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Review

Animal models of sepsis

Mitchell P Fink Departments of Surgery and Anesthesiology; David Geffen School of Medicine at UCLA; Los Angeles, CA USACorrespondence[email protected]
Pages 143-153 | Received 25 Jun 2013, Accepted 07 Aug 2013, Published online: 19 Aug 2013

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.

In a review article about animal models of sepsis published more than two decades ago, Stephen Heard and I wrote this sentence: “Despite the considerable progress in this field, sepsis is still an important cause of mortality.”Citation1 We also wrote this sentence: “Sepsis, as a clinical entity, is very heterogeneous and clinical data are invariably confounded by the effects of age, coexisting diseases, and supportive therapy.” Obviously, these words are as true today as they were in 1990. Sepsis remains a common, serious, and heterogeneous clinical entity, which 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 sepsis have been remarkably unsuccessful.

In 1982, Ziegler et al. reported results from a clinical trial in patients with septic shock of a polyclonal antibody directed against lipopolysaccharide (LPS) from a mutant strain of Escherichia coli called J5.Citation2 Since then, approximately 60 phase 2 (P2) or phase 3 (P3) randomized controlled clinical trials of pharmacological agents for the adjuvant treatment of sepsis have been conducted (). From inspection of , it quickly becomes apparent that survival has been favorably affected, at least in a statistically significant way, in only a very few of these trials. The previously mentioned study of an anti-J5 antiserum by Ziegler and colleagues yielded positive results, but not all patients enrolled in the study were included in the evaluation set and not all deaths were counted in the calculation of mortality rates.Citation2 The first P3 study of HA-1A, a human monoclonal antibody designed to neutralize the deleterious effects of LPS, showed improved survival for patients treated with the experimental agent.Citation2 The design and conduct of this study, however, were criticized by experts in the field,Citation3 and when HA-1A was tested in a canine peritonitis model, excess mortality was observed in the animals treated with the monoclonal antibody.Citation4 Accordingly, a follow-up multicentric randomized controlled clinical trial was performed, and HA-1A was not shown to provide any therapeutic benefit.Citation5 A statistically significant, dose-dependent reduction in 28-d mortality was observed in a preliminary, open label P2 trial of anakinra (recombinant human interleukin-1 receptor antagonist).Citation6 Two subsequent P3 studies, however, failed to validate the encouraging findings from the initial P2 trial.Citation7,Citation8 When results were adjusted using a logistic regression model that included the effects of pre-determined potential confounding variables, treatment with afelimomab, a F(ab')2 fragment of a murine anti-tumor necrosis factor monoclonal antibody, was shown to significantly improve survival in patients with sepsis and a high circulating concentration of interleukin (IL)-6.Citation9 A statistically significant improvement in survival was observed in a P2 dose-finding study of pafase (recombinant human platelet activating factor acetylhydrolase,Citation10 but a subsequent larger P3 trial showed no evidence of therapeutic benefit when patients were treated with the recombinant protein.Citation11 In a P2 trial, enteral administration of talactoferrin (recombinant human lactoferrin) improved survival of patients with severe sepsis and the treatment effect just missed being statistically significant (P = 0.052).Citation12 Unfortunately, when the same drug was evaluated in a much larger P3 study, enrollment of patients was stopped early by the data safety monitoring board (DSMB) because of excess mortality in the talactoferrin-treated arm.Citation13 The first P3 study of recombinant human activated protein C yielded unequivocally positive resultsCitation14 and led to regulatory approval of the agent in North America and Europe. Subsequent clinical trials of this agent, however, were uniformly disappointing,Citation15-Citation17 and the commercial product (Xigris®) was withdrawn from the market in 2012. A multicentric clinical trial of therapy with hydrocortisone plus a synthetic mineralocorticoid, which was conducted in 19 intensive care units in France, yielded marginally positive results,Citation18 but, because benefit was not confirmed in another, larger multicentric study of hydrocortisone,Citation19 the therapeutic value of adjunctive therapy with corticosteroids remains quite controversial.

