Background: Preterm infants exposed to inflammation during pregnancy are prone to apnoeas and require respiratory support at birth. These infants are also at increased risk of brain injury. The brainstem contains vital respiratory centres which can be inhibited by inflammation, particularly by prostaglandin E2 (PGE2). We aimed to investigate whether intrauterine inflammation alters fetal respiratory function, and whether this is associated with increases in PGE2 and inflammation in brainstem respiratory centres.
Methods: Fetal lambs (125 days gestation) were exteriorised and instrumented to measure fetal respiratory function (fetal breathing movements; FBMs), heart rate and blood pressure before being returned in utero. At 129 days gestation fetal lambs received saline or escalating doses of Lipopolysaccharide (LPS; 300ng, 600ng, 1.2ug intravenously) over 3 days. The frequency and duration of FBMs was assessed using LabChart (v8.0, ADInstruments). PGE2 expression in brainstem respiratory centres and cerebrospinal fluid (CSF) was assessed by immunohistochemistry and ELISA. Inflammation of brainstem respiratory centres was assessed by microglia immunohistochemistry. T-test was used for statistical analysis.
Results: LPS caused a significant reduction in FBMs, decreased oxygen saturation, increased blood lactate levels and caused mild acidosis (all p<0.05) on days 1 and 2 compared to the control group. However, tolerance to LPS was observed in response to day 3 treatments. LPS increased PGE2 expression in brainstem neurons and CSF and was associated with hyper-ramified and ameboid microglia in brainstem respiratory centres.
Conclusion: Acute exposure to LPS suppresses FBMs which coincides with increased PGE2 in brainstem neurons and CSF and microgliosis, suggesting that brainstem inflammation may have a significant role in respiratory depression in preterm newborns.