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Effect of Interleukin 1, Inflammation, and Surgery on the Incidence of Adhesion Formation and Death after Abdominal Irradiation in Mice¹

Department of Radiation Oncology and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90024-1714

There is clinical evidence that prior surgery and inflammation can increase the risk of the chronic complications of radiotherapy delivered to the pelvic/abdominal region. We have established a murine model to study this interaction using as end points mortality and late gut-associated peritoneal adhesion formation. A single dose of 16 Gy of total abdominal irradiation (TAI) was used. This gave no early deaths (<1 mo) and a relatively low mortality over the period 1 to 6 mo after TAI. The incidence of adhesions, which is the most serious complication 2 to 6 mo after TAI, was also low.

Injection of lipopolysaccharide (50 g, i.p.) or human recombinant interleukin 1 (IL-1) in doses as low as 100 units prior to TAI greatly enhanced both radiation-induced adhesion formation and death. Prior surgery also increased radiation-induced mortality, so much so that adhesions could not be accurately quantified. The timing of administration of lipopolysaccharide and IL-1 and of surgery relative to TAI was important in determining the outcome. For example, IL-1 enhanced adhesion formation and death if given from 3 days before to 1 day after, but not 4 days or 4 wk after, TAI. If given 20 hr or less before TAI, there was a dramatic increase in early mortality 1 to 3 wk later, which was not seen if IL-1 was given at other times. These early deaths were not caused by bone marrow or gut stem cell depletion and may be a result of fluid leakage.

We propose that surgery, bacterial invasion, or other inflammatory signals might act through a common mechanism of stimulating IL-1 production to enhance radiation-induced adhesion formation and the early and late morbidity and mortality associated with abdominal irradiation. If this is the case, blocking IL-1 production might inhibit the development of these late complications.

¹ This investigation was supported by USPHS Grants CA-31612 and CA-44384 awarded by the National Cancer Institute, Department of Health and Human Services.

Received 6/16/88. Revised 9/29/88. Accepted 10/ 5/88.

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