scholarly journals Endothelial Adenosine Monophosphate-Activated Protein Kinase-Alpha1 Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1913
Author(s):  
Ahmed Elsaie ◽  
Renuka T. Menon ◽  
Amrit K. Shrestha ◽  
Sharada H. Gowda ◽  
Nidhy P. Varghese ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Kinase ◽  
Lung Injury ◽  
Bronchopulmonary Dysplasia ◽  
Adenosine Monophosphate ◽  
Causative Factor ◽  
Nuclear Antigen ◽  
Tubule Formation ◽  
Neonatal Mice ◽  
Deficient Mice

Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKα1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKα1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKα1-sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1–P14. We also performed tubule formation assays on control- or AMPKα1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKα1-deficient mice. AMPKα1 siRNA knocked down AMPKα1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKα1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKα1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.

Anti-neutrophil chemokine preserves alveolar development in hyperoxia-exposed newborn rats

2001 ◽  
Vol 281 (2) ◽  
pp. L336-L344 ◽  
Author(s):  
Richard L. Auten ◽  
S. Nicholas Mason ◽  
David T. Tanaka ◽  
Karen Welty-Wolf ◽  
Mary H. Whorton
Keyword(s):  
Lung Injury ◽  
Bronchopulmonary Dysplasia ◽  
Antigen Expression ◽  
Lung Compliance ◽  
Nuclear Antigen ◽  
Brdu Incorporation ◽  
Newborn Rats ◽  
Alveolar Volume ◽  
Alveolar Development ◽  
Air Control

Inflammation may contribute to lung injury and impaired alveolar development in bronchopulmonary dysplasia. We treated hyperoxia-exposed newborn rats with antibodies to the neutrophil chemokine cytokine-induced neutrophil chemoattractant-1 (CINC-1) during 95% O2exposure to reduce adverse effects of hyperoxia-induced inflammation on lung development. Rats were exposed at birth to air, 95% O2, or 95% O2+ anti-CINC-1 (injected on days 3 and 4). Bromodeoxyuridine (BrdU) was injected 6 h before death. Anti-CINC-1 treatment improved weight gain but not survival at day 8. Anti-CINC-1 reduced bronchoalveolar lavage neutrophils at day 8 to levels equal to air controls. Total detectable lung CINC-1 was reduced to air control levels. Lung compliance was improved by anti-CINC-1, achieving air control levels in the 10-μg anti-CINC-1 group. Anti-CINC-1 preserved proliferating cell nuclear antigen expression in airway epithelium despite 95% O2exposure. BrdU incorporation was depressed by hyperoxia but preserved by anti-CINC-1 to levels similar to air control. Alveolar volume and surface density were decreased by hyperoxia but preserved by anti-CINC-1 to levels equal to air control. Blockade of neutrophil influx in newborns may avert early lung injury and avoid alveolar developmental arrest that contributes to bronchopulmonary dysplasia.

scholarly journals CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia

2011 ◽  
Vol 300 (3) ◽  
pp. L330-L340 ◽  
Author(s):  
Shaoyi Chen ◽  
Min Rong ◽  
Astrid Platteau ◽  
Dorothy Hehre ◽  
Heather Smith ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Bronchopulmonary Dysplasia ◽  
Vascular Remodeling ◽  
Tissue Growth ◽  
Clara Cell ◽  
Alveolar Type ◽  
Lung Pathology ◽  
Pulmonary Vascular Remodeling ◽  
Neonatal Mice ◽  
Gsk 3Β

The pathological hallmarks of bronchopulmonary dysplasia (BPD), one of the most common long-term pulmonary complications associated with preterm birth, include arrested alveolarization, abnormal vascular growth, and variable interstitial fibrosis. Severe BPD is often complicated by pulmonary hypertension characterized by excessive pulmonary vascular remodeling and right ventricular hypertrophy that significantly contributes to the mortality and morbidity of these infants. Connective tissue growth factor (CTGF) is a multifunctional protein that coordinates complex biological processes during tissue development and remodeling. We have previously shown that conditional overexpression of CTGF in airway epithelium under the control of the Clara cell secretory protein promoter results in BPD-like architecture in neonatal mice. In this study, we have generated a doxycycline-inducible double transgenic mouse model with overexpression of CTGF in alveolar type II epithelial (AT II) cells under the control of the surfactant protein C promoter. Overexpression of CTGF in neonatal mice caused dramatic macrophage and neutrophil infiltration in alveolar air spaces and perivascular regions. Overexpression of CTGF also significantly decreased alveolarization and vascular development. Furthermore, overexpression of CTGF induced pulmonary vascular remodeling and pulmonary hypertension. Most importantly, we have also demonstrated that these pathological changes are associated with activation of integrin-linked kinase (ILK)/glucose synthesis kinase-3β (GSK-3β)/β-catenin signaling. These data indicate that overexpression of CTGF in AT II cells results in lung pathology similar to those observed in infants with severe BPD and that ILK/GSK-3β/β-catenin signaling may play an important role in the pathogenesis of severe BPD.

