko Kato ◽  
Christian Drolet ◽  
Shi-Joon Yoo ◽  
Andrew Redington ◽  
Lars Grosse-Wortmann
Keyword(s):  
Pulmonary Artery ◽  
Tetralogy Of Fallot ◽  
Left Lung ◽  
Pulmonary Regurgitation ◽  
Left Pulmonary Artery ◽  
Flow Reversal ◽  
Left Hemithorax ◽  
Forward Flow ◽  
Lung Area ◽  
The Right

Introduction: The left pulmonary artery (LPA) contributes more than the right (RPA) to total pulmonary regurgitation (PR) in patients after tetralogy of Fallot (TOF) repair, but the mechanism of this difference is not well known. We hypothesized that unilaterally increased pulmonary vascular resistance (PVR), resulting from lung compression by the enlarged and levorotated heart leads to greater PR in the LPA. This study aimed to analyze the interplay between heart and lung size, mediastinal geometry, and differential PR. Methods: This is a single-center retrospective analysis of 50 magnetic resonance studies in patients after TOF repair. Patients with more than mild discrete branch pulmonary artery stenosis were excluded. Blood flow was measured by phase-contrast velocity encoding within the branch pulmonary arteries. On the axial image with the largest total cardiac surface area, cardiac angle (α) between the thoracic anterior-posterior line and the interventricular septum, right and left lung areas as well as right and left hemithorax areas were measured (Figure). Results: There was no difference in LPA and RPA diameters. The LPA showed significantly less total forward flow (p=0.04), smaller net forward flow (p=<0.001), and greater RF (p=0.001) than the RPA. Left lung area was smaller than the right (p<0.001). RVEDVi correlated with LPA RF (R=0.48, p<0.001), but not with RPA RF. Larger RVEDVi correlated with a larger α angle (R=0.46, p<0.001), i.e. a more leftward cardiac axis and with smaller left lung area (R=-0.58, p<0.001). LPA RF, but not RPA RF, correlated inversely with left lung area indexed to the left hemithorax area (R=-0.34, p=0.02). Conclusions: An enlarged and levorotated heart - as a result of PR - is associated with smaller left lung size, and augments diastolic flow reversal in the LPA, presumably via increased left PVR. By imposing a further volume load on the RV, LPA regurgitation may thus close a positive feed-back loop of PR and RV dilatation.

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