A murine model for the study of molecular pathogenesis of radiation proctitis.
OBJECTIVE
To establish a novel mouse brachytherapy model with which to study the role of inflammation in the pathogenesis of radiation proctitis.


METHODS
The distal rectums of BALB/c and C57BL/6 mice were irradiated with three to five fractions of 5.5 to 8 Gy. Tissues were harvested and evaluated for histopathology, using the radiation injury score (RIS). Cytokine mRNA expression was assessed using real-time PCR.


RESULTS
Fifty percent of the mice treated with 22 Gy delivered in four fractions of 5.5 Gy died as a result of anorectal stenosis and distal bowel obstruction prior to the time of scheduled sacrifice, with a latency period of 4 to 10 weeks for the BALB/c and 3 to 4 weeks for the C57BL/6 mice. The RISs were 7, 12, and 8 at 2, 6, and 11 weeks, respectively, in the BALB/c mice and was 8.7 in the C57BL/6 mice on week 6. A 100- to 300-fold increase in interleukin-1beta (IL-1beta) (p = 0.04) and IL-6 mRNA (p = 0.07) and a 5- to 6-fold increase in transforming growth factor (TGF) and tumor necrosis factor-alpha mRNA expression levels (p < 0.001 and p = 0.01) were observed at 2 to 6 weeks after radiation. Cytokine mRNA tissue expression correlated positively with radiation dose (p < 0.0001). The RIS correlated well with IL-1beta and IL-6 mRNA levels in the BALB/c mice and with IL-1beta, IL-6, and TGF mRNA levels in C57BL/6 mice. Analysis of receiver operating characteristic curve showed that IL-1beta and IL-6 have the largest area under the curve and therefore are good markers of radiation proctitis (p < 0.001).


CONCLUSIONS
Radiation-induced proctitis was associated with a dose-dependent, characteristic proinflammatory cytokine response pattern in a novel mouse model suitable for interventional studies.
Symon
Zvi
Z
Department of Radiation Oncology, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. symonz@sheba.health.gov.il
Goldshmidt
Yifat
Y
Picard
Orit
O
Yavzori
Miri
M
Ben-Horin
Shomron
S
Alezra
Dror
D
Barshack
Iris
I
Chowers
Yehuda
Y
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001918:Brachytherapy / Q000009:adverse effects*; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011349:Proctitis / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012372:ROC Curve; D011833:Radiation Injuries, Experimental / Q000378:metabolism* / Q000473:pathology; D012007:Rectum / Q000473:pathology / Q000528:radiation effects*; D013045:Species Specificity; D013997:Time Factors; D015291:Transforming Growth Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015431:Weight Loss
D015415:Biomarkers; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015291:Transforming Growth Factors