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Local Administration of Interleukin-11 Ameliorates Intestinal Radiation Injury in Rats

Departments of ¹ Pharmaceutical Sciences, ² Surgery, ³ Obstetrics and Gynecology, and ⁴ Surgery and Pathology, University of Arkansas for Medical Sciences; ⁵ Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

Requests for reprints: Marjan Boerma, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 522-3, Little Rock, AR 72205. Phone: 501-686-6599; Fax: 501-686-6057; E-mail: mboerma{at}uams.edu.

Intestinal radiation injury is dose limiting during abdominal and pelvic radiotherapy and critical for the outcome after accidental whole-body radiation exposure. The multifunctional cytokine, interleukin-11 (IL-11), ameliorates the intestinal radiation response, but its clinical use is hampered by severe toxicity after systemic administration. This study addressed whether protection against intestinal radiation injury can be achieved by intraluminal administration of IL-11. Male rats underwent surgical transposition of a 4-cm small bowel loop to the scrotum. For repeated intraluminal drug administration, an ileostomy, proximal to the bowel loop in the scrotum, was created. The transposed intestinal loop was exposed to 5 Gy fractions on 9 consecutive days. Recombinant human IL-11 (rhIL-11; 2 mg/kg/d) or vehicle was given through the ileostomy from 2 days before until 2 weeks after irradiation. At 2 weeks, structural, cellular, and molecular aspects of intestinal radiation injury were assessed. rhIL-11 ameliorated structural manifestations of radiation enteropathy, including radiation injury score (6.5 ± 0.6 in the vehicle group versus 4.0 ± 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 ± 0.1 versus 0.5 ± 0.03; P < 0.0001), and intestinal wall thickening (842 ± 66 µm versus 643 ± 54 µm; P = 0.02), reduced postradiation transforming growth factor-ß overexpression, and reduced numbers of ED2-positive cells. Postirradiation mucosal mast cell numbers were partially restored by rhIL-11. These data show that local administration of rhIL-11 ameliorates early intestinal radiation injury and support further development of rhIL-11 to reduce manifestations of intestinal radiation injury in the clinic. [Cancer Res 2007;67(19):9501–6]