Cecal ligation and perforation, when disrupting proper abscess formation, provides highly reproducible results and has common features with human data

Introduction

Sepsis-induced acute respiratory distress syndrome is generally accepted to be caused by neutrophil sequestration in the lung microvasculature with resultant pulmonary endothelial damage from neutrophilic enzymes and metabolites. Developing models to study this condition accurately is crucial if therapeutic goals are to be achieved. Currently, endotoxemia models such as systemic lipopolysaccharide (LPS) injection predominate in the study of this condition due to the poor reproducibility of septic models such as cecal ligation and perforation (CLP).

Methods

A method of CLP designed to inhibit proper abscess formation was compared against intraperitoneal injection of 0.5 mg/kg LPS using C57B/6 mice at various time points up to 24 hours. Outcomes included circulating leukocyte counts, lung myeloperoxidase levels, and a multitude of cytokines and chemokines using Luminex technology. Septic human plasma from patients in the ICU was also analyzed for comparison using Luminex technology.

Results

LPS-treated mice consistently demonstrated earlier and greater peak MPO, TNFα, IL-1α, IL-5, IL-6, IL-10, MIP-1α, MCP-1, and Rantes levels that were shorter lasting in duration when compared with our CLP model, which consistently demonstrated steadily increasing levels over time. Interestingly, IL-17 levels were observed to peak at 424.3 ± 7.0 pg/ml in our CLP model but only reached a level of 31.7 ± 17.8 pg/ml in the LPS model, which was comparable with the control value. Our CLP model demonstrated multiple comparable trends in cytokine and chemokine levels with the septic human plasma data taking into account the differences in time-point collection. The most apparent trend was the highest and consistently elevated IL-6 levels found to be 11,528.7 ± 955.3 pg/ml in septic C57B/6 mice and 11,718.7 ± 4511.0 pg/ml in septic human patients.

Conclusion

Systemic LPS effects are very robust and short-lived; therefore, this model is not as relevant as CLP with respect to human sepsis. Furthermore, septic effects such as those seen with IL-17 are not observed in LPS models. Here, we demonstrate that CLP with abscess impairment can be highly reproducible and comparable with human data.