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

Abstract

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 F 0.6 in the vehicle group versus 4.0 F 0.3 in the IL-11 group; P = 0.001), mucosal surface area loss (0.2 F 0.1 versus 0.5 F 0.03; P < 0.0001), and intestinal wall thickening (842 F 66 Mm versus 643 F 54 Mm; P = 0.02), reduced postradiation transforming growth factor-B 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]

Mesenchymal stem cells improve small intestinal integrity through regulation of endogenous epithelial cell homeostasis

“…[29][30][31] Each of these factors has been described earlier as facilitating intestinal mucosa repair, either through enhancement of cell proliferation or inhibition of epithelial cell apoptosis, or by a combination of both. [32][33][34][35] The therapeutic benefit of MSC reported in this study could be the consequence of releases and synergic effects of multiple paracrine factors. Further research is needed to elucidate this complex issue.…”

A panoramic review and in silico analysis of IL-11 structure and function

“…This function is exerted through promoting the proliferation and retraining the apoptosis of mature enterocytes and their progenitors [98,111,112,113], as well as regulating mucus production [20].…”

A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

“…Less frequent, chronic bowel toxicity may occur later and is characterised by progressive intestinal wall fibrosis and vascular sclerosis. Different approaches have been evaluated to protect the intestine against radiation toxicity such as interleukin-11, immunomodulators, inhibitors of proteinase-activated receptors, inhibitors of thrombin and statins [35][36][37][38][39]. Prophylaxis with antioxidant and radioprotectant agents such as amifostine may also be considered to limit possible radiation damage in normal tissues [40].…”