Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-β-driven pulmonary vascular remodeling
| Autor: | Maricela Castellon, Jiwang Chen, Marcelo G. Bonini, Suellen D. S. Oliveira, Xiaowu Gu, Roberto F. Machado, Richard D. Minshall, Michael H. Elliott |
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| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine ARDS Pathology Time Factors Physiology Caveolin 1 030204 cardiovascular system & hematology 0302 clinical medicine Transforming Growth Factor beta Endothelial dysfunction Lung Respiratory Distress Syndrome Middle Aged Endothelial stem cell Cytokines Female Inflammation Mediators medicine.symptom Bronchoalveolar Lavage Fluid Research Article Adult Pulmonary and Respiratory Medicine medicine.medical_specialty Nitric Oxide Synthase Type III Acute Lung Injury Inflammation Acute respiratory distress Pulmonary Artery Vascular Remodeling Lung injury Biology Bone Morphogenetic Protein Receptors Type II Models Biological 03 medical and health sciences Physiology (medical) medicine Animals Humans Cell Shape Aged Interleukin-6 Endothelial Cells Cell Biology medicine.disease Actins Mice Inbred C57BL 030104 developmental biology Proteolysis Receptors Transforming Growth Factor beta Transforming growth factor |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 312:L760-L771 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | Endothelial cell (EC) activation and vascular injury are hallmark features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Caveolin-1 (Cav-1) is highly expressed in pulmonary microvascular ECs and plays a key role in maintaining vascular homeostasis. The aim of this study was to determine if the lung inflammatory response to Escherichia coli lipopolysaccharide (LPS) promotes priming of ECs via Cav-1 depletion and if this contributes to the onset of pulmonary vascular remodeling. To test the hypothesis that depletion of Cav-1 primes ECs to respond to profibrotic signals, C57BL6 wild-type (WT) mice ( Tie2.Cre−;Cav1fl/fl) were exposed to nebulized LPS (10 mg; 1 h daily for 4 days) and compared with EC-specific Cav1−/−( Tie2.Cre+;Cav1fl/fl). After 96 h of LPS exposure, total lung Cav-1 and bone morphogenetic protein receptor type II (BMPRII) expression were reduced in WT mice. Moreover, plasma albumin leakage, infiltration of immune cells, and levels of IL-6/IL-6R and transforming growth factor-β (TGF-β) were elevated in both LPS-treated WT and EC-Cav1−/−mice. Finally, EC-Cav1−/−mice exhibited a modest increase in microvascular thickness basally and even more so on exposure to LPS (96 h). EC-Cav1−/−mice and LPS-treated WT mice exhibited reduced BMPRII expression and endothelial nitric oxide synthase uncoupling, which along with increased TGF-β promoted TGFβRI-dependent SMAD-2/3 phosphorylation. Finally, human lung sections from patients with ARDS displayed reduced EC Cav-1 expression, elevated TGF-β levels, and severe pulmonary vascular remodeling. Thus EC Cav-1 depletion, oxidative stress-mediated reduction in BMPRII expression, and enhanced TGF-β-driven SMAD-2/3 signaling promote pulmonary vascular remodeling in inflamed lungs. |
| Databáze: | OpenAIRE |
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