Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-α

2003 ◽  
Vol 285 (5) ◽  
pp. L1046-L1054 ◽  
Author(s):  
Timothy D. Le Cras ◽  
William D. Hardie ◽  
Karen Fagan ◽  
Jeffrey A. Whitsett ◽  
Thomas R. Korfhagen

Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of transforming growth factor (TGF)-α and its receptor EGFR have been associated. The aim of this study was to determine whether overexpression of TGF-α disrupts pulmonary vascular development and causes pulmonary hypertension. Lung-specific expression of TGF-α in transgenic mice was driven with the human surfactant protein (SP)-C promoter. Pulmonary arteriograms and arterial counts show that pulmonary vascular development was severely disrupted in TGF-α mice. TGF-α mice developed severe pulmonary hypertension and vascular remodeling characterized by abnormally extensive muscularization of small pulmonary arteries. Pulmonary vascular development was significantly improved and pulmonary hypertension and vascular remodeling were prevented in bitransgenic mice expressing both TGF-α and a dominant-negative mutant EGF receptor under the control of the SP-C promoter. Vascular endothelial growth factor (VEGF-A), an important angiogenic factor produced by the distal epithelium, was decreased in the lungs of TGF-α adults and in the lungs of infant TGF-α mice before detectable abnormalities in pulmonary vascular development. Hence, overexpression of TGF-α caused severe pulmonary vascular disease, which was mediated through EGFR signaling in distal epithelial cells. Reductions in VEGF may contribute to the pathogenesis of pulmonary vascular disease in TGF-α mice.

2015 ◽  
Vol 309 (4) ◽  
pp. L333-L347 ◽  
Author(s):  
Alistair C. Church ◽  
Damien H. Martin ◽  
Roger Wadsworth ◽  
Gareth Bryson ◽  
Andrew J. Fisher ◽  
...  

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.


CHEST Journal ◽  
1986 ◽  
Vol 89 (5) ◽  
pp. 694-698 ◽  
Author(s):  
Shigeo Yamaki ◽  
Togo Horiuchi ◽  
Makoto Miura ◽  
Yasuyuki Suzuki ◽  
Eiji Ishizawa ◽  
...  

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