TY - JOUR
T1 - "Pulmonary Endothelial Cell Barrier Enhancement by Novel FTY720 Analogs
T2 - Methoxy-FTY720, Fluoro-FTY720, and β-Glucuronide-FTY720"
AU - Camp, Sara M.
AU - Chiang, Eddie T.
AU - Sun, Chaode
AU - Usatyuk, Peter V.
AU - Bittman, Robert
AU - Natarajan, Viswanathan
AU - Garcia, Joe G.N.
AU - Dudek, Steven M.
N1 - Funding Information:
This work was supported by the National Institutes of Health grants P01HL 58064 (JGNG) and P01HL 98050 (VN). This article is dedicated to the memory of Dr. Robert Bittman. Dr. Bittman was a dear friend and exceptional lipid biochemist without whose insight, enthusiasm, and friendship this research would have never been completed. The conception, design, and synthesis of the novel compounds described in this study were performed entirely under his direction and would not have been possible without his vast experience and outstanding scientific acumen.
Funding Information:
This work was supported by the National Institutes of Health grants P01HL 58064 (JGNG) and P01HL 98050 (VN). This article is dedicated to the memory of Dr. Robert Bittman. Dr. Bittman was a dear friend and exceptional lipid biochemist without whose insight, enthusiasm, and friendship this research would have never been completed. The conception, design, and synthesis of the novel compounds described in this study were performed entirely under his direction and would not have been possible without his vast experience and outstanding scientific acumen.
Publisher Copyright:
© 2015 Elsevier Ireland Ltd. All rights reserved.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Effective therapeutic agents are lacking for the prevention and reversal of vascular leak, a frequent pathophysiologic result of inflammatory processes such as acute respiratory distress syndrome (ARDS) and sepsis. We previously demonstrated the potent barrier-enhancing effects of related compounds sphingosine 1-phosphate (S1P), the pharmaceutical agent FTY720, and its analog (S)-FTY720 phosphonate (Tys) in models of inflammatory lung injury. In this study, we characterize additional novel FTY720 analogs for their potential to reduce vascular leak as well as utilize them as tools to better understand the mechanisms by which this class of agents modulates permeability. Transendothelial resistance (TER) and labeled dextran studies demonstrate that (R)-methoxy-FTY720 ((R)-OMe-FTY), (R)/(S)-fluoro-FTY720 (FTY-F), and β-glucuronide-FTY720 (FTY-G) compounds display in vitro barrier-enhancing properties comparable or superior to FTY720 and S1P. In contrast, the (S)-methoxy-FTY720 ((S)-OMe-FTY) analog disrupts lung endothelial cell (EC) barrier integrity in TER studies in association with actin stress fiber formation and robust intracellular calcium release, but independent of myosin light chain or ERK phosphorylation. Additional mechanistic studies with (R)-OMe-FTY, FTY-F, and FTY-G suggest that lung EC barrier enhancement is mediated through lipid raft signaling, Gi-linked receptor coupling to downstream tyrosine phosphorylation events, and S1PR1-dependent receptor ligation. These results provide important mechanistic insights into modulation of pulmonary vascular barrier function by FTY720-related compounds and highlight common signaling events that may assist the development of novel therapeutic tools in the prevention or reversal of the pulmonary vascular leak that characterizes ARDS.
AB - Effective therapeutic agents are lacking for the prevention and reversal of vascular leak, a frequent pathophysiologic result of inflammatory processes such as acute respiratory distress syndrome (ARDS) and sepsis. We previously demonstrated the potent barrier-enhancing effects of related compounds sphingosine 1-phosphate (S1P), the pharmaceutical agent FTY720, and its analog (S)-FTY720 phosphonate (Tys) in models of inflammatory lung injury. In this study, we characterize additional novel FTY720 analogs for their potential to reduce vascular leak as well as utilize them as tools to better understand the mechanisms by which this class of agents modulates permeability. Transendothelial resistance (TER) and labeled dextran studies demonstrate that (R)-methoxy-FTY720 ((R)-OMe-FTY), (R)/(S)-fluoro-FTY720 (FTY-F), and β-glucuronide-FTY720 (FTY-G) compounds display in vitro barrier-enhancing properties comparable or superior to FTY720 and S1P. In contrast, the (S)-methoxy-FTY720 ((S)-OMe-FTY) analog disrupts lung endothelial cell (EC) barrier integrity in TER studies in association with actin stress fiber formation and robust intracellular calcium release, but independent of myosin light chain or ERK phosphorylation. Additional mechanistic studies with (R)-OMe-FTY, FTY-F, and FTY-G suggest that lung EC barrier enhancement is mediated through lipid raft signaling, Gi-linked receptor coupling to downstream tyrosine phosphorylation events, and S1PR1-dependent receptor ligation. These results provide important mechanistic insights into modulation of pulmonary vascular barrier function by FTY720-related compounds and highlight common signaling events that may assist the development of novel therapeutic tools in the prevention or reversal of the pulmonary vascular leak that characterizes ARDS.
KW - Acute respiratory distress syndrome
KW - Endothelial barrier regulation
KW - FTY720
KW - G protein-couple receptors
KW - Sphingosine 1-phosphate
UR - http://www.scopus.com/inward/record.url?scp=84954388268&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84954388268&partnerID=8YFLogxK
U2 - 10.1016/j.chemphyslip.2015.10.004
DO - 10.1016/j.chemphyslip.2015.10.004
M3 - Article
C2 - 26496151
AN - SCOPUS:84954388268
SN - 0009-3084
VL - 194
SP - 85
EP - 93
JO - Chemistry and Physics of Lipids
JF - Chemistry and Physics of Lipids
ER -