Antenatal Endotoxin Impairs Lung Mechanics and Increases Sensitivity to Ventilator-Induced Lung Injury in Newborn Rat Pups.

Erica W Mandell,Courtney Mattson,Sharon Ryan,Tania Gonzalez,Steven H Abman,Bradford J Smith,Alison Wallbank,Elisa M Bye,Gregory Seedorf

doi:10.3389/fphys.2020.614283

Abstract

Perinatal inflammation due to chorioamnionitis and ventilator-induced lung injury (VILI) at birth is independent risk factors for the development of bronchopulmonary dysplasia (BPD). We have previously shown that antenatal endotoxin (ETX) causes abnormal lung structure and function in 2-week-old rats, but whether ETX impairs lung mechanics at birth and increases risk for VILI is unknown. Fetal rats were exposed to 10 μg endotoxin or saline via intra-amniotic injection. At birth (D0) or 7 days (D7), rats received 90 min of lung protective ventilation [PROTECT group; tidal volume (Vt) = 6 ml/kg with positive end expiratory pressure (PEEP) = 2 cmH2O]; P20 ventilation [plateau pressure (Pplat) = 20 cmH2O, PEEP = 0]; or P24 ventilation (Pplat = 24 cmH2O, PEEP = 0, only applied to D7). Prior to prolonged ventilation at D0, endotoxin-exposed rats had decreased compliance and inspiratory capacity (IC) compared to controls. At D7, endotoxin was associated with reduced compliance. High-pressure ventilation (P20 and P24) tended to increase IC and compliance in all saline-treated groups. Ventilation at D0 with P20 increased IC and compliance when applied to saline-treated but not endotoxin-exposed pups. At D7, P24 ventilation of endotoxin-exposed pups increased elastance, bronchoalveolar lavage protein content, and IL-1b and TEN-C mRNA expression in comparison to the saline group. In summary, antenatal endotoxin exposure alters lung mechanics at birth and 1 week of life and increases susceptibility to VILI as observed in lung mechanics, alveolocapillary barrier injury, and inflammatory mRNA expression. We speculate that antenatal inflammation primes the lung for a more marked VILI response, suggesting an adverse synergistic effect of antenatal and postnatal exposures.

Highlights

Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows preterm birth, is characterized by persistent respiratory disease and strongly associated with severe lifelong co-morbidities (Husain et al, 1998; Jobe, 1999; Thébaud and Abman, 2007; Islam et al, 2015; Schmidt et al, 2015)
One of three ventilation patterns was applied for 18 5-min epochs (Table 1): The PROTECT groups received the baseline ventilation, the P20 and P24 groups received a plateau pressure of 20 cmH2O or 24 cmH2O, respectively, with respiratory rate (RR) = 50 breaths/min; I:E = 1:2; and positive end expiratory pressure (PEEP) = 0 to cause ventilator-induced lung injury (VILI) as we previously described in adult mice (Smith et al, 2017; Hamlington et al, 2018a,b)
Other studies have demonstrated the deleterious effects of mechanical ventilation on the preterm lung and the risk factors for abnormal lung development, bronchopulmonary dysplasia (BPD), and late respiratory outcomes in preterm infants (Keller et al, 2017; Morrow et al, 2017)

Summary

Introduction

Bronchopulmonary dysplasia (BPD), the chronic lung disease that follows preterm birth, is characterized by persistent respiratory disease and strongly associated with severe lifelong co-morbidities (Husain et al, 1998; Jobe, 1999; Thébaud and Abman, 2007; Islam et al, 2015; Schmidt et al, 2015). Understanding of BPD pathophysiology and prevention has evolved significantly over the past 50 years with advances in maternal care, antenatal steroids, continuous positive airway pressure (CPAP), improved ventilator strategies, surfactant therapy, and other interventions (Jobe and Bancalari, 2001; Abman et al, 2017; Owen et al, 2017). Even with these improvements in the respiratory care of preterm infants, the incidence of BPD has remained around 40% of preterm births prior to 29 weeks (Stoll et al, 2010, 2015). Data from diverse sources support the concept that BPD has its origins during fetal life and that antenatal events are potent determinants of the persistent rate of BPD despite advances in postnatal care (Taglauer et al, 2018)

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