title: Role of sphingolipids in murine radiation-induced lung injury: protection by sphingosine 1-phosphate analogs.
abstract: Clinically significant radiation-induced lung injury (RILI) is a common toxicity in patients administered thoracic radiotherapy. Although the molecular etiology is poorly understood, we previously characterized a murine model of RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and genome-wide lung gene mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We hypothesized that sphingolipid signaling components serve as modulators and novel therapeutic targets of RILI. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to sphingosine 1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and lung tissue. Mice with a targeted deletion of SphK1 (SphK1(-/-)) or with reduced expression of S1P receptors (S1PR1(+/-), S1PR2(-/-), and S1PR3(-/-)) exhibited marked RILI susceptibility. Finally, studies of 3 potent vascular barrier-protective S1P analogs, FTY720, (S)-FTY720-phosphonate (fTyS), and SEW-2871, identified significant RILI attenuation and radiation-induced gene dysregulation by the phosphonate analog, fTyS (0.1 and 1 mg/kg i.p., 2×/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2×/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.
authors.affiliation: Institute for Personalized Respiratory Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Biji
authors.initials: B
authors.lastname: Mathew
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Evgeny
authors.initials: E
authors.lastname: Berdyshev
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Sun
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Lynnette M
authors.initials: LM
authors.lastname: Gerhold
authors.forename: Jessica
authors.initials: J
authors.lastname: Siegler
authors.forename: Carrie
authors.initials: C
authors.lastname: Evenoski
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Rafe
authors.initials: R
authors.lastname: Zaidi
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.forename: Chin Tu
authors.initials: CT
authors.lastname: Chen
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: LaRiviere
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002518:Ceramides / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology; D008168:Lung / Q000528:radiation effects*; D008246:Lysophospholipids / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011833:Radiation Injuries, Experimental; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002518:Ceramides; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine