title: Differential effects of sphingosine 1-phosphate receptors on airway and vascular barrier function in the murine lung.
abstract: The therapeutic options for ameliorating the profound vascular permeability, alveolar flooding, and organ dysfunction that accompanies acute inflammatory lung injury (ALI) remain limited. Extending our previous finding that the intravenous administration of the sphingolipid angiogenic factor, sphingosine 1-phosphate (S1P), attenuates inflammatory lung injury and vascular permeability via ligation of S1PR(1), we determine that a direct intratracheal or intravenous administration of S1P, or a selective S1P receptor (S1PR(1)) agonist (SEW-2871), produces highly concentration-dependent barrier-regulatory responses in the murine lung. The intratracheal or intravenous administration of S1P or SEW-2871 at < 0.3 mg/kg was protective against LPS-induced murine lung inflammation and permeability. However, intratracheal delivery of S1P at 0.5 mg/kg (for 2 h) resulted in significant alveolar-capillary barrier disruption (with a 42% increase in bronchoalveolar lavage protein), and produced rapid lethality when delivered at 2 mg/kg. Despite the greater selectivity for S1PR(1), intratracheally delivered SEW-2871 at 0.5 mg/kg also resulted in significant alveolar-capillary barrier disruption, but was not lethal at 2 mg/kg. Consistent with the S1PR(1) regulation of alveolar/vascular barrier function, wild-type mice pretreated with the S1PR(1) inverse agonist, SB-649146, or S1PR(1)(+/-) mice exhibited reduced S1P/SEW-2871-mediated barrier protection after challenge with LPS. In contrast, S1PR(2)(-/-) knockout mice as well as mice with reduced S1PR(3) expression (via silencing S1PR3-containing nanocarriers) were protected against LPS-induced barrier disruption compared with control mice. These studies underscore the potential therapeutic effects of highly selective S1PR(1) receptor agonists in reducing inflammatory lung injury, and highlight the critical role of the S1P delivery route, S1PR(1) agonist concentration, and S1PR(1) expression in target tissues.
authors.affiliation: Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Tamara
authors.initials: T
authors.lastname: Mirzapoiazova
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Singleton
authors.forename: Eddie T
authors.initials: ET
authors.lastname: Chiang
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Evenoski
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Biji
authors.initials: B
authors.lastname: Mathew
authors.forename: Aliya
authors.initials: A
authors.lastname: Husain
authors.forename: Jaideep
authors.initials: J
authors.lastname: Moitra
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Sun
authors.forename: Luis
authors.initials: L
authors.lastname: Nunez
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D055371:Acute Lung Injury / Q000503:physiopathology; D000818:Animals; D015824:Blood-Air Barrier / Q000187:drug effects / Q000503:physiopathology*; D001826:Body Fluids; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D054314:Drug Inverse Agonism; D017353:Gene Deletion; D020868:Gene Silencing / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010069:Oxadiazoles / Q000819:agonists / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013876:Thiophenes / Q000819:agonists / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes