Secondary Logo

Journal Logo

Institutional members access full text with Ovid®

Old Mice Demonstrate Organ Dysfunction as well as Prolonged Inflammation, Immunosuppression, and Weight Loss in a Modified Surgical Sepsis Model*

Stortz, Julie A. MD1; Hollen, McKenzie K. BA1; Nacionales, Dina C. MD1; Horiguchi, Hiroyuki MD1; Ungaro, Ricardo BS1; Dirain, Marvin L. MS1; Wang, Zhongkai MS2; Wu, Quran MS1; Wu, Kevin K. MD3; Kumar, Ashok PhD4; Foster, Thomas C. PhD4; Stewart, Brian D. MD5; Ross, Julia A. PhD5; Segal, Marc MD, PhD6; Bihorac, Azra MD, MS6; Brakenridge, Scott MD, MSCS1; Moore, Frederick A. MD1; Wohlgemuth, Stephanie E. PhD3; Leeuwenburgh, Christiaan PhD3; Mohr, Alicia M. MD1; Moldawer, Lyle L. PhD1; Efron, Philip A. MD1

doi: 10.1097/CCM.0000000000003926
Online Laboratory Investigations
Buy
SDC

Objectives: Our goal was to “reverse translate” the human response to surgical sepsis into the mouse by modifying a widely adopted murine intra-abdominal sepsis model to engender a phenotype that conforms to current sepsis definitions and follows the most recent expert recommendations for animal preclinical sepsis research. Furthermore, we aimed to create a model that allows the study of aging on the long-term host response to sepsis.

Design: Experimental study.

Setting: Research laboratory.

Subjects: Young (3–5 mo) and old (18–22 mo) C57BL/6j mice.

Interventions: Mice received no intervention or were subjected to polymicrobial sepsis with cecal ligation and puncture followed by fluid resuscitation, analgesia, and antibiotics. Subsets of mice received daily chronic stress after cecal ligation and puncture for 14 days. Additionally, modifications were made to ensure that “Minimum Quality Threshold in Pre-Clinical Sepsis Studies” recommendations were followed.

Measurements and Main Results: Old mice exhibited increased mortality following both cecal ligation and puncture and cecal ligation and puncture + daily chronic stress when compared with young mice. Old mice developed marked hepatic and/or renal dysfunction, supported by elevations in plasma aspartate aminotransferase, blood urea nitrogen, and creatinine, 8 and 24 hours following cecal ligation and puncture. Similar to human sepsis, old mice demonstrated low-grade systemic inflammation 14 days after cecal ligation and puncture + daily chronic stress and evidence of immunosuppression, as determined by increased serum concentrations of multiple pro- and anti-inflammatory cytokines and chemokines when compared with young septic mice. In addition, old mice demonstrated expansion of myeloid-derived suppressor cell populations and sustained weight loss following cecal ligation and puncture + daily chronic stress, again similar to the human condition.

Conclusions: The results indicate that this murine cecal ligation and puncture + daily chronic stress model of surgical sepsis in old mice adhered to current Minimum Quality Threshold in Pre-Clinical Sepsis Studies guidelines and met Sepsis-3 criteria. In addition, it effectively created a state of persistent inflammation, immunosuppression, and weight loss, thought to be a key aspect of chronic sepsis pathobiology and increasingly more prevalent after human sepsis.

1Department of Surgery, University of Florida College of Medicine, Gainesville, FL.

2Department of Biostatistics, University of Florida College of Medicine, Gainesville, FL.

3Department of Aging and Geriatric Research, University of Florida College of Medicine, Gainesville, FL.

4Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL.

5Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.

6Department of Medicine, University of Florida College of Medicine, Gainesville, FL.

*See also p. 1673.

Dr. Stortz, Mr. Hollen, Dr. Nacionales, Dr. Horiguchi, and Dr. Kumar contributed extensively to data collection as well as drafting of the article, revision of its content, and approval of the article in its final form. Mr. Ungaro, Mr. Dirain, Mr. Wang, Mr. Q. Wu, Dr. K. Wu, and Dr. Ross contributed to data analysis and interpretation. Drs. Stortz, Foster, Stewart, Segal, Bihorac, Brakenridge, Moore, Wohlgemuth, Leeuwenburgh, Mohr, Moldawer, and Efron contributed to the conception and design of the project as well as data analysis, interpretation, drafting of the article, revision of its content, and approval of the article in its final form.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by the following National Institutes of Health grants: R01 GM-040586 and R01 GM-104481 (to Dr. Moldawer), R01 GM-113945 (to Dr. Efron), P50 GM-111152 (to Drs. Bihorac, Brakenridge, Moore, Mohr, Moldawer, and Efron) awarded by the National Institute of General Medical Sciences (NIGMS), and the National Institutes of Aging grants R01AG049711, R01AG052258, and the Evelyn F. McKnight Brain Research Foundation (to Dr. Foster). In addition, this work was supported, in part, by a postgraduate training grant T32 GM-008721 (to Dr. Stortz) in burns, trauma, and perioperative injury by NIGMS.

Dr. Stortz, Ms. Hollen, Drs. Nacionales and Horiguchi, Mr. Ungaro, Mr. Dirain, Mr. Wang, Mr. Q. Wu, and Drs. K. Wu, Kumar, Foster, Stewart, Ross, Segal, Bihorac, Brakenridge, Moore, Leeuwenburgh, Mohr, Moldawer, and Efron received support for article research from the National Institutes of Health (NIH). Dr. Stortz, Ms. Hollen, Drs. Nacionales and Horiguchi, Mr. Ungaro, Mr. Dirain, Mr. Wang, Mr. Q. Wu, and Drs. Stewart’s, Ross’, and Brakenridge’s institutions received funding from the National Institute of General Medical Sciences. Dr. Foster’s institution received funding from the National Institute on Aging. Dr. Bihorac’s institution received funding from R01 GM-110240 and P50 GM- 111152. Dr. Moore’s institution received funding from the NIH. Dr. Wohlgemuth disclosed that she does not have any potential conflicts of interest.

For information regarding this article, E-mail: philip.efron@surgery.ufl.edu

Copyright © 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.