Animal models of sepsis

Abstract

Sepsis remains a common, serious, and heterogeneous clinical entity that is difficult to define adequately. Despite its importance as a public health problem, efforts to develop and gain regulatory approval for a specific therapeutic agent for the adjuvant treatment of sepsis have been remarkably unsuccessful. One step in the critical pathway for the development of a new agent for adjuvant treatment of sepsis is evaluation in an appropriate animal model of the human condition. Unfortunately, the animal models that have been used for this purpose have often yielded misleading findings. It is likely that there are multiple reasons for the discrepancies between the results obtained in tests of pharmacological agents in animal models of sepsis and the outcomes of human clinical trials. One of important reason may be that the changes in gene expression, which are triggered by trauma or infection, are different in mice, a commonly used species for preclinical testing, and humans. Additionally, many species, including mice and baboons, are remarkably resistant to the toxic effects of bacterial lipopolysaccharide, whereas humans are exquisitely sensitive. New approaches toward the use of animals for sepsis research are being investigated. But, at present, results from preclinical studies of new therapeutic agents for sepsis must be viewed with a degree of skepticism.

Integrative “Omic” Analysis of Experimental Bacteremia Identifies a Metabolic Signature That Distinguishes Human Sepsis from Systemic Inflammatory Response Syndromes

“…Second, it has been well documented that experimental models and clinical results are often incongruous. This is caused in part by differential genomic responses and clinical relevance of the experimental models (47,48), and a heterogeneous response in humans related to site-of-infection, etiologic agent, genetics, comorbidities, and age-related confounders (2). However, the metabolomic changes found in the primate model strongly correlate to metabolomic findings noted in human sepsis.…”

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…This may be due to circulating factors in the plasma of mice suppressing the production of pro-inflammatory cytokines following LPS challenge, such as hemopexin (424). This may at least in part explain the vast difference in LPS sensitivity between mice and humans, with mice requiring an LD50 of 1-25 mg/kg body wt, a million times greater dosage than required to induce fever in humans (199,666). Seok et al (628) even conclude that "while the genomic responses to different acute inflammatory stresses are highly similar in humans, these responses are not reproduced in current mouse models" (628).…”

“…Also, CLP animals are often of young age (although considered as adult; use of few weeks old animals may serve as models for human pediatric CIM in future) and without co-morbidities such as usually seen in older patients with peritoneal sepsis. Moreover, the time window of CLP sepsis in rodents is uncomparibly compressed to a few days at most, unlike in patients (199). However, the most prominent argument excluding a simple transfer of the rodent procedure to the human situation of peritoneal sepsis-induced critical illness is the lack of supportive measures in CLP-treated mice or rats, such as mechanical ventilation or complete immobilization shown to produce the CIM pathology (i.e., preferential and significant myosin loss, Ref.…”

“…This section focuses on distinct differences of both techniques and their strengths and weaknesses, while details on the procedures are given in several reviews elsewhere (317,588). Although being used in abundance, several lines of critique have recently emerged to the use of CLP and LPS models to adequately reflect conclusions drawn for sepsis in humans (199,587,628). …”

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…Some species, like humans and sheep, are very sensitive to LPS, whereas other species, such as mice and nonhuman primates are much more resistant. For instance, the LD 50 dose of LPS in mice is 10 6 times greater than the typical doses used in humans (45). The dose used in our previous NHP study (0.1 mg/kg) is equivalent to a 4 ng/kg dose in humans in terms of blood levels of inflammatory cytokines (46).…”