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HB-EGF Protects the Intestines From Radiation Therapy-Induced Intestinal Injury

Saturday, October 20, 2012: 9:44 AM
Versailles Ballroom (Hilton Riverside)
Mika A.B. Matthews, MD1, Daniel Watkins, MD1, Amanda Darbyshire, BS1, William E. Carson III, MD2 and Gail E. Besner, M.D.1, (1)The Center for Perinatal Research and The Department of Pediatric Surgery, Nationwide Children's Hospital, Columbus, OH, (2)Deparment of Surgery, Division of Surgical Oncology, Wexner Medical Center at the Ohio State University, Columbus, OH

Purpose: Radiation therapy (RT) often leads to radiation enteritis in cancer patients by inhibiting mucosal crypt cell proliferation and inducing intestinal epithelial cell (IEC) apoptosis, causing ischemia, ulceration, and necrosis of the intestinal lining. We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) downregulates pro-inflammatory cytokine expression, reduces reactive oxygen species production, and protects the intestines from several different forms of intestinal injury. The objective of the current study was to evaluate whether HB-EGF affects radiation therapy-induced intestinal injury.

Methods: Adult mice were given IP injections of HB-EGF (800 µg/kg) or PBS once daily for 3 days, followed by total body irradiation (TBI). Animals were injected with BrdU 3 days after TBI, followed by harvesting of intestinal tissue for BrdU immunohistochemistry to identify proliferating mucosal crypts (defined as crypts containing ≥3 BrdU-positive cells). To determine gut barrier function, FITC-dextran was administered via gavage 4 days after TBI, followed by determination of serum FITC-dextran levels using spectrophotofluorometry. After serum collection, multiple intestinal segments were harvested to assess histologic injury. Tissue sections were scored blindly by two investigators using a radiation injury grading scale. 

Results: We found that exposure to RT significantly decreased the mean percentage of proliferative mucosal crypts in all segments of the small intestine compared with non-irradiated intestine (p<0.05). Treatment of irradiated mice with HB-EGF significantly increased the percentage of proliferative crypts compared with non-HB-EGF-treated irradiated mice in the duodenum (79.2% ± 6.8 vs. 55.1% ± 9.3, p<0.001), jejunum (75.7% ± 11.2 vs. 54.1% ± 9.9, p<0.005), and ileum (63% ± 14.1 vs. 42.2% ± 8.4, p<0.05). Exposure to RT led to significant intestinal histologic injury compared with non-irradiated intestine (p<0.005). Treatment of irradiated mice with HB-EGF decreased the severity of histologic injury compared with non-HB-EGF-treated irradiated mice in the ileum (2.8 ± 0.8 vs. 3.25 ± 0.7, p<0.05) and descending colon/rectum (1.1 ± 0.3 vs. 1.6 ± 0.7, p<0.005). Plasma FITC dextran levels were significantly higher in mice exposed to RT compared with non-irradiated mice (0.09 µg/mL ± 0.02 vs. 0.04 µg/mL ± 0.005, p<0.01). HB-EGF treatment resulted in a decrease in plasma FITC dextran levels compared with non-HB-EGF-treated irradiated mice (0.07 µg/mL ± 0.02 vs. 0.09 µg/mL ± 0.02, p=0.08). 

Conclusion: These results provide evidence that administration of HB-EGF preserves mucosal crypt cell proliferation, reduces intestinal histologic injury, and maintains gut barrier function after exposure to radiation therapy. Administration of HB-EGF may represent a novel therapy for the prevention of radiation therapy-induced intestinal injury in the future.