Respiratory Function in a Novel Neonatal Rat Model of Early Life Oxygen Dysregulation and Subsequent Immune Challenge

Abstract

Preterm infant immaturity is characterised by unstable cardiorespiratory control, with male infants exhibiting poorer clinical outcomes. Very/Extremely preterm infants are at an increased risk of infection in early life. Infections are often caused by Gram‐positive bacteria that activate inflammatory pathways. We sought to characterise respiratory function and redox status in response to early life oxygen dysregulation (intermitted hypoxia and hyperoxia) and subsequent immune challenge using gram positive bacterial proteins.This study was approved by local animal ethics committee and the national regulatory body, HPRA Ireland. On postnatal day (PND) three, Sprague Dawley litters were exposed for 10 days to either cIHH or sham conditions. Following intraperitoneal (i.p) administration of LTA+PGN or vehicle solution on PND13, animals were monitored for 3 hours using whole body plethysmography. VCO2 was measured in parallel. A separate cohort of animals were exposed to an autoresuscitation protocol which consisted of acute anoxia until primary gasp and subsequent recovery in normoxic conditions (FiO2 21%). In littermates exposed to either cIHH/Sham and subsequent LTA+PGN/vehicle administration, blood, plasma and tissue was collected post‐mortem. Blood (pH and lactate) analysis was performed, plasma cortisol concentrations were quantified, and mRNA expression of NAD(P)H Quinone Dehydrogenase 1 was quantified in the diaphragm muscle. All data were analysed using a three‐way ANOVA (factors: sex, gas, drug), n=8‐10.There was a small decrease in the ventilatory equivalent following cIHH exposure (gas P<0.05). However, there was no evidence of acid‐base disturbance. We observed increased number of sighs in cIHH treated female animals (gas x sex P<0.05). NQO1 mRNA expression was upregulated in both sexes following cIHH gas exposure (gas factor P<0.05), most evident in males. Post‐sigh apnoea duration was decreased following immune challenge in both male and female rats (P<0.05). Cortisol concentrations were upregulated in both males and females following immune challenge (drug P<0.05 and sex x drug P<0.05), with higher expression evident in males. Primary apnoea duration in response to anoxia was similar across all groups. Although total number of gasps in the 30seconds post primary apnoea was significantly increased in sham females that received LTA&PGN (gas x drug interaction P<0.05). Gasping was significantly decreased in cIHH exposed females.cIHH upregulation of the anti‐oxidant pathway likely protects against oxidative stress and inflammation. cIHH also enhanced the number of sighs, known to be important in homeostatically regulating breathing variability. Neonatal exposure to immune challenge potently increased the stress hormone cortisol and increased post‐anoxic gasping in control conditions. This research has also revealed interesting sex‐specific effects as well as interactions between neonatal oxygen dysregulation and a subsequent immune challenge that need to be explored further.