Table 1. Summary of clinical trials of pharmacological interventions for the adjuvant treatment of sepsis, which have been reported since 1982

With the exception of the positive results mentioned in the previous paragraph, all other P3 trials of adjunctive pharmacological therapies for sepsis or septic shock performed since 1982 have failed to provide evidence for improved survival. Indeed, treatment with etanercept, a recombinant fusion protein that combines two extracellular binding domains of the human p75 TNF receptor (TNFR2) with the Fc portion of human IgG1, was shown to worsen outcome for septic patients.Citation20 Similarly, treatment with 546C88 (l-monomethyl arginine, an isoform unselective nitric oxide synthase inhibitor) significantly and dramatically worsened survival for patients with septic shock.Citation21

This dismal record likely has many causes. For example, neither of the two anti-LPS monoclonal antibodies, which have been tested in P3 clinical trials, has been shown to effectively neutralize the pro-inflammatory effects of LPS.Citation22,Citation23 In many trials, the duration of therapy with the experimental agent was arbitrarily determined rather than being adjusted based on clinical or biochemical data. Thus, the period of treatment in some cases might have been too short (or, for that matter, too long).

In a few cases, pharmacological agents were advanced into P2 or even P3 clinical trials in the absence of convincing evidence of efficacy from preliminary studies using animal models of sepsis or septic shock. However, in the vast majority of cases, preliminary studies, using various animal models of sepsis or septic shock, provided evidence for efficacy and supported the decision to carry out clinical trials. Some examples of compounds that failed in one or more P3 clinical trials but were effective in one or more animal models are listed in .

Table 2. Examples of some pharmacological agents, which have been evaluated in an animal model of sepsis and yielded negative results in one or more human clinical trials

The lack of a truly clinically relevant and predictive animal model appears to be one of the key barriers hampering the development of an effective therapeutic for the adjuvant treatment of sepsis. Over the past couple of decades, literally hundreds of different animal models of sepsis have been used by scientists. In some cases, studies using animal models of sepsis have been used as part of the development pathway for novel therapeutic agents. However, more often animal models have been used as a proxy for the human condition in order to gain insights into pathophysiology. Numerous previous reviews have cataloged in considerable detail the myriad approaches, which have been employed in an effort to recapitulate key features of severe sepsis or septic shock in human beings.Citation1,Citation24-Citation31 Accordingly, no effort will be made here to repeat this exercise. Rather, the discussion will focus on a concise critique of the most widely employed animal models of sepsis, focusing on why use of these models have failed to lead to the development of one or more useful pharmacological therapies for the syndrome in humans.

The most popular preclinical sepsis models use mice. Being very small mammals, mice pose little or no danger to laboratory personnel. Inbred strains are widely available from suppliers, and, generally speaking, are relatively inexpensive to acquire and maintain. Moreover, using genetically modified strains of mice is an elegant way to explore the importance of particular gene products in the pathogenesis of sepsis (or the response of septic animals to a pharmacological intervention). While laboratory experiments using any species of animal, especially ones that use organ dysfunction or mortality as a read-out, provoke intense scrutiny from regulatory and oversight groups, mice are not regarded as “companion animals” and, therefore, studies using mice may be regarded as being more ethical than are studies that enroll cats, dogs, horses, or non-human primates as research subjects. Finally, numerous immunological reagents and/or assay kits designed for murine systems are commercially available. These reagents and kits facilitate the measurement of cytokines or other mediators in biological fluids.

Injecting mice with purified LPS (“endotoxin”) via either the intraperitoneal (i.p.) route or the intravenous (i.v.) route leads to systemic activation of the innate immune system. If the dose of LPS is large enough, then the animals manifest physiological and biochemical changes that are reminiscent of certain very fulminant forms of gram-negative bacterial infection in humans, most notably overwhelming meningococcemia. Some of the manifestations of acute endotoxemia in mice include systemic arterial hypotension (i.e., shock), lactic acidosis, impaired myocardial contractility, a short-lived monophasic spike in the circulating level of TNF, a more prolonged elevation in the circulating level of IL-6, and a delayed increase in the circulating level of high mobility group box (HMGB)-1. Shock, lactic acidosis, impaired myocardial contractility, and increased circulating levels of TNF, IL-6, and HMGB1 all are features of sepsis or septic shock in humans, although the temporal kinetics and the magnitude of these changes from normal physiology are often different from what is observed in acute murine endotoxemia.

