Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review protocol

Zhang, MengQi; Fergusson, Dean; Sharma, Rahul; Khoo, Ciel; Mendelson, Asher A.; McDonald, Braedon; Macala, Kimberly F.; Sharma, Neha; Gill, Sean E.; Fiest, Kirsten M.; Lehmann, Christian; Shorr, Risa; Jahandideh, Forough; Bourque, Stéphane; Liaw, Patricia C.; Fox-Robichaud, Alison; Lalu, Manoj M; Charbonney, Emmanuel; Kristof, Arnold S.; Vázquez-Grande, Gloria; Veldhuizen, Ruud A. W.; Winston, Brent W.; Qureshi, Salman T.

doi:10.1186/s13643-023-02189-2

Cited by 2 publications

(1 citation statement)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, there is a sexual dimorphism in response to systemic inflammation in both patients and animal models (30)(31)(32)(33)(34)(35)(36). In fact, females usually have a better outcome.…”

Section: Introductionmentioning

confidence: 99%

Retinal response to systemic inflammation differs between sexes and neurons

Rodríguez-Ramírez,

Norte-Muñoz,

Lucas-Ruiz

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

BackgroundNeurological dysfunction and glial activation are common in severe infections such as sepsis. There is a sexual dimorphism in the response to systemic inflammation in both patients and animal models, but there are few comparative studies. Here, we investigate the effect of systemic inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS) on the retina of male and female mice and determine whether antagonism of the NLRP3 inflammasome and the extrinsic pathway of apoptosis have protective effects on the retina.MethodsA single intraperitoneal injection of LPS (5 mg/kg) was administered to two months old C57BL/6J male and female mice. Retinas were examined longitudinally in vivo using electroretinography and spectral domain optical coherence tomography. Retinal ganglion cell (RGC) survival and microglial activation were analysed in flat-mounts. Retinal extracts were used for flow cytometric analysis of CD45 and CD11b positive cells. Matched plasma and retinal levels of proinflammatory cytokines were measured by ELISA. Retinal function and RGC survival were assessed in animals treated with P2X7R and TNFR1 antagonists alone or in combination.ResultsIn LPS-treated animals of both sexes, there was transient retinal dysfunction, loss of vision-forming but not non-vision forming RGCs, retinal swelling, microglial activation, cell infiltration, and increases in TNF and IL-1β. Compared to females, males showed higher vision-forming RGC death, slower functional recovery, and overexpression of lymphotoxin alpha in their retinas. P2X7R and TNFR1 antagonism, alone or in combination, rescued vision-forming RGCs. P2X7R antagonism also rescued retinal function. Response to treatment was better in females than in males.ConclusionsSystemic LPS has neuronal and sex-specific adverse effects in the mouse retina, which are counteracted by targeting the NLRP3 inflammasome and the extrinsic pathway of apoptosis. Our results highlight the need to analyse males and females in preclinical studies of inflammatory diseases affecting the central nervous system

show abstract

Section: Introductionmentioning

confidence: 99%

Retinal response to systemic inflammation differs between sexes and neurons

Rodríguez-Ramírez,

Norte-Muñoz,

Lucas-Ruiz

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

show abstract

Sex differences in skin microcirculatory vascular reactivity in experimental lipopolysaccharide-induced endotoxinemia

Chkhaidze

2024

Regional blood circulation and microcirculation

View full text Add to dashboard Cite

Bacterial lipopolysaccharide (LPS) plays a leading role in the development of a systemic inflammatory response and endogenous intoxication. However, the sex differences in the functional state of the microcirculatory bed in LPS-induced endotoxinemia have been poorly studied. Objective. To study the characteristics of skin microcirculatory vascular reactivity in experimental LPS-induced endotoxinemia in male and female rats. Material and methods. Modeling of endotoxinemia was performed by intraperitoneal injection of LPS of the cell wall of the bacterium Salmonella enterica to male and female Wistar stock rats. Two doses of LPS were used: 50 mg/kg and 10 mg/kg. We used laser Doppler flowmetry to evaluate skin perfusion before and after LPS injection, blood flow changes under test conditions with local contact hypothermia caused by a thermoelement. Results. 48 hours after LPS injection, a decrease in blood flow was observed, especially pronounced at a dose of LPS 50 mg/kg. During the test with local cooling of the skin, a change in the kinetics of the reaction was noted. Blood flow reduction was 75% (LPS 50 mg/kg) and 51% (LPS 10 mg/kg), statistically significantly different from the control groups. At the same time, the classic phenomenon of “cold vasodilation” observed in control rats was absent in all groups with the injection of LPS. Maximum perfusion after restoration of blood flow in females was achieved 3 times faster than in males (LPS 10 mg/kg). Conclusion. In experimental LPS-induced endotoxinemia, a dose-dependent decrease in skin perfusion was revealed. We obtained new data on the absence of pronounced “cold vasodilation” at local contact hypothermia. The results of the study indicate a violation of the mechanisms of neurogenic vasoconstriction and endothelium-dependent vasodilation, reflecting systemic disorders of microcirculation regulation. At the same time, the females showed a more positive dynamics of blood flow restoration in the test with local cooling of the skin, indicating a greater functional reserve and a more effective mechanism of autoregulation of the blood microcirculation system. A functional test with local contact cooling of the skin is highly informative for assessing vascular reactivity and preservation of the autoregulation mechanism of microcirculation in modeling endogenous intoxication

show abstract

Sex-based analysis of treatment responses in animal models of sepsis: a preclinical systematic review protocol

Cited by 2 publications

References 30 publications

Retinal response to systemic inflammation differs between sexes and neurons

Retinal response to systemic inflammation differs between sexes and neurons

Sex differences in skin microcirculatory vascular reactivity in experimental lipopolysaccharide-induced endotoxinemia

Contact Info

Product

Resources

About