The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury

Gastroenterology. 2007 May;132(5):1834-51. doi: 10.1053/j.gastro.2007.03.038. Epub 2007 Mar 24.


Background & aims: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Apoptosis / radiation effects*
  • Cell Line
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Female
  • GTP-Binding Proteins / physiology
  • Gamma Rays / adverse effects
  • Gene Expression Regulation
  • Injections, Intraperitoneal
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / radiation effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / physiology
  • Nerve Tissue Proteins / pharmacology
  • Organophosphorus Compounds / administration & dosage
  • Organophosphorus Compounds / pharmacology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Radiation Injuries, Experimental / metabolism
  • Radiation Injuries, Experimental / pathology
  • Radiation Injuries, Experimental / prevention & control*
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / physiology*
  • Signal Transduction / physiology
  • Tumor Necrosis Factor-alpha / pharmacology


  • Ltap protein, mouse
  • Nerve Tissue Proteins
  • Organophosphorus Compounds
  • Receptors, Lysophosphatidic Acid
  • Tumor Necrosis Factor-alpha
  • octadecenyl thiophosphate
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins