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Arginyl-Glutamine Dipeptide or Docosahexaenoic Acid Attenuates Hyperoxia-induced Small Intestinal Injury in Neonatal Mice

Li, Nan*; Ma, Liya*; Liu, Xueyan*; Shaw, Lynn; Calzi, Sergio Li; Grant, Maria B.; Neu, Josef*

Journal of Pediatric Gastroenterology & Nutrition: April 2012 - Volume 54 - Issue 4 - p 499–504
doi: 10.1097/MPG.0b013e3182330867
Original Articles: Gastroenterology

Background and Objective: Supplementation studies of glutamine, arginine, and docosahexaenoic acid (DHA) have established the safety of each of these nutrients in neonates; however, the potential for a more stable and soluble dipeptide, arginyl-glutamine (Arg-Gln) or DHA with anti-inflammatory properties, to exert benefits on hyperoxia-induced intestinal injury has not been investigated. Arg-Gln dipeptide has been shown to prevent retinal damage in a rodent model of oxygen-induced injury. The objective of the present study was to investigate whether Arg-Gln dipeptide or DHA could also attenuate markers of injury and inflammation to the small intestine in this same model.

Methods: Seven-day-old mouse pups were placed with their dams in 75% oxygen for 5 days. After 5 days of hyperoxic exposure (P7–P12), pups were removed from hyperoxia and allowed to recover in atmospheric conditions for 5 days (P12–P17). Mouse pups received Arg-Gln (5 g · kg−1 · day−1) or DHA (5 g · kg−1 · day−1) or vehicle orally started on P12 through P17. Distal small intestine (DSI) histologic changes, myeloperoxidase (MPO), lactate dehydrogenase (LDH), inflammatory cytokines, and tissue apoptosis were evaluated.

Results: Hyperoxic mice showed a greater distortion of overall villus structure and with higher injury score (P < 0.05). Arg-Gln dipeptide and DHA supplementation groups were more similar to the room air control group. Supplementation of Arg-Gln or DHA reduced hyperoxia-induced MPO activity (P < 0.05). Supplementation of Arg-Gln or DHA returned LDH activity to the levels of control. Hyperoxia induced apoptotic cell death in DSIs, and both Arg-Gln and DHA reversed this effect (P < 0.05).

Conclusions: Supplementation with either Arg-Gln or DHA may limit some inflammatory and apoptotic processes involved in hyperoxic-induced intestinal injury in neonatal mice.

*Department of Pediatrics

Department of Pharmacology, University of Florida, Gainesville, FL.

Address correspondence and reprint requests to Josef Neu, MD, Department of Pediatrics, University of Florida, 1600 SW Archer Rd, Gainesville, FL 32610 (e-mail:

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Received 10 June, 2011

Accepted 15 August, 2011

Drs Nan Li and Liya Ma participated equally in this study.

This research was funded by a grant from Mead Johnson Nutritionals.

The authors report no conflicts of interest.

Copyright 2012 by ESPGHAN and NASPGHAN