Host responses to sepsis vary in different low-lethality murine models.
BACKGROUND
Animal models for the study of sepsis are being increasingly scrutinized, despite their essential role for early translational research. In particular, recent studies have suggested that at the level of the leukocyte transcriptome, murine models of burns, trauma and endotoxemia markedly differ from their human equivalents, and are only weakly similar amongst themselves. We compared the plasma cytokine and leukocyte transcriptome responses between two different low-lethality murine models of polymicrobial intra-abdominal sepsis.


METHODS
Six to ten week male C57BL/6j mice underwent either the 'gold standard' cecal ligation and puncture (CLP) model of intra-abdominal sepsis or administration of a cecal slurry (CS), where cecal contents are injected intraperitoneally. Surviving mice were euthanized at two hours, one or three days after sepsis.


RESULTS
The murine leukocyte transcriptomic response to the CLP and CS models of sepsis was surprisingly dissimilar at two hours, one, and three days after sepsis. The Pearson correlation coefficient for the maximum change in expression for the entire leukocyte transcriptome that changed significantly over time (n = 19,071) was R = 0.54 (R2 = 0.297). The CS model resulted in greater magnitude of early inflammatory gene expression changes in response to sepsis with associated increased production of inflammatory chemokines and cytokines. Two hours after sepsis, CLP had more significant expression of genes associated with IL-10 signaling pathways, whereas CS had greater expression of genes related to CD28, apoptosis, IL-1 and T-cell receptor signaling. By three days, the changes in gene expression in both sepsis models were returning to baseline in surviving animals.


CONCLUSIONS
These analyses reveal that the murine blood leukocyte response to sepsis is highly dependent on which model of intra-abdominal sepsis is employed, despite their similar lethality. It may be difficult to extrapolate findings from one murine model to another, let alone to human sepsis.
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Lori F
LF
Gentile
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Dina C
DC
Nacionales
Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States of America.
M Cecilia
MC
Lopez
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Erin
E
Vanzant
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Angela
A
Cuenca
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Benjamin E
BE
Szpila
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Alex G
AG
Cuenca
Institute on Aging, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Anna
A
Joseph
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Frederick A
FA
Moore
Institute on Aging, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Christiaan
C
Leeuwenburgh
Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Henry V
HV
Baker
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Lyle L
LL
Moldawer
Departments of Surgery, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Philip A
PA
Efron
D056704:Adaptive Immunity; D000818:Animals; D016000:Cluster Analysis; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000097:blood; D007958:Leukocyte Count; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018805:Sepsis / Q000097:blood* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D013997:Time Factors; D059467:Transcriptome
D016207:Cytokines; D018836:Inflammation Mediators