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.

scholarly journals Thrombin-mediated activation of Akt signaling contributes to pulmonary vascular remodeling in pulmonary hypertension

2013 ◽  
Vol 1 (7) ◽  
pp. e00190 ◽  
Author(s):  
Aiko Ogawa ◽  
Amy L. Firth ◽  
Sanae Ariyasu ◽  
Ichiro Yamadori ◽  
Hiromi Matsubara ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Akt Signaling ◽  
Pulmonary Vascular Remodeling

scholarly journals Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension

2016 ◽  
Vol 360 (2) ◽  
pp. 267-279 ◽  
Author(s):  
Robert J. Aiello ◽  
Patricia-Ann Bourassa ◽  
Qing Zhang ◽  
Jeffrey Dubins ◽  
Daniel R. Goldberg ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Tryptophan Hydroxylase ◽  
Pulmonary Vascular Remodeling ◽  
Rat Models

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 2-Methoxyestradiol Attenuates the Development and Retards the Progression of Hypoxia-And Alpha-Naphthylthiourea-Induced Pulmonary Hypertension

PRILOZI ◽  
2021 ◽  
Vol 42 (1) ◽  
pp. 41-51
Author(s):  
Stevan P. Tofovic ◽  
Xinchen Zhang ◽  
Tom J. Jones ◽  
Gordana Petruševska
Keyword(s):  
Pulmonary Hypertension ◽  
Acute Lung Injury ◽  
Pleural Effusion ◽  
Lung Injury ◽  
Right Ventricle ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Biological Effects ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling

Abstract Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that dysregulated estradiol (E2) metabolism influences the development of PH and that some of the biological effects of E2 are mediated by its major non-estrogenic metabolite, 2-metyhoxyestradiol (2ME). The objective of this study was to examine effects of 2ME in chronic hypoxia (CH)-induced PH and alpha-naphthylthiourea (ANTU)-induced acute lung injury and PH. In addition, we investigated the effects of exposure to different levels of CH on development of PH. Chronic exposure to 15% or 10% oxygen produced similar increases in right ventricle peak systolic pressure (RVPSP) and pulmonary vascular remodeling, but oxygen concentration-dependent increase in hematocrit. Notably, right ventricle (RV) hypertrophy correlated with level of hypoxia and hematocrit, rather than with magnitude of RVPSP. The latter suggests that, in addition to increased afterload, hypoxia (via increased hematocrit) significantly contributes to RV hypertrophy in CH model of PH. In CH-PH rats, preventive and curative 2ME treatments reduced both elevated RVPSP and pulmonary vascular remodeling. Curative treatment with 2ME was more effective in reducing hematocrit and right ventricular hypertrophy, as compared to preventive treatment. Single ANTU injection produced lung injury, i.e., increased lungs weight and induced pleural effusion. Treatment with 2ME significantly reduced pleural effusion and, more importantly, eliminated acute mortality induced by ANTU (33% vs 0%, ANTU vs. ANTU+2ME group). Chronic treatment with ANTU induced PH and RV hypertrophy and increased lungs weight. 2-ME significantly attenuated severity of disease (i.e., reduced RVPSP, RV hypertrophy and pulmonary vascular injury). This study demonstrates that 2ME has beneficial effects in chronic hypoxia- and acute lung injury-induced PH and provides preclinical justification for clinical evaluation of 2ME in pulmonary hypertension.

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

2003 ◽  
Vol 285 (1) ◽  
pp. L199-L208 ◽  
Author(s):  
Jan Herget ◽  
Jana Novotná ◽  
Jana Bíbová ◽  
Viera Povýšilová ◽  
Marie Vaňková ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Causative Factor ◽  
Systemic Arterial Pressure ◽  
Collagenolytic Activity ◽  
Pulmonary Vascular Remodeling ◽  
Arterial Blood ◽  
Fraction Of Inspired Oxygen ◽  
Lung Vessels

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 ± 3 mmHg in hypoxic controls, 24 ± 1 mmHg in Batimastat-treated hypoxic rats, and 16 ± 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

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