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Cancer causes increased mortality and is associated with altered apoptosis in murine sepsis*

Fox, Amy C. MD; Robertson, Charles M. MD; Belt, Brian BA; Clark, Andrew T. MS; Chang, Katherine C. PhD; Leathersich, Ann M. MD; Dominguez, Jessica A. PhD; Perrone, Erin E. MD; Dunne, W. Michael PhD; Hotchkiss, Richard S. MD; Buchman, Timothy G. MD, PhD, FCCM; Linehan, David C. MD; Coopersmith, Craig M. MD, FCCM

doi: 10.1097/CCM.0b013e3181c8fdb1
Laboratory Investigations

Objective: Whereas most septic patients have an underlying comorbidity, most animal models of sepsis use mice that were healthy before the onset of infection. Malignancy is the most common comorbidity associated with sepsis. The purpose of this study was to determine whether mice with cancer have a different response to sepsis than healthy animals.

Design: Prospective, randomized controlled study.

Setting: Animal laboratory in a university medical center.

Subjects: C57Bl/6 mice.

Interventions: Animals received a subcutaneous injection of either 250,000 cells of the transplantable pancreatic adenocarcinoma cell line Pan02 (cancer) or phosphate-buffered saline (healthy). Three weeks later, mice given Pan02 cells had reproducible, nonmetastatic tumors. Both groups of mice then underwent intratracheal injection of either Pseudomonas aeruginosa (septic) or 0.9% NaCl (sham). Animals were killed 24 hrs postoperatively or followed-up 7 days for survival.

Measurements and Main Results: Mice with cancer and healthy mice appeared similar when subjected to sham operation, although cancer animals had lower levels of T- and B-lymphocyte apoptosis. Septic mice with cancer had increased mortality compared to previously healthy septic mice subjected to the identical injury (52% vs. 28%; p = .04). This was associated with increased bacteremia but no difference in local pulmonary infection. Septic mice with cancer also had increased intestinal epithelial apoptosis. Although sepsis induced an increase in T- and B-lymphocyte apoptosis in all animals, septic mice with cancer had decreased T- and B-lymphocyte apoptosis compared to previously healthy septic mice. Serum and pulmonary cytokines, lung histology, complete blood counts, and intestinal proliferation were similar between septic mice with cancer and previously healthy septic mice.

Conclusions: When subjected to the same septic insult, mice with cancer have increased mortality compared to previously healthy animals. Decreased systemic bacterial clearance and alterations in intestinal epithelial and lymphocyte apoptosis may help explain this differential response.

From Departments of Surgery (ACF, BB, ATC, JAD, EEP, DCL, CMC), Anesthesiology (CMR, KCC, RSH), Pathology and Immunology (AML, WMD), Washington University School of Medicine, St. Louis, MO; Department of Surgery (TGB), Emory University School of Medicine, Emory University, Atlanta, GA.

This work was supported by funding from National Institutes of Health (GM66202, GM072808, GM08795, GM044118, GM082008, P30 DK52574).

Drs. Fox and Robertson contributed equally to this work.

The authors have not disclosed any potential conflicts of interest.

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© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins