Abstract
Aim: Survivors of neonatal chronic lung disease or bronchopulmonary dysplasia (BPD) suffer from compromised lung function and are at high risk for developing lung injury by multiple insults later in life. Because neonatal lysophosphatidic acid receptor-1 (LPAR1)-deficient rats are protected against hyperoxia-induced lung injury, we hypothesize that LPAR1-deficiency may protect adult survivors of BPD from a second hit response against lipopolysaccharides (LPS)-induced lung injury.Methods: Directly after birth, Wistar control and LPAR1-deficient rat pups were exposed to hyperoxia (90%) for 8 days followed by recovery in room air. After 7 weeks, male rats received either LPS (2 mg kg−1) or 0.9% NaCl by intraperitoneal injection. Alveolar development and lung inflammation were investigated by morphometric analysis, IL-6 production, and mRNA expression of cytokines, chemokines, coagulation factors, and an indicator of oxidative stress.Results: LPAR1-deficient and control rats developed hyperoxia-induced neonatal emphysema, which persisted into adulthood, as demonstrated by alveolar enlargement and decreased vessel density. LPAR1-deficiency protected against LPS-induced lung injury. Adult controls with BPD exhibited an exacerbated response toward LPS with an increased expression of pro-inflammatory mRNAs, whereas LPAR1-deficient rats with BPD were less sensitive to this “second hit” with a decreased pulmonary influx of macrophages and neutrophils, interleukin-6 (IL-6) production, and mRNA expression of IL-6, monocyte chemoattractant protein-1, cytokine-induced neutrophil chemoattractant 1, plasminogen activator inhibitor-1, and tissue factor.Conclusion: LPAR1-deficient rats have increased hyperoxia-induced BPD survival rates and, despite the presence of neonatal emphysema, are less sensitive to an aggravated “second hit” than Wistar controls with BPD. Intervening in LPA-LPAR1-dependent signaling may not only have therapeutic potential for neonatal chronic lung disease, but may also protect adult survivors of BPD from sequelae later in life.
Highlights
Very preterm infants are at high risk of developing severe respiratory distress syndrome (RDS) secondary to lung immaturity and surfactant-deficiency
This study demonstrates that [1] acute lung injury in adulthood induces an aggravated second hit response in rats with neonatal hyperoxia-induced bronchopulmonary dysplasia (BPD), [2] LPAR1-deficiency results in emphysema and reduced vascularization in adult rats, and
In agreement with our previous studies, we found that neonatal hyperoxia-induced emphysema persists into adulthood and confirm similar observations in mice with BPD (O’Reilly et al, 2008; McGrath-Morrow et al, 2011)
Summary
Very preterm infants are at high risk of developing severe respiratory distress syndrome (RDS) secondary to lung immaturity and surfactant-deficiency. Lung function in neonatal survivors of BPD is affected directly after birth, and later in life, as these children are more susceptible to lower respiratory tract infections, wheezing and asthma, and PAH at relatively young ages (Bhandari and McGrath-Morrow, 2013; Carraro et al, 2013; Gough et al, 2014). Their quality of life and the burden to society of survivors of BPD is affected by frequent rehospitalization after discharge and BPD-associated pathology, such as poor neurodevelopmental outcome due to cerebral and cerebellar hemorrhages and hypoxic insults, delayed growth, and long-term gastro-intestinal problems (Dammann et al, 2004). Treatment of BPD is mainly symptomatic and focuses on gentler respiratory support to reduce neonatal lung damage and pharmacological interventions, such as diuretics for lung edema, caffeine to stimulate central respiratory drive, bronchodilators for life-threatening episodes of severe bronchospasm, and postnatal corticosteroids as anti-inflammatory agents (Baraldi and Filippone, 2007; Gien and Kinsella, 2011; Jain and Bancalari, 2014)
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