title: Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro.
abstract: Novel therapies are needed to address the vascular endothelial cell (EC) barrier disruption that occurs in inflammatory diseases such as acute lung injury (ALI). We previously demonstrated the potent barrier-enhancing effects of both sphingosine 1-phosphate (S1P) and the structurally similar compound FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] in inflammatory lung injury. In this study, we examined the therapeutic potential of several novel FTY720 analogs to reduce vascular leak. Similar to S1P and FTY720, the (R)- and (S)-enantiomers of FTY720 phosphonate and enephosphonate analogs produce sustained EC barrier enhancement in vitro, as seen by increases in transendothelial electrical resistance (TER). In contrast, the (R)- and (S)-enantiomers of FTY720-regioisomeric analogs disrupt EC barrier integrity in a dose-dependent manner. Barrier-enhancing FTY720 analogs demonstrate a wider protective concentration range in vitro (1-50 microM) and greater potency than either S1P or FTY720. In contrast to FTY720-induced EC barrier enhancement, S1P and the FTY720 analogs dramatically increase TER within minutes in association with cortical actin ring formation. Unlike S1P, these FTY720 analogs exhibit differential phosphorylation effects without altering the intracellular calcium level. Inhibitor studies indicate that barrier enhancement by these analogs involves signaling via G(i)-coupled receptors, tyrosine kinases, and lipid rafts. Consistent with these in vitro responses, the (S)-phosphonate analog of FTY720 significantly reduces multiple indices of alveolar and vascular permeability in a lipopolysaccharide-mediated murine model of ALI (without significant alterations in leukocyte counts). These results demonstrate the capacity for FTY720 analogs to significantly decrease pulmonary vascular leakage and inflammation in vitro and in vivo.
authors: Department of Medicine, University of Chicago, IL 60637, USA.
authors: S M
authors: SM
authors: Camp
authors: R
authors: R
authors: Bittman
authors: E T
authors: ET
authors: Chiang
authors: L
authors: L
authors: Moreno-Vinasco
authors: T
authors: T
authors: Mirzapoiazova
authors: S
authors: S
authors: Sammani
authors: X
authors: X
authors: Lu
authors: C
authors: C
authors: Sun
authors: M
authors: M
authors: Harbeck
authors: M
authors: M
authors: Roe
authors: V
authors: V
authors: Natarajan
authors: J G N
authors: JG
authors: Garcia
authors: S M
authors: SM
authors: Dudek
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology*; D002460:Cell Line; D000068876:Fingolimod Hydrochloride / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000138:chemical synthesis* / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011409:Propylene Glycols / Q000138:chemical synthesis* / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C000606732:2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol phosphonate; D018836:Inflammation Mediators; D063065:Organophosphonates; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine