The Lysophosphatidic Acid Type 2 Receptor Is Required for Protection Against Radiation-Induced Intestinal Injury

Wenlin Deng, Shuyu E, Ryoko Tsukahara, William J. Valentine, Gangadhar Durgam, Veeresa Gududuru, Louisa Balazs, Venkatraman Manickam, Marcello Arsura, Lester Vanmiddlesworth, Leonard R. Johnson, Abby L. Parrill, Duane Miller, Gabor Tigyi

Research output: Contribution to journalArticle

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Abstract

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 LPA1 and LPA2 knockout mice exposed to different apoptotic stimuli. Results: OTP was more efficacious than LPA in reducing gamma irradiation-, camptothecin-, or tumor necrosis factor α/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 LPA2 but not LPA1 and LPA3 transfectants. In C57BL/6 and LPA1 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 LPA2 knockout mice. OTP, with higher efficacy than LPA, enhanced intestinal crypt survival in C57BL/6 mice but was without any effect in LPA2 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 LPA2 receptor subtype.

Original languageEnglish (US)
Pages (from-to)1834-1851
Number of pages18
JournalGastroenterology
Volume132
Issue number5
DOIs
StatePublished - Jan 1 2007

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Radiation Protection
Wounds and Injuries
Knockout Mice
Lysophosphatidic Acid Receptors
Caspase 3
Radiation
Apoptosis
Cell Line
Camptothecin
octadecenyl thiophosphate
lysophosphatidic acid
Caspase 9
Caspase 8
Cycloheximide
Intestinal Mucosa
Inbred C57BL Mouse
Tumor Necrosis Factor-alpha
Epithelial Cells

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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The Lysophosphatidic Acid Type 2 Receptor Is Required for Protection Against Radiation-Induced Intestinal Injury. / Deng, Wenlin; E, Shuyu; Tsukahara, Ryoko; Valentine, William J.; Durgam, Gangadhar; Gududuru, Veeresa; Balazs, Louisa; Manickam, Venkatraman; Arsura, Marcello; Vanmiddlesworth, Lester; Johnson, Leonard R.; Parrill, Abby L.; Miller, Duane; Tigyi, Gabor.

In: Gastroenterology, Vol. 132, No. 5, 01.01.2007, p. 1834-1851.

Research output: Contribution to journalArticle

Deng, W, E, S, Tsukahara, R, Valentine, WJ, Durgam, G, Gududuru, V, Balazs, L, Manickam, V, Arsura, M, Vanmiddlesworth, L, Johnson, LR, Parrill, AL, Miller, D & Tigyi, G 2007, 'The Lysophosphatidic Acid Type 2 Receptor Is Required for Protection Against Radiation-Induced Intestinal Injury', Gastroenterology, vol. 132, no. 5, pp. 1834-1851. https://doi.org/10.1053/j.gastro.2007.03.038
Deng, Wenlin ; E, Shuyu ; Tsukahara, Ryoko ; Valentine, William J. ; Durgam, Gangadhar ; Gududuru, Veeresa ; Balazs, Louisa ; Manickam, Venkatraman ; Arsura, Marcello ; Vanmiddlesworth, Lester ; Johnson, Leonard R. ; Parrill, Abby L. ; Miller, Duane ; Tigyi, Gabor. / The Lysophosphatidic Acid Type 2 Receptor Is Required for Protection Against Radiation-Induced Intestinal Injury. In: Gastroenterology. 2007 ; Vol. 132, No. 5. pp. 1834-1851.
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AU - Deng, Wenlin

AU - E, Shuyu

AU - Tsukahara, Ryoko

AU - Valentine, William J.

AU - Durgam, Gangadhar

AU - Gududuru, Veeresa

AU - Balazs, Louisa

AU - Manickam, Venkatraman

AU - Arsura, Marcello

AU - Vanmiddlesworth, Lester

AU - Johnson, Leonard R.

AU - Parrill, Abby L.

AU - Miller, Duane

AU - Tigyi, Gabor

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N2 - 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 LPA1 and LPA2 knockout mice exposed to different apoptotic stimuli. Results: OTP was more efficacious than LPA in reducing gamma irradiation-, camptothecin-, or tumor necrosis factor α/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 LPA2 but not LPA1 and LPA3 transfectants. In C57BL/6 and LPA1 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 LPA2 knockout mice. OTP, with higher efficacy than LPA, enhanced intestinal crypt survival in C57BL/6 mice but was without any effect in LPA2 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 LPA2 receptor subtype.

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