Activation of systemic inflammation by LPS in mice is largely mediated via interaction of the bacterial product with Toll-like receptor (TLR) 4, which is expressed on the surface of both “professional” immune cells, such as monocytes and macrophages, as well as many other cell types, including alveolar epithelial cells and myocardial cells. The intracellular signaling pathways, which are triggered by the interaction of LPS with TLR4, have been extensively investigated and there are many detailed reviews in the literature.Citation32,Citation33 Certain inbred strains, such as C3H/HeJ miceCitation34 and TLR4-deficient (“knockout”) mice,Citation34 are hyporesponsive to LPS. It is important to note, however, that C3H/HeJ mice are hyporesponsive but are not entirely unresponsive, to the toxic effects of LPS. For example, the dose of LPS required to induce weight loss in C3H/HeJ mice is about 40-fold less than the dose that is required to produce a similar degree of weight loss in congenic LPS-sensitive C3H/HeN mice.Citation35 Similarly, there is about a 40-fold difference between the lethal dose of LPS in LPS-responsive (A/HeJ) as compared with LPS-resistant (C3H/HeN) strains of mice.Citation36

Compared with humans, mice, even “normally responsive” strains, are remarkably less sensitive to the toxic or lethal effects of LPS. Thus, the dose of LPS, which leads to death in approximately half of mice (i.e., the LD50 dose) is about 1–25 mg/kg.Citation37-Citation39 This dose is about 1 000 000 times greater than the typical dose of LPS (2–4 ng/kg), which has been used in studies with human volunteer to induce symptoms (e.g., fever or myalgia) and the release of proinflammtory cytokines, such as TNF, into the circulation.Citation40,Citation41 The LD50 dose of LPS in mice is about 1000-fold to 10 000-fold greater than the dose of LPS that is required to induce severe illness and hypotension in humans.Citation42 In other words, the roughly 40-fold difference in the dose of LPS that is required to produce toxicity or death in “normally responsive” vs. “hyporesponsive” strains of mice is orders of magnitude smaller than is the difference in LPS dose that is required to produce death or serious illness in “normally responsive” mice as compared with human beings. The biological mechanism(s) that are responsible for the enormous difference between mice and humans with respect to responsiveness to LPS remain to be fully elucidated, but recent evidence obtained by Warren and colleagues suggests that one or more factors, which are present in murine sera, but are absent (or present in much lower concentrations) in human sera, are capable of suppressing the production of pro-inflammatory cytokines by murine (or human) mononuclear cells following stimulation with LPS or other TLR agonists, such as peptidoglycan (major component of the cell wall of gram-positive bacteria), zymosan (a glucan present in the cell wall of yeast) or bacterial DNA.Citation43 One of these factors may be the iron-binding acute phase protein, hemopexin.Citation44 Other factors, which have yet to be identified, may be important as well. In any event, the marked discrepancy in LPS sensitivity between mice and people suggests that data obtained using murine models of sepsis may be inapplicable to the human illness.

This view is strengthened by recently published findings from a systematic analysis of the genomic responses in three human conditions, which are associated with activation of the innate immune system, namely burn injury, trauma, and acute endotoxemia, and the corresponding insults in murine models.Citation45 In this important study, total cellular RNA was extracted from leukocytes isolated from blood, and gene expression profiles were obtained using appropriate Affymetrix GeneChip arrays. The samples from trauma and burn patients were obtained at 7 Level I trauma centers or 4 burn centers in the United States in the course of The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program (“Glue Grant”), which was funded by the National Institutes of Health. The human endotoxemia samples were obtained from eight healthy volunteers, who were challenged with a small i.v. dose of LPS (2 ng/kg). Of note, there was high degree of similarity in the gene expression profiles in leukocytes from human subjects with burn injuries, major trauma, or acute endotoxemia. In marked contrast, there was minimal correlation of expression changes between the human conditions and their murine orthologs in the mouse models. For example, when the gene expression profile for human endotoxemia was compared with the gene expression profile for murine endotoxema, the Pearson correlation analysis yielded an R2 value of 0.01 (i.e., essential no correlation at all). Interestingly, the time to recovery (i.e., the time required to restore normal gene expression levels) was far longer in humans (months) as compared with mice (hours to days).

