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LPA2 receptor Agonist Radioprotectin-1 Attenuates Radiation-Induced Apical Junctional Complex Disruption and Barrier Dysfunction in Mouse Colon
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  • Pradeep Shukla,
  • Avtar Meena,
  • Ruchika Gangwar,
  • Erzsebet Szabo,
  • Andrea Balogh,
  • Sue Chin Lee,
  • Alain Vandewalle,
  • Gabor Tigyi,
  • RadhaKrishna Rao
Pradeep Shukla
University of Tennessee Health Science Center
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Avtar Meena
University of Tennessee Health Science Center
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Ruchika Gangwar
University of Tennessee Health Science Center
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Erzsebet Szabo
University of Tennessee Health Science Center
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Andrea Balogh
University of Tennessee Health Science Center
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Sue Chin Lee
University of Tennessee Health Science Center
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Alain Vandewalle
INSERM U373
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Gabor Tigyi
University of Tennessee Health Science Center
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RadhaKrishna Rao
University of Tennessee Health Science Center
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Abstract

Background and Purpose The colonic epithelium is highly sensitive to ionizing radiation, leading to impaired barrier function. Lysophosphatidic acid (LPA) is protective against radiation-induced intestinal mucosal injury and genotoxic stress. We evaluated the effect of LPA and its analog, Radioprotein-1 in radiation-induced colonic epithelial barrier dysfunction. Experimental approach Caco-2 and m-ICC12 cell monolayers were exposed up to g-radiation, and the barrier function was evaluated by measuring and unidirectional flux of FITC-inulin. Mice were subjected to either total body irradiation (TBI) or partial body irradiation (PBI-BM5). Intestinal barrier function was analyzed by evaluating mucosal permeability to inulin and measuring plasma lipopolysaccharide (LPS) levels. Tight junction and adherens junction integrity was examined by confocal microscopy. Oxidative stress was assessed by measuring protein thiol oxidation and antioxidant mRNA. Key Results In Caco-2 and m-ICC12 cell monolayers, LPA attenuates radiation-induced redistribution of tight junction proteins from the junctions, which was blocked by Rho-kinase inhibitor. In mice, TBI and PBI-BM5 disrupt colonic epithelial tight junction and adherens junction, increases mucosal inulin permeability and elevates plasma LPS. RP1 administered 30 min pre-irradiation or 24 hours post-irradiation alleviates TBI and PBI-BM5-induced tight junction disruption, barrier dysfunction, and endotoxemia. The RP1 effects on radiation-induced colonic injury was associated with protein thiol oxidation, suppression of antioxidant gene expression, cofilin activation and remodeling of actin cytoskeleton. Conclusion and Implications These data demonstrate that LPA2 receptor agonists prevent and mitigate g-irradiation-induced colonic mucosal barrier dysfunction and endotoxemia, indicating their potential therapeutic benefit in the treatment of the gastrointestinal acute radiation syndrome.