title: The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury.
abstract: OBJECTIVE
  We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. The objective of the present study was to evaluate the effect of octadecenyl thiophosphate (OTP), a novel rationally designed, metabolically stabilized LPA mimic, on radiation-induced apoptosis of intestinal epithelial cells in vitro and in vivo.
  
  
  METHODS
  The receptors and signaling pathways activated by OTP were examined in IEC-6 and RH7777 cell lines and wild-type and LPA(1) and LPA(2) knockout mice exposed to different apoptotic stimuli.
  
  
  RESULTS
  OTP was more efficacious than LPA in reducing gamma irradiation-, camptothecin-, or tumor necrosis factor alpha/cycloheximide-induced apoptosis and caspase-3-8, and caspase-9 activity in the IEC-6 cell line. In RH7777 cells lacking LPA receptors, OTP selectively protected LPA(2) but not LPA(1) and LPA(3) transfectants. In C57BL/6 and LPA(1) knockout mice exposed to 15 Gy gamma irradiation, orally applied OTP reduced the number of apoptotic bodies and activated caspase-3-positive cells but was ineffective in LPA(2) knockout mice. OTP, with higher efficacy than LPA, enhanced intestinal crypt survival in C57BL/6 mice but was without any effect in LPA(2) knockout mice. Intraperitoneally administered OTP reduced death caused by lethal dose (LD)(100/30) radiation by 50%.
  
  
  CONCLUSIONS
  Our data indicate that OTP is a highly effective antiapoptotic agent that engages similar prosurvival pathways to LPA through the LPA(2) receptor subtype.
authors.affiliation: Department of Physiology, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Deng
authors.forename: E
authors.initials: E
authors.lastname: Shuyu
authors.forename: Ryoko
authors.initials: R
authors.lastname: Tsukahara
authors.forename: William J
authors.initials: WJ
authors.lastname: Valentine
authors.forename: Gangadhar
authors.initials: G
authors.lastname: Durgam
authors.forename: Veeresa
authors.initials: V
authors.lastname: Gududuru
authors.forename: Louisa
authors.initials: L
authors.lastname: Balazs
authors.forename: Venkatraman
authors.initials: V
authors.lastname: Manickam
authors.forename: Marcello
authors.initials: M
authors.lastname: Arsura
authors.forename: Lester
authors.initials: L
authors.lastname: VanMiddlesworth
authors.forename: Leonard R
authors.initials: LR
authors.lastname: Johnson
authors.forename: Abby L
authors.initials: AL
authors.lastname: Parrill
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D005720:Gamma Rays / Q000009:adverse effects; D005786:Gene Expression Regulation; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D009943:Organophosphorus Compounds; D049368:Receptors, Lysophosphatidic Acid; D014409:Tumor Necrosis Factor-alpha; C520653:octadecenyl thiophosphate; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins