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ToxSci Advance Access published online on October 6, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi002
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 7, 2004
Accepted September 22, 2004

Systems Toxicology

IL-1 and TNF Antagonists Prevent Inhibition of Fracture Healing by Ethanol in Rats

Daniel S. Perrien 1, Elizabeth C. Wahl 2, William R. Hogue 3, Ulrich Feige 4, James Aronson 5, Martin J. J. Ronis 6, Thomas M. Badger 7, and Charles K. Lumpkin Jr.8*

1 Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Little Rock, AR, 72202; Department of Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205; Center for Orthopaedic Research, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205
2 Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Little Rock, AR, 72202
3 Center for Orthopaedic Research, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205; Department of Orthopaedic Surgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205
4 Department of Inflammation Research, Amgen, Inc., Thousand Oaks, CA, 91320
5 Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Little Rock, AR, 72202; Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205; Department of Orthopaedic Surgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205
6 Department of Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205; Arkansas Children's Nutrition Center, Little Rock, AR, 72202
7 Arkansas Children's Nutrition Center, Little Rock, AR, 72202
8 Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Little Rock, AR, 72202; Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205

* To whom correspondence should be addressed. E-mail: Lumpkincharlesk{at}uams.edu.


  Abstract

We tested the hypothesis that combined administration of IL-1 and TNF antagonists would protect fracture healing from inhibition by chronic ethanol exposure. Adult male rats were fed a liquid diet ± ethanol (CON and ETOH) by intragastric infusion for three weeks prior to and three weeks after creation of an externally fixated tibial fracture. Beginning the day of fracture, one-half of each dietary group received 2.0 mg/kg/day IL-1ra and 2.0 mg/kg/2-days sTNFR1 (CON+ANTAG and ETOH+ANTAG), while all other animals received vehicle alone (CON+VEH and ETOH+VEH). Scoring of ex vivo radiographs and analysis by pQCT revealed a significantly lower incidence of bridging and reduced total mineral content in the ETOH+VEH group compared to all other groups. These results support, for the first time, the hypothesis that IL-1 and TNF antagonists are capable of protecting fracture healing from the inhibition associated with chronic ethanol consumption.

Keywords: Alcohol; Tumor Necrosis Factor; Interleukin-1; Interleukin-1 Recombinant Antagonist; Repair; Total Enteral Nutrition.
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