Detailed Characterization of a Long-Term Rodent Model of Critical Illness and Recovery

Abstract

Objective: To characterize a long-term model of recovery from critical illness, with particular emphasis on cardiorespiratory, metabolic and muscle function Design: Randomized controlled animal study Setting: University research laboratory Subjects: Male Wistar ratsInterventions: Intraperitoneal injection of the fungal cell wall constituent, zymosan or n-saline. Measurements and Main Results:Following intervention, rats were followed for up to two weeks.Animals with zymosan peritonitis reached a clinical and biochemical nadir on day 2. Initial reductions were seen in body weight, total body protein and fat, and muscle mass. Leg muscle fiber diameter remained subnormal at 14 days with evidence of persisting myonecrosis, even though gene expression of regulators of muscle mass (e.g. MAFbx, MURF1, myostatin) had peaked on days 2-4 but had normalized by Day 7. Treadmill exercise capacity, forelimb grip strength and in vivo maximum tetanic force were also reduced. Food intake was minimal until Day 4 but increased thereafter. This did not relate to appetite hormone levels with early (6h) rises in plasma insulin and leptin followed by persisting subnormal levels; ghrelin levels did not change. Serum IL-6 level peaked at 6h but had normalized by Day 2 whereas IL-10 remained persistently elevated and HDL cholesterol persistently depressed. There was an early myocardial depression and rise in core temperature, yet reduced oxygen consumption and respiratory exchange ratio with a loss of diurnal rhythmicity that showed a gradual but incomplete recovery by Day 7.Conclusions: This detailed physiological, metabolic, hormonal, functional and histological muscle characterization of a model of critical illness and recovery reproduces many of the findings reported in human critical illness. It can be used to assess putative therapies that may attenuate loss, or enhance recovery, of muscle mass and function.

The future of murine sepsis and trauma research models

“…Although not novel in and of itself, the authors' methodology of examination of the rodents and their emphasis on examination of the chronic effects of inflammation are novel [48]. PT Ninety minutes of hemorrhagic shock are followed by multicompartmental injuries (long bone fracture and cecectomy), creating a much higher injury severity score for the mouse [32,40].…”

“…Several attempts have been made to create models of CCI. One such approach has been the sterile administration of zymosan, a fungal cell-wall product [48]. This produces a triphasic response associated with early mortality, a transient recovery period followed ultimately by death from multiple organ failure, 2-3 wk after induction [48].…”

“…One such approach has been the sterile administration of zymosan, a fungal cell-wall product [48]. This produces a triphasic response associated with early mortality, a transient recovery period followed ultimately by death from multiple organ failure, 2-3 wk after induction [48]. Although on the surface, the timing and the phenotype of the inflammation recapitulate human CCI, a detailed investigation has revealed that the model is one of persistent hyperinflammation, without evidence of a simultaneous immune suppression, as is seen in humans with CCI and PICS [49].…”

Impact of ghrelin on body composition and muscle function in a long-term rodent model of critical illness

“…Critical illness was induced on Day 0 using zymosan (Sigma Aldrich, St. Louis, MO) (30 mg/100g body mass) mixed with liquid paraffin to a concentration of 25 mg/ml, and injected intraperitoneally via a 19G needle through the anterior abdominal wall, as previously described [ 19 ]. All injections were given under brief anesthesia with inhaled isoflurane.…”

“…We thus sought to assess the impact of ghrelin treatment in a validated long-term rodent model of zymosan peritonitis [ 19 ]. This model recapitulates many aspects of human critical illness, including weight loss, muscle weakness and anorexia, which improves with clinical recovery [ 19 ]. We chose not to intervene in the immediate post-insult period as early nutrition has been associated with poor outcomes [ 20 ].…”