Mechanical ventilation induces brainstem inflammation in preterm fetal sheep

Kayla Vidinopoulos; Zahrah Azman; Ainsley Somers; Valerie A Zahra; Alison Thiel; Hui Lu; Yen Pham; Nhi Thao Tran; Beth J Allison; Eric Herlenius; Stuart Hooper; Robert Galinsky; Graeme R Polglase

doi:10.3389/fped.2023.1225294

Mechanical ventilation induces brainstem inflammation in preterm fetal sheep

Front Pediatr. 2023 Oct 23:11:1225294. doi: 10.3389/fped.2023.1225294. eCollection 2023.

Authors

Kayla Vidinopoulos^{1

2}, Zahrah Azman^{1

2}, Ainsley Somers^{1

2}, Valerie A Zahra¹, Alison Thiel¹, Hui Lu¹, Yen Pham¹, Nhi Thao Tran^{1

2}, Beth J Allison^{1

2}, Eric Herlenius³, Stuart Hooper^{1

2}, Robert Galinsky^{1

2}, Graeme R Polglase^{1

2}

Affiliations

¹ The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.
² Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia.
³ Department of Women's and Children's Health, Astrid Lindgren Children's Hospital, Karolinska Institutet, Stockholm, Sweden.

Abstract

Background: Preterm infants have immature respiratory drive and often require prolonged periods of mechanical ventilation. Prolonged mechanical ventilation induces systemic inflammation resulting in ventilation-induced brain injury, however its effect on brainstem respiratory centers is unknown. We aimed to determine the effects of 24 h of mechanical ventilation on inflammation and injury in brainstem respiratory centres of preterm fetal sheep.

Methods: Preterm fetal sheep at 110 ± 1 days (d) gestation were instrumented to provide mechanical ventilation in utero. At 112 ± 1 d gestation, fetuses received either mechanical ventilation (VENT; n = 7; 3 ml/kg) for 24 h, or no ventilation (CONT; n = 6). At post-mortem, fetal brainstems were collected for assessment of mRNA and histological markers of inflammation and injury.

Results: In utero ventilation (IUV) did not alter any blood-gas parameters. IUV significantly increased systemic IL-6 and IL-8 concentrations over the 24 h period compared to CONT. The number of ameboid microglia within the nucleus tractus solitarius and the raphe nucleus increased in VENT fetuses (p < 0.05 for both vs. control). The % area fraction of GFAP + staining was not significantly higher within the preBötzinger complex (p = 0.067) and retrotrapezoid nucleus and parafacial respiratory group (p = 0.057) in VENT fetuses compared to CONT. Numbers of caspase-3 and TUNEL-positive cells were similar between groups. Gene expression (mRNA) levels of inflammation, injury, cell death and prostaglandin synthesis within the brainstem were similar between groups.

Conclusion: Mechanical ventilation induces a systemic inflammatory response with only moderate inflammatory effects within the brainstem respiratory centres of preterm fetal sheep.

Keywords: brainstem; inflammation; mechanical ventilation; preterm birth; ventilation-induced brain injury.