Low-dose cyclophosphamide improves survival in a murine treatment model of sepsis

Ian Elliott Brown, Oliver Bellevue, Alexandra Shawo, Hiwot Woldesemayat, Victoria Lyo, Benjamin Rayikanti, Michelle Lee, Ezechinyerem D. Uzosike, Shiva Kasravi, Hobart W. Harris

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Sepsis is a complex medical condition characterized by a systemic inflammatory response in the setting of infection. We hypothesized that combining antibiotics plus an immunosuppressant would protect against the morbidity and mortality of polymicrobial sepsis in mice better than would antibiotics alone. We used a murine cecal-ligation-and-puncture model in which mice were treated either with imipenem plus cyclophosphamide or imipenem alone. Titration to a low cyclophosphamide dose revealed that combination therapy increased survival by 20% compared with imipenem alone (56% vs. 36%, P G 0.001). To investigate the mechanism by which combination therapy did this, we reviewed quantitative and qualitative markers of the systemic immune response, end-organ damage, and the local immune response at the site of injury. Cyclophosphamide treatment was not associated with depletion of peripheral leukocytes or differences in pulmonary damage. However, mice that received combination therapy had higher plasma granulocyte colony-stimulating factor levels than did those treated with antibiotics alone. In addition, mice treated with cyclophosphamide had higher levels of bacterial colonization in intestinal Peyer's patch lymph nodes at 72 h after the septic insult. Intraperitoneal macrophage phenotypes and phagocytosis activity did not differ between groups.We conclude that the inflammatory response plays a significant role in themortality of polymicrobial sepsis and that the regulation of this element is both feasible and beneficial in this disease model.

Original languageEnglish (US)
Pages (from-to)92-98
Number of pages7
JournalShock
Volume43
Issue number1
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Cyclophosphamide
Imipenem
Sepsis
Anti-Bacterial Agents
Peyer's Patches
Granulocyte Colony-Stimulating Factor
Therapeutics
Immunosuppressive Agents
Punctures
Phagocytosis
Ligation
Leukocytes
Biomarkers
Lymph Nodes
Macrophages
Morbidity
Phenotype
Lung
Mortality
Wounds and Injuries

Keywords

  • Cecal ligation and puncture
  • Immunomodulation
  • Immunosuppression
  • Severe sepsis

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Brown, I. E., Bellevue, O., Shawo, A., Woldesemayat, H., Lyo, V., Rayikanti, B., ... Harris, H. W. (2015). Low-dose cyclophosphamide improves survival in a murine treatment model of sepsis. Shock, 43(1), 92-98. https://doi.org/10.1097/SHK.0000000000000263

Low-dose cyclophosphamide improves survival in a murine treatment model of sepsis. / Brown, Ian Elliott; Bellevue, Oliver; Shawo, Alexandra; Woldesemayat, Hiwot; Lyo, Victoria; Rayikanti, Benjamin; Lee, Michelle; Uzosike, Ezechinyerem D.; Kasravi, Shiva; Harris, Hobart W.

In: Shock, Vol. 43, No. 1, 2015, p. 92-98.

Research output: Contribution to journalArticle

Brown, IE, Bellevue, O, Shawo, A, Woldesemayat, H, Lyo, V, Rayikanti, B, Lee, M, Uzosike, ED, Kasravi, S & Harris, HW 2015, 'Low-dose cyclophosphamide improves survival in a murine treatment model of sepsis', Shock, vol. 43, no. 1, pp. 92-98. https://doi.org/10.1097/SHK.0000000000000263
Brown, Ian Elliott ; Bellevue, Oliver ; Shawo, Alexandra ; Woldesemayat, Hiwot ; Lyo, Victoria ; Rayikanti, Benjamin ; Lee, Michelle ; Uzosike, Ezechinyerem D. ; Kasravi, Shiva ; Harris, Hobart W. / Low-dose cyclophosphamide improves survival in a murine treatment model of sepsis. In: Shock. 2015 ; Vol. 43, No. 1. pp. 92-98.
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