Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

Efron, Philip A.; Darden, Dijoia B; Wang, Zhongkai; Nacionales, Dina C.; Lopez, Maria-Cecilia; Hawkins, Russell B.; Cox, Michael C.; Rincón, Jaimar; Ungaro, Ricardo; Dirain, Marvin; Ghita, Gabriela; Chen, Tianmeng; Billiar, Timothy R.; Delano, Matthew J.; Leeuwenburgh, Christiaan; Brakenridge, Scott C.; Moore, Frederick A.; Mohr, Alicia M.; Tompkins, Ronald G.; Brumback, Babette; Baker, Henry V.; Upchurch, Gilbert R.; Moldawer, Lyle L.

doi:10.1096/fj.202002150r

Cited by 9 publications

(9 citation statements)

References 60 publications

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“…Animal septic shock models have been largely used over the past decades to better understand pathophysiological mechanisms. Interestingly, several studies observed a similar modification of the gene expression profiles between the sepsis model and clinical samples, suggesting that animal models are relevant to evaluate the molecular mechanisms involved in the pathophysiology of sepsis [ 52 , 53 , 54 ], although this may be discussed as to their relevance to the clinic [ 55 , 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression

Dupas

Persello

Blangy-Letheule

et al. 2022

IJMS

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The young population, which is particularly at risk of sepsis, is, paradoxically, rarely studied. Acute stimulation of O-GlcNAcylation, a post-translational modification involved in metabolic regulation, cell survival and stress response, is beneficial in young rats with sepsis. Considering that sepsis impacts the gene expression profile and that O-GlcNAcylation is a regulator of transcription, the aims of this study are to (i) unveil beneficial mechanisms of O-GlcNAcylation and (ii) decipher the relationship between O-GlcNAcylation and transcription during sepsis. Endotoxemic challenge was induced in 28-day-old male rats using a lipopolysaccharide injection (E. coli O111:B4, 20 mg·kg−1) and compared to control rats (NaCl 0.9%). One hour after, rats were assigned to no therapy or fluidotherapy (NaCl 0.9%, 10 mL.kg−1) ± NButGT (10 mg·kg−1) to stimulate O-GlcNAc levels. Cardiac O-GlcNAcylation levels were evaluated via Western blot and gene transcription using 3′ SRP analysis. Lipopolysaccharide injection favorizes inflammatory state with the overexpression of genes involved in the NF-κB, JAK/STAT and MAPK pathways. NButGT treatment increased cardiac O-GlcNAcylation levels (p < 0.05). Yet, the mRNA expression was not impacted two hours after fluidotherapy or NButGT treatment. In conclusion, O-GlcNAc stimulation-induced beneficial effects are not dependent on the gene expression profile at the early phase of sepsis.

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Section: Discussionmentioning

confidence: 99%

Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression

Dupas

Persello

Blangy-Letheule

et al. 2022

IJMS

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“…One murine sepsis model can be used to recapitulate infection and inflammatory responses with definite sepsis etiologies but cannot be extrapolated to all types of sepsis. Philip and his colleagues clearly proved that CLP þ DCS model mice can replicate surgical sepsis rather than community-acquired human sepsis in transcriptomic responses (28). CLP model mice do show PIICS characteristics and tend to recover (11,29).…”

Section: Discussionmentioning

confidence: 99%

Mouse Model of Critical Persistent Inflammation, Immunosuppression, and Catabolism Syndrome

Chen

et al. 2021

Shock

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Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is a growing challenge in intensive care units (ICUs). PIICS causes a severe illness with high mortality. Currently, treatment is expensive, and the outcomes are dismal. Herein, we established a PIICS model to study the disease pathophysiology and its potential treatment. Using a modified sublethal cecal ligation and puncture (CLP) to induce sepsis (day 1) and the injection of lipopolysaccharide (LPS) to induce an aggravated inflammation response (day 11), CLP þ LPS mice recapitulating PIICS features were successfully generated (day 14). Adult male mice were divided into CLP þ LPS, CLP þ daily chronic stress (DCS), CLP, DCS, LPS, and sham control groups. A survival curve was generated, and phenotypes were analyzed using markers for catabolism, inflammation, and immunosuppression. The CLP þ LPS model showed two mortality peaks (after CLP and after LPS), whereas the CLP þ DCS and CLP groups showed one peak. Surviving CLP þ LPS mice exhibited significantly increased catabolism and inflammatory cytokine levels and aggravated inflammation, including organ inflammation. CLP þ LPS mice exhibited strong immune suppression as evidenced by decreased splenic cluster of differentiation (CD)8 þ and interferon-g þ CD8 þ T cell counts and a concomitant and significant increase in the myeloid-derived suppressor cell population. This CLPþLPS-induced PIICS model differs from acute sepsis models, showing two mortality peaks and a protracted course of 14 days. Compared to previous PIICS models, ours shows a re-aggravated status and higher catabolism, inflammation, and immunosuppression levels. Our aim was to use the PIICS model to simulate PIICS pathophysiology and course in the ICU, enabling investigation of its mechanism and treatment.

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“…DCS was conducted by placing mice in weighted plexiglass animal restraint holders (Kent Scientific; Torrington, CT) for 2 hours daily commencing the day after CLP. DCS was combined with CLP (CLP+DCS) to mimic the stress that occurs in patients when residing in an intensive care unit and better reflects human sepsis relative to CLP alone [34,35]. This model was previously used to describe age and sex-related changes in hippocampal transcription [15].…”

Section: Intra-abdominal Sepsis and Daily Chronic Stress Modelmentioning

confidence: 99%

Influence of age and sex on microRNA response and recovery in the hippocampus following sepsis

Rani

Barter

Kumar

et al. 2022

Aging

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Sepsis, defined as a dysregulated host immune response to infection, is a common and dangerous clinical syndrome. The excessive host inflammatory response can induce immediate and persistent cognitive decline, which can be worse in older individuals. Sex-specific differences in the outcome of infectious diseases and sepsis appear to favor females. We employed a murine model to examine the influence of age and sex on the brain's microRNA (miR) response following sepsis. Young and old mice of both sexes underwent cecal ligation and puncture (CLP) with daily restraint stress. Expression of hippocampal miR was examined in age-and sex-matched controls at 1 and 4 days post-CLP. Few miR were modified in a similar manner across age or sex and these few miR were generally associated with neuroprotection against inflammation. Similar to previous work examining transcription, young females exhibited a better recovery of the miR profile from day 1 to day 4, relative to young males and old females. For young males and all female groups, the initial response mainly involved a decrease in miR expression. In contrast, old males exhibited only upregulated miR on day 1 and day 4 and many of the miR upregulated on day 1 and day 4 were linked to neurodegeneration, increased neuroinflammation, and cognitive impairment. The results emphasize age and sex differences in epigenetic mechanisms that likely contribute to susceptibility or resilience to cognitive impairment due to sepsis.

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Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis

Cited by 9 publications

References 60 publications

Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression

Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression

Mouse Model of Critical Persistent Inflammation, Immunosuppression, and Catabolism Syndrome

Influence of age and sex on microRNA response and recovery in the hippocampus following sepsis

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