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Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis
- Source :
- Am J Respir Cell Mol Biol
- Publication Year :
- 2021
-
Abstract
- Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell–(EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC-S1pr1(−/−)) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC-S1pr1(−/−) mice had increased and persistent vascular permeability compared with wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC-S1pr1(−/−) mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM-overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.
- Subjects :
- Pulmonary and Respiratory Medicine
Clinical Biochemistry
Vascular permeability
Mice, Transgenic
Lung injury
Bleomycin
Capillary Permeability
Idiopathic pulmonary fibrosis
chemistry.chemical_compound
Fibrosis
Sphingosine
Pulmonary fibrosis
Medicine
Animals
RNA-Seq
Molecular Biology
Blood Coagulation
Lung
Sphingosine-1-Phosphate Receptors
S1PR1
Original Research
business.industry
Endothelial Cells
Cell Biology
respiratory system
medicine.disease
Idiopathic Pulmonary Fibrosis
respiratory tract diseases
Mice, Inbred C57BL
medicine.anatomical_structure
Phenotype
chemistry
Cancer research
Lysophospholipids
Single-Cell Analysis
business
Gene Deletion
Subjects
Details
- ISSN :
- 15354989
- Volume :
- 66
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- American journal of respiratory cell and molecular biology
- Accession number :
- edsair.doi.dedup.....c67d11fc3fdced4d69fa7beeeb07c905