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Murine P-glycoprotein Deficiency Alters Intestinal Injury Repair and Blunts Lipopolysaccharid-Induced Radioprotection.


Radiat Res. 2012 Jul 10;


Authors: Staley EM, Yarbrough VR, Schoeb TR, Daft JG, Tanner SM, Steverson D, Lorenz RG


Abstract

P-glycoprotein (P-gp) has been reported to increase stem cell proliferation and regulate apoptosis. Absence of P-gp results in decreased repair of intestinal epithelial cells after chemical injury. To further explore the mechanisms involved in the effects of P-gp on intestinal injury and repair, we used the well-characterized radiation injury model. In this model, injury repair is mediated by production of prostaglandins (PGE(2)) P-gp deficient and lipopolysaccharid (LPS) has been shown to confer radioprotection. B6.mdr1a(-/-) mice and wild-type controls were subjected to 12 Gy total body X-ray irradiation and surviving crypts in the proximal jejunum and distal colon were evaluated 3.5 days after irradiation. B6.mdr1a(-/-) mice exhibited normal baseline stem cell proliferation and COX dependent crypt regeneration after irradiation. However, radiation induced apoptosis was increased and LPS-induced radioprotection was blunted in the C57BL6.mdr1a(-/-) distal colon, compared to B6 wild-type controls. Lipopolysaccharid treatment induced gene expression of radioprotective cytokine IL-1α, in B6 wild-type control but not in B6.mdr1a(-/-) animals. Lipopolysaccharid-induced radioprotection was absent in IL-1R1(-/-) animals, indicating a role for IL-1α in radioprotection, and demonstrating that P-gp deficiency interferes with IL-1α gene expression in response to systemic exposure to LPS.

PMID: 22780103 [PubMed - as supplied by publisher]