Mouse Models of Resuscitated Shock

Abstract

Studies of sepsis in humans are difficult because the seriousness of the disease mandates immediate intervention and because the heterogeneity of patient presentations imposes substantial limitations on clinical trials. Thus, animal models have been used extensively to explore the pathogenesis of sepsis and to generate preclinical data for therapeutic interventions. Translation of findings in these models into therapeutic strategies has been difficult, in part because of limitations in preclinical models and in part to imperfect understanding of the pathophysiology of sepsis. It is important to use an animal model that reproduces the relevant physiologic parameters present in patients with septic shock. Mouse models are particularly useful for the dissection of molecular mechanisms of disease because of the proliferation of transgenic strains. We have developed a murine model of sepsis with fluid resuscitation and antibiotic treatment that reproduces the timing and degree of mortality seen in patients with septic shock. Using continuous micromanometric pressure monitoring and assessment of hemodynamics by echocardiography, we have shown that this model reproduces the hyperdynamic state with hypotension seen in clinical sepsis. The use of transgenic technology in appropriate murine models is exciting because of its potential to permit significant strides in our understanding of the molecular mechanisms of sepsis, multiple organ system failure, and other diseases. The use of reproducible and clinically relevant mouse models of shock is essential for delineation of pathogenetic mechanisms and for initial testing of potential therapeutic strategies.

Endotoxin impairs cardiac hemodynamics by affecting loading conditions but not by reducing cardiac inotropism

“…Such preload reduction was obvious in our study, as indicated by the significant decrease of LVEDV, 6 h after endotoxin, which is in agreement with similar observations previously made in rodent endotoxemia (12,24,57,58). It must be underscored that animals were given only a limited amount of fluid by intraperitoneal route (ϳ20 ml/kg), which is not different from the general use in this murine model of endotoxemia (14).…”

Actinonin, a Meprin a Inhibitor, Protects the Renal Microcirculation During Sepsis

“…After recovering from anesthesia, mice were placed in individual cages and set on a warming pad. Mice studied at 18 h post CLP received imipenem/cilastatin (14 mg/kg, s.c.) in 1.5 ml of two-thirds normal saline (40 ml/kg) for fluid resuscitation (21, 22) at 6 h post CLP. Survival at 18 h post CLP was 100%.…”

Mouse Injury Model of Polytrauma and Shock

“…Some of these models have been combined in an attempt to better imitate the human condition ( see Table 1). These previous rodent models of trauma and shock have made significant contributions to our understanding of the biological response to injury, yet critical analysis and revision of these models are necessary with technological advances and our expanding knowledge of the biology of inflammation, particularly at the genomic level [15, 16, 18, 28–30]. …”

“…The criticisms surrounding current murine trauma and shock models are longstanding [15–19, 28, 29], but recent concerns stem from studies that have further highlighted the inherent differences in the murine and human genomic response to inflammatory diseases [13, 14, 16, 31]. The Mouse ENCODE Consortium [32] and the “Inflammation and Host Response to Injury” (Glue Grant) [30, 33] have catalogued the transcriptomic response in both health and disease in mice and humans.…”