Of course, some concerns have been raised, regarding the findings from the Glue Grant program, which were summarized in the previous paragraph.Citation46 For example, the gene expression responses of humans were compared with those of only one inbred strain of mice, and it is well known that strain differences in the murine system can markedly affect immunological responses. Furthermore, some of the differences between “mice and men” might reflect the impact of therapeutic interventions rather than just differences between the species with regard to gene expression responses to acute insults, such as trauma or infection. Still, the results obtained by Seok et al.Citation45 should prompt all researchers to be appropriately skeptical about extrapolating findings from murine sepsis models to the problem of sepsis in patients.

All acute endotoxemia models, irrespective of whether the animals under study are mice or some other species, suffer from the same problem. In these models, activation of the innate immune system can only have deleterious effects; therefore, any intervention that blunts the inflammatory response is likely to be beneficial. In contrast, sepsis in patients is triggered by an infectious process and the immunological responses to microbial challenge can have both salutary and deleterious effects.

Because sepsis in patients often starts with a focus of infection in the lungs or peritoneal cavity,Citation31 investigators and funding agencies have grown enamored in recent years with animal, especially murine, models of pneumonia and peritonitis. Because of its simplicity and, when performed correctly, its reproducibility, cecal ligation and puncture (CLP), which is a murine model of bacterial peritonitis, has been regarded, at least until the publication of the paper by Seok et al. cited above, as the “gold standard” animal model of sepsis. CLP in mice reproduces a number of key features of secondary bacterial peritonitis in humans, including polymicrobial infection,Citation47 persistently elevated circulating HMGB1 levels,Citation48 hyperdynamic circulatory system,Citation49 and development of acute lung injury.Citation50 Moreover, some studies, using the murine CLP model, yielded results, which are concordant with the lack of efficacy in human clinical trials of some important pharmacological approaches for the adjuvant treatment of sepsis, such as the administration of antibodies against TNFCitation51,Citation52 or the administration of IL-1RA.Citation53 In other cases, however, studies performed using the murine CLP model suggested that therapeutic interventions, such as administration of a PAF receptor antagonistCitation54 or exogenous PAF acetylhydrolase,Citation55 would improve survival. In clinical trials, however, these approaches were unsuccessful.

Although the murine CLP paradigm has some features to recommend it, this model of severe sepsis also has some serious flaws. First, as already discussed, at a gene expression level, acute systemic inflammatory responses in mice appear to be quite different from those that occur in humans. Second, sepsis in humans is, by and large, a disease that occurs at the extremes of age.Citation56 In contrast, in the vast majority of studies using the murine CLP model, sepsis is induced in young adult animals without any co-morbid conditions. It is noteworthy in this regard that CLP-induced sepsis in young adult mice is not associated with the development of acute kidney injury (AKI), a common problem in human sepsis, whereas CLP-induced sepsis in aged animals does lead to development of AKI.Citation57 Third, septic patients typically receive multiple forms of supportive care, including: mechanical ventilation, if indicated; resuscitation of intravascular volume; infusion of vasopressors and/or inotropic agents; administration of anti-microbial agents; renal replacement therapy, if indicated; surgical source control, if indicated; and enteral (or, less commonly, parenteral) administration of nutritional supplements. Some of these forms of supportive of care, such as the administration of antibiotics, are sometimes included in murine studies. However, the more complex interventions, such as renal replacement therapy or prolonged mechanical ventilation, are rarely, if ever, employed. Fourth, the temporal course of the septic process—from the onset of symptoms to death—in the murine CLP model is compressed into an interval that lasts at most a few days. In contrast, patients with lethal sepsis often survive for weeks before succumbing to their illness.

