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.