Newly Published
Critical Care Medicine  |   March 2018
Early-phase Innate Immune Suppression in Murine Severe Sepsis Is Restored with Systemic Interferon-β
Author Notes
  • From the Department of Anesthesiology (Y.K., K.U., T.T., Y.T., H.T., K.H., K.C., Y. Yamada), and Department of Acute Medicine (T.H.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and the Discovery Research Department, Pharmaceutical Research and Development Division, Maruishi Pharmaceutical Co., Ltd., Osaka, Japan (Y. Yamamura).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Part of the work presented in this article has been presented at the American Thoracic Society International Conference 2013, Philadelphia, Pennsylvania, May 19, 2013, and at the American Thoracic Society International Conference 2014, May 18, 2014, San Diego, California.
    Part of the work presented in this article has been presented at the American Thoracic Society International Conference 2013, Philadelphia, Pennsylvania, May 19, 2013, and at the American Thoracic Society International Conference 2014, May 18, 2014, San Diego, California.×
  • Submitted for publication August 17, 2017. Accepted for publication February 19, 2018.
    Submitted for publication August 17, 2017. Accepted for publication February 19, 2018.×
  • Acknowledgments: The authors thank Baasanjav Uranbileg, M.D., Ph.D., Department of Clinical Laboratory Medicine, University of Tokyo, Tokyo, Japan, for her excellent technical assistance. We are indebted to Yasuyuki Seto, M.D., Ph.D., Department of Stomach and Esophageal Surgery, and Kyoji Moriya, M.D., Ph.D., Division of Infection Control and Prevention Service, University of Tokyo Hospital, Tokyo, Japan, for their valuable comments on the manuscript. We also thank Shiroh Isono, M.D., Ph.D., Department of Anesthesiology, Graduate School of Medicine, Chiba University, Chiba, Japan, for critical reading of the manuscript. We thank the Edanz Group (www.edanzediting.com/ac), Fukuoka, Japan, for editing a draft of this manuscript.
    Acknowledgments: The authors thank Baasanjav Uranbileg, M.D., Ph.D., Department of Clinical Laboratory Medicine, University of Tokyo, Tokyo, Japan, for her excellent technical assistance. We are indebted to Yasuyuki Seto, M.D., Ph.D., Department of Stomach and Esophageal Surgery, and Kyoji Moriya, M.D., Ph.D., Division of Infection Control and Prevention Service, University of Tokyo Hospital, Tokyo, Japan, for their valuable comments on the manuscript. We also thank Shiroh Isono, M.D., Ph.D., Department of Anesthesiology, Graduate School of Medicine, Chiba University, Chiba, Japan, for critical reading of the manuscript. We thank the Edanz Group (www.edanzediting.com/ac), Fukuoka, Japan, for editing a draft of this manuscript.×
  • Research Support: Supported by grants from the National Institute for Health and Human Development, Japan Society for the Promotion of Science (A232490720001, to Drs. Yamada and Uchida; B24390364, to Drs. Yamada and Uchida; and 15H06176, to Dr. Hiruma), Tokyo, Japan, and the Japan Ministry of Health Labor and Welfare (H24-Nanchitou [Nanchi]-Ippan-035, H24-Rinkensui-Ippan-003, to Dr. Uchida), Tokyo, Japan.
    Research Support: Supported by grants from the National Institute for Health and Human Development, Japan Society for the Promotion of Science (A232490720001, to Drs. Yamada and Uchida; B24390364, to Drs. Yamada and Uchida; and 15H06176, to Dr. Hiruma), Tokyo, Japan, and the Japan Ministry of Health Labor and Welfare (H24-Nanchitou [Nanchi]-Ippan-035, H24-Rinkensui-Ippan-003, to Dr. Uchida), Tokyo, Japan.×
  • Competing Interests: Drs. Uchida and Yamada had a collaborative research agreement with Maruishi Pharmaceutical Co. Ltd., Osaka, Japan (2012 -2015). Maruishi Pharmaceutical Co. Ltd. provided the interferon-β used in this study. The other authors declare no competing interests.
    Competing Interests: Drs. Uchida and Yamada had a collaborative research agreement with Maruishi Pharmaceutical Co. Ltd., Osaka, Japan (2012 -2015). Maruishi Pharmaceutical Co. Ltd. provided the interferon-β used in this study. The other authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Uchida: Department of Anesthesiology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. uchidak-ane@h.u-tokyo.ac.jp. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Critical Care / Infectious Disease
Critical Care Medicine   |   March 2018
Early-phase Innate Immune Suppression in Murine Severe Sepsis Is Restored with Systemic Interferon-β
Anesthesiology Newly Published on March 29, 2018. doi:10.1097/ALN.0000000000002185
Anesthesiology Newly Published on March 29, 2018. doi:10.1097/ALN.0000000000002185
Abstract

Background: Sepsis is a leading cause of death in the intensive care unit. Immune modulatory therapy targeting sepsis-associated proinflammatory responses has not shown survival benefit. Here, the authors evaluated innate immunity at the early stage of murine mild or severe peritoneal sepsis induced by cecal ligation and puncture, and the effect of systemic interferon-β, a potent inflammatory mediator, on severe sepsis as well as its mechanism of action.

Methods: Mild and severe sepsis was induced in C57BL/6 mice by cecal ligation and puncture with 22- and 18-gauge needles for puncture, respectively. Interferon-β (700 U/g) was subcutaneously administered either before or 12 h after cecal ligation and puncture for the severe sepsis group.

Results: Severe sepsis resulted in significantly lower 6-day survival rates than mild sepsis (n = 48, 25% vs. n = 11, 81.8%, P = 0.002), significantly less phagocytic capacity of peritoneal exudate cells, and lower CXC chemokine receptor-2 expression on circulating neutrophils at 24 h after cecal ligation and puncture. Interferon-β administration 12 h after cecal ligation and puncture associated with significantly improved survival (n = 34, 52.9%, P = 0.017) increased the number and function of peritoneal exudate cells, peritoneal/systemic inflammatory cytokine/chemokine concentrations, and CXC chemokine receptor-2 on neutrophils, compared with the severe sepsis controls. However, those responses were not observed in the prophylactic interferon-β group (n = 24). Interferon-β increased lipopolysaccharide-induced interleukin-6 messenger RNA/protein expression of lipopolysaccharide-tolerant murine peritoneal macrophages, which was not observed in nontolerant cells.

Conclusions: In severe sepsis, immune suppression occurs within 24 h and is associated with worse mortality. Interferon-β given after the onset of peritonitis restores impaired innate immunity in vivo and in vitro.