Effects of Hyperthermia and Muramyl Dipeptide on IL-1|[bgr]|, IL-6, and Mortality in a Neonatal Rat Model

摘要

The mechanism of sudden infant death syndrome (SIDS) may be linked to an interaction between the SIDS risk factors of hyperthermia and infection, and between their effect on cytokine production and arousal. This study investigated the effects of hyperthermia and a surrogate of infection (muramyl dipeptide or MDP) on cytokine production and mortality in a neonatal rat model. Four temperature groups were studied: 34°C (baseline), 38°C, 39°C, and 40°C. Body temperatures of neonatal rat pups in the hyperthermic groups were raised and maintained at the desired temperature (38°C, 39°C, or 40°C) for 1 h and then returned to the baseline temperature (34°C) for a further hour. The heat source was a covered, heatable aluminum metal plate in a Perspex heating chamber. Intraperitoneal (IP) injection of 0.1 mL normal saline was given 30 min before the start to control for MDP (protocol A). Four equivalent treatment groups were pretreated with MDP (25 nmol/animal) instead of normal saline (protocol B). IP ketamine (55 mg/kg) was used for anesthesia during the experiments and for euthanasia. Blood was collected by direct cardiac puncture immediately after the 2-h experiments and assayed for the cytokines IL-6 and IL-1β by ELISA. Hyperthermia significantly increased the production of IL-6 (p = 0.049) but not IL-1β and significantly increased mortality. Administration of MDP significantly increased the IL-1β production (p = 0.006) but not IL-6. Cox regression analysis showed that MDP in combination with hyperthermia had a significant effect on mortality in the neonatal rat. The risk of experiencing mortality was two and half times higher in the MDP group than in the non-MDP group (p = 0.016) [hazard ratio (95% confidence interval) = 2.66 (1.20–5.92)]. We conclude that hyperthermia and a surrogate of infection (MDP) influence cytokine production and that the combination of heat stress and MDP increases mortality in the neonatal rat.Abbreviations: SIDS, sudden infant death syndrome; TNF, tumor necrosis factor; LPS, lipopolysaccharide; MDP, muramyl dipeptide or N-acetyl-muramyl-l-alanyl-d-isoglutamine; WBH, whole-body hyperthermia; HPA, hypothalamic-pituitary-adrenal; SHRP, stress-hyporesponsive period; CRF, corticotrophin-releasing factor