Abstract
The preterm lung is particularly vulnerable to ventilator-induced lung injury (VILI) as a result of mechanical ventilation. However the developmental and pathological cellular mechanisms influencing the changing patterns of VILI have not been comprehensively delineated, preventing the advancement of targeted lung protective therapies. This study aimed to use SWATH-MS to comprehensively map the plasma proteome alterations associated with the initiation of VILI following 60 minutes of standardized mechanical ventilation from birth in three distinctly different developmental lung states; the extremely preterm, preterm and term lung using the ventilated lamb model. Across these gestations, 34 proteins were differentially altered in matched plasma samples taken at birth and 60 minutes. Multivariate analysis of the plasma proteomes confirmed a gestation-specific response to mechanical ventilation with 79% of differentially-expressed proteins altered in a single gestation group only. Six cellular and molecular functions and two physiological functions were uniquely enriched in either the extremely preterm or preterm group. Correlation analysis supported gestation-specific protein-function associations within each group. In identifying the gestation-specific proteome and functional responses to ventilation we provide the founding evidence required for the potential development of individualized respiratory support approaches tailored to both the developmental and pathological state of the lung.
Highlights
With advances in perinatal care, preterm birth has become a major public health issue[1]
gestational age (GA)-specific alterations in gas exchange included increased oxygenation index (OI) and alveolar-arterial oxygen difference (AaDO2) in extremely preterm and preterm animals when compared with term animals (Table 1)
Essential for survival, mechanical ventilation is closely associated with a high risk of developing ventilation induced lung injury (VILI)
Summary
With advances in perinatal care, preterm birth has become a major public health issue[1]. The respiratory system is the most acutely compromised in early life, being structurally immature, surfactant deficient and prone to collapse[2] These defects often necessitate the application of mechanical respiratory support in the form of positive pressure ventilation to sustain life. Minimizing VILI remains a key goal of neonatal intensive care Whilst major advances, such as exogenous surfactant[15], antenatal steroids[16], better nutritional support[17] and non-invasive ventilation[18], have significantly improved outcomes, more than 50% of extremely preterm infants (
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