Abstract

Bronchopulmonary dysplasia (BPD) is a devastating disease of prematurity that is associated with mechanical ventilation and hyperoxia. We used preterm pigs delivered at gestational day 102 as a translational model for 26–28-week infants to test the hypothesis administering recombinant human keratinocyte growth factor (rhKGF) at initiation of mechanical ventilation will stimulate type II cell proliferation and surfactant production, mitigate ventilator induced lung injury, and reduce epithelial to mesenchymal transition considered as a precursor to BPD. Newborn preterm pigs were intubated and randomized to receive intratracheal rhKGF (20 μg/kg; n = 6) or saline (0.5 ml 0.9% saline; control; n = 6) before initiating 24 h of ventilation followed by extubation to nasal oxygen for 12 h before euthanasia and collection of lungs for histopathology and immunohistochemistry to assess expression of surfactant protein B and markers of epithelial to mesenchymal transition. rhKGF pigs required less oxygen during mechanical ventilation, had higher tidal volumes at similar peak pressures indicative of improved lung compliance, and survival was higher after extubation (83% vs. 16%). rhKGF increased surfactant protein B expression (p < 0.05) and reduced TGF-1β (p < 0.05), that inhibits surfactant production and is a prominent marker for epithelial to mesenchymal transition. Our findings suggest intratracheal administration of rhKGF at initiation of mechanical ventilation enhances surfactant production, reduces ventilator induced lung injury, and attenuates epithelial-mesenchymal transition while improving pulmonary functions. rhKGF is a potential therapeutic strategy to mitigate pulmonary responses of preterm infants that require mechanical ventilation and thereby reduce the incidence and severity of bronchopulmonary dysplasia.

Highlights

  • Despite advances in mechanical ventilation, the mortality, morbidity, and childhood disability associated with bronchopulmonary dysplasia (BPD) remains unchanged due to the increasing numbers of extremely preterm infants surviving birth before 28 weeks of gestation that require mechanical ventilation

  • The impact of mechanical ventilation on the lungs is greater for preterm than newborn term pigs [16], causing changes in expression of proinflammatory cytokines and growth factors such as transforming growth factor (TGF)-β1 and Keratinocyte growth factor (KGF) [17], mimicking the greater sensitivity and responses to mechanic ventilation of preterm compared with term infants

  • Endogenous KGF was not evaluated, the intratracheal administration of recombinant human keratinocyte growth factor (rhKGF) at the initiation of mechanical ventilation likely compensated for the lower expression of KGF in response to the ventilator-induced lung injury (VILI) caused by the assist control volume guarantee (AC+VG) and hyperoxia from the increase FiO2

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Summary

Introduction

Despite advances in mechanical ventilation, the mortality, morbidity, and childhood disability associated with bronchopulmonary dysplasia (BPD) remains unchanged due to the increasing numbers of extremely preterm infants surviving birth before 28 weeks of gestation that require mechanical ventilation. Exposing the immature lungs of extremely preterm infants to a combination of the shear stress of intermittent positive-pressure ventilation that causes ventilator-induced lung injury (VILI) [1, 2] and hyperoxia to maintain targeted blood gases [3] decreases production of surfactant, alters expression of pulmonary growth factors, and initiates the pathophysiologic changes of BPD. Mechanical ventilation and hyperoxia disturb secretion of the transforming growth factor (TGF)-beta superfamily of growth factors, leading to EMT, disrupting lung development, and causing lung fibrosis that are hallmarks of BPD [4, 6]. Exposure of the preterm lung to increased TGF-β inhibits proliferation of ATII cells and decreases surfactant expression

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