scholarly journals Serotonin 2A receptor inhibition protects against the development of pulmonary hypertension and pulmonary vascular remodeling in neonatal mice

2018 ◽  
Vol 314 (5) ◽  
pp. L871-L881 ◽  
Author(s):  
Cassidy Delaney ◽  
Laurie Sherlock ◽  
Susan Fisher ◽  
Joanne Maltzahn ◽  
Clyde Wright ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Vascular Remodeling ◽  
Tryptophan Hydroxylase ◽  
Mapk Signaling ◽  
Akt Signaling ◽  
Pulmonary Vascular Remodeling ◽  
Neonatal Mice ◽  
Neonatal Lung ◽  
Neonatal Lung Injury

Pulmonary hypertension (PH) complicating bronchopulmonary dysplasia (BPD) worsens clinical outcomes in former preterm infants. Increased serotonin (5-hydroxytryptamine, 5-HT) signaling plays a prominent role in PH pathogenesis and progression in adults. We hypothesized that increased 5-HT signaling contributes to the pathogenesis of neonatal PH, complicating BPD and neonatal lung injury. Thus, we investigated 5-HT signaling in neonatal mice exposed to bleomycin, previously demonstrated to induce PH and alveolar simplification. Newborn wild-type mice received intraperitoneal PBS, ketanserin (1 mg/kg), bleomycin (3 U/kg) or bleomycin (3 U/kg) plus ketanserin (1 mg/kg) three times weekly for 3 wk. Following treatment with bleomycin, pulmonary expression of the rate-limiting enzyme of 5-HT synthesis, tryptophan hydroxylase-1 (Tph1), was significantly increased. Bleomycin did not affect pulmonary 5-HT 2A receptor (R) expression, but did increase pulmonary gene expression of the 5-HT 2BR and serotonin transporter. Treatment with ketanserin attenuated bleomycin-induced PH (increased RVSP and RVH) and pulmonary vascular remodeling (decreased vessel density and increased muscularization of small vessels). In addition, we found that treatment with ketanserin activated pulmonary MAPK and Akt signaling in mice exposed to bleomycin. We conclude that 5-HT signaling is increased in a murine model of neonatal PH and pharmacological inhibition of the 5-HT 2AR protects against the development of PH in neonatal lung injury. We speculate this occurs through restoration of MAPK signaling and increased Akt signaling.

Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-κB and AP-1

2002 ◽  
Vol 282 (6) ◽  
pp. L1209-L1221 ◽  
Author(s):  
Luis A. Ortiz ◽  
Hunter C. Champion ◽  
Joseph A. Lasky ◽  
Federica Gambelli ◽  
Evelyn Gozal ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Injury ◽  
Mrna Expression ◽  
Ace Inhibitor ◽  
Pulmonary Arterial ◽  
Factor Α ◽  
Deficient Mice ◽  
Enalapril Treatment ◽  
Necrosis Factor ◽  
Inhibitor Treatment

The present study was undertaken to investigate the effects of treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in a mouse model of pulmonary hypertension induced by bleomycin. Bleomycin-induced lung injury in mice is mediated by enhanced tumor necrosis factor-α (TNF) expression in the lung, which determines the murine strain sensitivity to bleomycin, and murine strains are sensitive (C57BL/6) or resistant (BALB/c). Bleomycin induced significant pulmonary hypertension in C57BL/6, but not in BALB/c, mice; average pulmonary arterial pressure (PAP) was 26.4 ± 2.5 mmHg ( P < 0.05) vs. 15.2 ± 3 mmHg, respectively. Bleomycin treatment induced activation of nuclear factor (NF)-κB and activator protein (AP)-1 and enhanced collagen and TNF mRNA expression in the lung of C57BL/6 but not in BALB/c mice. Double TNF receptor-deficient mice (in a C57BL/6 background) that do not activate NF-κB or AP-1 in response to bleomycin did not develop bleomycin-induced pulmonary hypertension (PAP 14 ± 3 mmHg). Treatment of C57BL/6 mice with enalapril significantly ( P < 0.05) inhibited the development of pulmonary hypertension after bleomycin exposure. Enalapril treatment inhibited NF-κB and AP-1 activation, the enhanced TNF and collagen mRNA expression, and the deposition of collagen in bleomycin-exposed C57BL/6 mice. These results suggest that ACE inhibitor treatment decreases lung injury and the development of pulmonary hypertension in bleomycin-treated mice.

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