New Approaches to Treat Sepsis: Animal Models «Do Not Work» (Review)

Abstract

Like many other pathological infectious processes, sepsis is mainly studied in vivo using mice models. Over the past 30 years, such studies have led to significant achievements in understanding of the sepsis pathophysiology. However, unfortunately, none of them led to any «discoveries» in the treatment of patients. In this review, we question the relevance of the experimental models applied, list some aspects rarely taken into account and discuss ways to resolve the deadlock.The text is a translation of the article: Cavail-lon J. M. New methods of treating sepsis: failure of animal models, Bull. Assoc. Anc. El. Inst. Pastor, 2017, 59,230, 58—60. Translation from French by «Akademperevod», Moscow, Russia.

Mouse Models of Sepsis and Septic Shock

“…Cecal ligation and puncture (CLP) [20,[60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75] • The model mimics the development of polymicrobial peritonitis with tissue ischemia.…”

“…The dynamics of sepsis development is possible to regulate by varying the length of the cecal region to be ligated, the needle size (18-25G), and the number of punctures (to a lesser extent), performing infusion therapy, administering antibiotics, or mimicking appendectomy by removing the necrotic cecal region via a second surgery [61]. It should be noted that the model is reproducible only when the experimental animal sample is large enough because the method is difficult to standardize because of the variation in surgery parameters, such as the type of anesthesia, the laparotomy technique, the cecal ligation length, the needle size, and the number of punctures and the dependence on the mouse genetic strain, gender, age, microbiota composition, and rearing conditions [20,65,72].…”

“…Mice are several orders of magnitude more resistant to toxins (LPS and diphtheria toxin) than humans; have a lower total neutrophil fraction in the blood, a lower neutrophil enzymatic capacity, lower activity of the complement system, and a different set of pentraxins involved in the inflammatory process; and lack genes for important components of the immune system, such as IL-8, IL-37, TLR10, ICAM-3, etc. [72,124,125]. Combining several sepsis models, each of which is not universal when used alone, may provide for a better understanding of the molecular mechanisms of sepsis.…”

“…These mice may have limited diversity of the microbiota, which directly affects the immune system and the development of pathological conditions [128]. Moreover, persistent virus infections (for example, herpesviruses) are activated in humans, but not in SPF mice, with septic complications and may change the resistance to bacterial coinfections [72,96,97]. "Dirty" mice are possibly better suitable for mimicking human pathologies [129].…”

“…Humanized mouse strains are important to use more broadly to experimentally model sepsis because the pathology development in humans is better reproduced in such models [134,[141][142][143][144][145]. However, it should be noted that immune system components are primarily subject to humanization, while the nervous system, the epithelium, the endothelium, and metabolic pathways important for the development of sepsis remain mouse [72,[146][147][148][149].…”