TY - JOUR
T1 - Role of sphingolipids in murine radiation-induced lung injury
T2 - Protection by sphingosine 1-phosphate analogs
AU - Mathew, Biji
AU - Jacobson, Jeffrey R.
AU - Berdyshev, Evgeny
AU - Huang, Yong
AU - Sun, Xiaoguang
AU - Zhao, Yutong
AU - Gerhold, Lynnette M.
AU - Siegler, Jessica
AU - Evenoski, Carrie
AU - Wang, Ting
AU - Zhou, Tong
AU - Zaidi, Rafe
AU - Moreno-Vinasco, Liliana
AU - Bittman, Robert
AU - Chen, Chin Tu
AU - LaRiviere, Patrick J.
AU - Sammani, Saad
AU - Lussier, Yves A
AU - Dudek, Steven M.
AU - Natarajan, Viswanathan
AU - Weichselbaum, Ralph R.
AU - Garcia, Joe G.N.
PY - 2011/10
Y1 - 2011/10
N2 - 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., 2x/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2x/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.
AB - 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., 2x/wk) and to a lesser degree by SEW-2871 (1 mg/kg i.p., 2x/wk), compared with those in controls. These results support the targeting of S1P signaling as a novel therapeutic strategy in RILI.
KW - FTY720
KW - Gene dysregulation
KW - S1P receptors
KW - fTysiponate
UR - http://www.scopus.com/inward/record.url?scp=80053928581&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053928581&partnerID=8YFLogxK
U2 - 10.1096/fj.11-183970
DO - 10.1096/fj.11-183970
M3 - Article
C2 - 21712494
AN - SCOPUS:80053928581
SN - 0892-6638
VL - 25
SP - 3388
EP - 3400
JO - FASEB Journal
JF - FASEB Journal
IS - 10
ER -