Editorial: Mouse models to study sepsis syndrome in humans

The pathophysiology of sepsis in humans is poorly understood. This common syndrome, responsible for killing hundreds of thousands of patients each year in the United States alone [1], was defined by a consensus statement in 1992 to consist of certain criteria that provide evidence for inflammation in the setting of infection [2]. Severe sepsis was defined as organ failure in the setting of sepsis, and septic shock was defined as severe sepsis where the organ failure was hypotension. The definition for severe sepsis has become the basis for the entry criteria for most clinical trials of sepsis, lumping together heterogenous patients who have some type of infection, some type of secondary inflammation, and some kind of organ failure. The inherent concept in these definitions is that inappropriate or over-abundant inflammation is central to the pathophysiology of the syndrome. At the time that these definitions were made, there were limited numbers of proinflammatory cytokines described (notably, IL-1 and TNF). The dominant hypothesis was that the pathophysiology of sepsis syndrome was related or caused by microbial wall components (such as bacterial LPS), activating immune cells to produce these cytokines, which then in turn induced uncontrolled inflammation. Treatment attempts at blocking these two proinflammatory cytokines failed in patients with sepsis syndrome. Ironically, we now know that deficiency of these cytokines leads to immunocompromise and infections that cause sepsis. Proof of the hypothesis that microbial-induced inflammation is causative in sepsis syndrome is still lacking; this proof will need to come from a study in humans in which part of this cascade is blocked, and there is clear and reproducible, therapeutic benefit. In the meanwhile, numerous experiments worldwide are performed in mouse models with the hope of better understanding microbial-induced inflammation so that such new therapies can be developed. For decades, mouse models to study sepsis have fallen into one of two broad categories: intoxication and infection. In intoxication models, mice are challenged with a noninfectious, proinflammatory compound, such as LPS or killed bacteria. In infection models, the mice are challenged with live bacteria. Multiple variations of these models have been tried over the years with differing endpoints and routes of administration. One of the most-used models, the CLP model, was developed to try to better mimic sepsis in patients in which there is a mixed bacterial species in a relevant tissue compartment. In this model, the cecum of rodents is ligated and punctured with a needle, resulting in spillage of the intestinal contents into the peritoneum and the development of secondary bacterial peritonitis [3]. Unfortunately, all of the mouse models have one substantial and over-riding disadvantage: The disease that mice develop in response to microbial challenge seems to differ from what is seen clinically in humans. Compared with what is seen in sepsis syndrome in humans, mice challenged with high numbers of bacteria, such as in the CLP model, tend to have a shorter duration of disease, which is often terminated with a quite sudden death and less organ failure. Secondary derangements in kidney, lung, and liver function that are such an important part of sepsis syndrome and that often lead to death in humans are therefore not easily studied in these mouse models. Rodents are highly resistant to most types of induced inflammation compared with humans. The challenge dose of LPS used in most published in vivo studies in mice is 1–25 mg/kg, which approximates the dose that causes death in half of the mice [4 –7]. This dose is 1000 –10,000 times the dose required to induce severe disease with shock in humans [8, 9] and 1,000,000 times the dose used in carefully controlled study environments in which human volunteers are challenged with highly characterized preparations of 2– 4 ng/kg LPS to elicit fever and cytokines [10]. A direct comparison between the species for live bacteria is obviously not possible. However, in most mouse models, it is necessary to administer high doses of live bacteria to induce illness (usu-