Interleukin-1β and interleukin-6 enhance thermal prolongation of the LCR in decerebrate piglets

Abstract

Thermal stress and prior upper respiratory tract infection are risk factors for the Sudden Infant Death Syndrome. The adverse effects of prior infection are likely mediated by interleukin-1β (IL-1β). Therefore, we examined the single and combined effects of IL-1β and elevated body temperature on the duration of the Laryngeal Chemoreflex (LCR) in decerebrate neonatal piglets ranging in age from post-natal day (P) 3 to P7. We examined the effects of intraperitoneal (I.P.) injections of 0.3 mg/Kg IL-1β with or without I.P. 10 mg/Kg indomethacin pretreatment on the duration of the LCR, and in the same animals we also examined the duration of the LCR when body temperature was elevated approximately 2 °C. We found that IL-1β significantly increased the duration of the LCR even when body temperature was held constant. There was a significant multiplicative effect when elevated body temperature was combined with IL-1β treatment: prolongation of the LCR was significantly greater than the sum of independent thermal and IL-1β-induced prolongations of the LCR. The effects of IL-1β, but not elevated body temperature, were blocked by pretreatment with indomethacin alone. We also tested the interaction between IL-6 given directly into the nucleus of the solitary tract (NTS) bilaterally in 100 ngm microinjections of 50 μL and pre-treatment with indomethacin. Here again, there was a multiplicative effect of IL-6 treatment and elevated body temperature, which significantly prolonged the LCR. The effect of IL-6 on the LCR, but not elevated body temperature, was blocked by pretreatment with indomethacin. We conclude that cytokines interact with elevated body temperature, probably through direct thermal effects on TRPV1 receptors expressed pre-synaptically in the NTS and through cytokine-dependent sensitization of the TRPV1 receptor. This sensitization is likely initiated by cyclo-oxygenase-2 dependent synthesis of prostaglandin E2, which is stimulated by elevated levels of IL-1β or IL-6. Inflammatory sensitization of the LCR coupled with thermal prolongation of the LCR may increase the propensity for apnea and Sudden Infant Death Syndrome.

Activation of serotonergic neurons in the medullary caudal raphe shortens the laryngeal chemoreflex in anaesthetized neonatal rats

“…), which also appear to cause a form of reflex allodynia when cytokines, such as interleukin‐1β or interleukin‐6, cause phosphorylation of the TRPV1 channels (Xia et al . ). Thus, risk factors for SIDS, such as maternal smoking, thermal stress and recent infections, all serve to sensitize and enhance the LCR, and possibly other apnoea‐generating reflexes.…”

“…; Xia et al . , , , ). Many investigators have suggested that the LCR is the first step in a process that starts with respiratory inhibition and apnoea and ends with failed termination of apnoea, failed restoration of regular breathing and failed arousal, leading to sudden infant death syndrome (SIDS) and asphyxial deaths in human infants (Downing & Lee, ; Page & Jeffery, ; Thach, ).…”

“…Previously, we investigated the first part of this hypothesis, identifying risk factors for SIDS that increase the sensitivity and strength of the LCR (Xia et al . , , , ). More recently, we turned our attention to the second part of the hypothesis.…”

Serotonin in the solitary tract nucleus shortens the laryngeal chemoreflex in anaesthetized neonatal rats

“…First, infants at risk for SIDS have a variety of risk factors that seem to increase the propensity for reflex apnoeas, especially the LCR (Leiter & Böhm, ; Xia et al . ). Second, infants at risk for SIDS seem to have deficient serotonergic function (Paterson et al .…”

“…Thus, infants at risk for SIDS may have a dual set of deficits; they may be unusually prone to reflex apnoea because of non‐serotonergic mechanisms that sensitize reflex apnoeic mechanisms (Xia et al . ); they may be particularly susceptible to hypoxic depression of breathing; and they may, owing to deficient 5‐HT and/or deficiencies of 5‐HT receptor subtypes, have inadequate arousal responses capable of terminating apnoea and restoring eupnoea. The increased propensity for apnoeas, when combined with defects in arousal secondary to reduced serotonergic function, may make these infants susceptible to a downward spiral of apnoeic and hypoxic inhibition of eupnoea from which they cannot arouse, ultimately ending in death.…”