Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis
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Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis. / Knipe, Rachel S.; Spinney, Jillian J.; Abe, Elizabeth A.; Probst, Clemens K.; Franklin, Alicia; Logue, Amanda; Giacona, Francesca; Drummond, Matt; Griffith, Jason; Brazee, Patricia L.; Hariri, Lida P.; Montesi, Sydney B.; Black, Katherine E.; Hla, Timothy; Kuo, Andrew; Cartier, Andreane; Engelbrecht, Eric; Christoffersen, Christina; Shea, Barry S.; Tager, Andrew M.; Medoff, Benjamin D.
In: American Journal of Respiratory Cell and Molecular Biology, Vol. 66, No. 1, 2022, p. 38-52.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis
AU - Knipe, Rachel S.
AU - Spinney, Jillian J.
AU - Abe, Elizabeth A.
AU - Probst, Clemens K.
AU - Franklin, Alicia
AU - Logue, Amanda
AU - Giacona, Francesca
AU - Drummond, Matt
AU - Griffith, Jason
AU - Brazee, Patricia L.
AU - Hariri, Lida P.
AU - Montesi, Sydney B.
AU - Black, Katherine E.
AU - Hla, Timothy
AU - Kuo, Andrew
AU - Cartier, Andreane
AU - Engelbrecht, Eric
AU - Christoffersen, Christina
AU - Shea, Barry S.
AU - Tager, Andrew M.
AU - Medoff, Benjamin D.
N1 - Publisher Copyright: © 2022 by the American Thoracic Society.
PY - 2022
Y1 - 2022
N2 - 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-S1pr12/2) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC-S1pr12/2 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-S1pr12/2 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.
AB - 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-S1pr12/2) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC-S1pr12/2 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-S1pr12/2 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.
KW - Lung fibrosis
KW - Sphingosine-1- phosphate 1 receptor
KW - Sphingosine-1-phosphate
KW - Vascular permeability
U2 - 10.1165/rcmb.2020-0408OC
DO - 10.1165/rcmb.2020-0408OC
M3 - Journal article
C2 - 34343038
AN - SCOPUS:85122314979
VL - 66
SP - 38
EP - 52
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 1
ER -
ID: 290117293