The CLP model likely can be improved, but the fixes are expensive and certainly not guaranteed to improve the model enough to make it a reliable step in the pathway toward the development of effective pharmacological agents for the adjuvant treatment of human sepsis. One improvement, already noted above, is to use aged mice, as described by the Star laboratory at the National Institutes of Health.Citation27,Citation57 Another improvement is to use “humanized mice” as described by Unsinger and colleagues.Citation58 These mice are generated by transplanting human CD34+ cord blood hematopoetic stem cells into gamma-irradiated neonatal NOD-scidIL2rγnull mice. These mice develop a complete lineage of human cells of the innate and adaptive immune systems, including monocytes, macrophages, plasmacytoid and myeloid dendritic cells, NK cells, T cells, and B cells. Sepsis is induced by performing CLP. Although the model might be useful, it is important to note that many key cell types, such as endothelial cells and intestinal and respiratory tract epithelial cells, are still murine. And, these cells, although not components of the “professional” immune system, are nonetheless important in the pathogenesis of the septic phenotype. Furthermore, generating “humanized” mice is a complex, time-consuming, and very expensive process, which is unlikely to be widely adopted. Finally, as yet, it is unknown whether results obtained with this model can predict the outcome of a clinical trial of a novel pharmacological intervention in patients with severe sepsis or septic shock.

Another way to solve some of the problems of the murine CLP model is to use a larger animal species, especially one that is more like humans with regard to sensitivity to LPS and possibly other pathogen-associated molecular pattern (PAMP) molecules. Following this sort of reasoning, our laboratory developed a rabbit peritonitis model, wherein sepsis was induced by i.p. injection of a known quantity of viable bacteria mixed with substances, namely hemoglobin and mucin, which are known to enhance the lethality of infections.Citation59 We employed a highly pathogenic strain of bacteria (E. coli O18:K1). The animals were treated with an appropriate antibiotic and were adequately resuscitated via an indwelling i.v. catheter. Studies performed with the rabbit paradigm indicated that tifacogin is an effective therapeutic agent, but contrary results were obtained in clinical trials.Citation60-Citation62 Thus, even this rabbit paradigm, which was developed to address many of the problems with earlier sepsis models, failed to predict the results of human clinical trials.

Sheep are docile large animals. Like humans, they are extremely sensitive to LPS. For example, continuous infusion of LPS at a rate as low as 9 ng/kg per h leads to marked changes in pulmonary arterial pressure, cardiac output, and lung microvascular permeability.Citation63 True sepsis, rather than endotoxemia, can be induced in sheep in a variety of ways, such as by infusing viable Pseudomonas aeruginosa i.v.Citation64 For ethical reasons, sheep are rarely used for survival studies, and thus it is not known whether ovine models of sepsis should be incorporated into the critical pathway for the development of new pharmacological agents for the treatment of sepsis.

In view of their close phylogenetic proximity to humans, nonhuman primate species, such as Papio anubis, would seem be good choices for preclinical models of sepsis. But, baboons and other monkey species tend to be remarkably resistant to the lethal effects of intravenously administered LPS or viable bacteria. Thus, in the classic Hinshaw model of lethal sepsis in baboons, the animals are infused with more than 1010 colony forming units (cfu)/kg of viable E. coli bacteria.Citation65 Blood cultures in this model contain 103 to 107 cfu/ml, i.e., levels of bacteria that are much greater than are commonly observed in lethal human septic shock. In numerous studies (), findings obtained using this model to test pharmacological interventions have failed to predict the outcome of human clinical trials.

In summary, most animal models of human sepsis are flawed. Studies using very complex models, such as ones that employ “humanized” mice, may represent a major advance, but, at present, data obtained in this way are quite limited. Experiments using animal models will remain in the critical pathway for the development of new agents for the pharmacological treatment of severe sepsis or septic shock. But, results from these preclinical studies never should be extrapolated directly to the problem of human sepsis.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

10.4161/viru.26083

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