110 Reduced Expression of Microsomal Prostaglandin Synthase 1 Attenuates Ventilatory Effects of Interleukin-1â in Neonatal DBA/1LACJ Mice

Abstract

Background: Infection and apnea represent major medical concerns in the neonatal population, and the pro-inflammatory cytokine interleukin-1Â (IL-1Â ) may serve as a critical link between these events. We recently showed that IL-1Â depresses respiration and anoxic survival via a prostaglandin-dependent mechanism (Olsson et al, 2003). In brain, microsomal prostaglandin E synthase 1 (mPGES-1) has been demonstrated crucial for the development of endotoxin-induced fever and is widely expressed in endothelial cells of the blood-brain-barrier after IL-1Â provocation. These same cells also express the IL-1 receptor as well as cyclooxygenase-2, which catalyzes the formation of prostaglandin H2 (PGH2) from arachidonic acid. mPGES-1 subsequently synthesizes prostaglandin E2 (PGE2) from PGH2. This study tested the hypothesis that IL-1Â alters respiratory control in newborn mice via a PGE2-mediated pathway.Methods: Respiratory behavior was examined using flow plethysmography in 9 day-old DBA/1lacJ wildtype mice and heterozygote knockout mice for mPGES-1. At 70 min after an intraperitoneal injection of either IL-1Â or saline, mice were placed unrestrained in the plethysmograph chamber. Basal respiration and the ventilatory response to anoxia (100% N2) and hyperoxia (100% O2) were then examined. Genotyping was performed after experimentation in all animals.Results: During normoxia, wildtype mice given IL-1Â exhibited a reduced respiratory frequency and tidal volume compared to control animals. Heterozygote knockout mice for mPGES-1 experienced less depression of basal respiration by IL-1Â. In response to anoxia, the IL-1Â -treated wildtype mice displayed fewer gasps and were unable to sustain gasping efforts for as long as control animals. They also were less able to autoresuscitate and survive following severe hypoxic apnea compared to control animals. These deleterious effects of IL-1Â were prevented in mice with a reduced expression of mPGES-1. Skin temperature was similar between groups prior to and following experimentation, suggesting that the results observed here are not due to confounding systemic changes induced by IL-1Â.Conclusion: This study indicates that IL-1Â adversely affects respiration and autoresuscitation in newborn mice and that these changes are mediated by PGE2. These findings may have clinical implications for the screening and treatment of neonatal apnea associated with infection.