Our studies investigated the relationship between formation of plasma lipid metabolite levels in premature infants and the development of BPD. While we initially identified associations, these were no longer significant following correction for gestational age and gender in our analyses. Plasma PGE2
levels have previously been measured in infants at days of life 1, 3, and 7 (17
); however, similar to the present study, no differences were detected. Though the authors did not control for gestational age, they speculated that maturational changes in lipid metabolism might account for their findings and our data support their speculation.
The secondary analyses indicated that several individual or combined lipid metabolites were correlated with gestational age at birth. It is important to note that eight of the eleven identified metabolites associated with gestational age can be formed through activity of lipoxygenase enzymes. One interpretation of these data is that extremely preterm infants may be deficient lipoxygenase pathways enzymes.
HETEs can be generated by multiple mechanisms including free radical oxidation or oxidation through the activities of individual lipoxygenases (18
). Our data indicates that absolute quantities of HETEs were higher in the infants that developed BPD and most were correlated with gestational age. HETEs are biologically active molecules that increase in response to injury and repair and modulate cell proliferation (19
). The increases in these products as a function of gestational age suggest that these pathways are adaptive rather than injurious. LTB4
is the most potent chemotactic agent produced from arachidonic acid (20
), is often associated with neutrophil adhesion and infiltration at sites of inflammation, and likely contributes significantly to hyperoxic lung injury (21
). Increased endothelial cell permeability is a significant event associated with hyperoxic lung injury (22
). EETs are formed by cytochrome P450 activity and play a direct role in regulating endothelial cell permeability (23
), vasodilatation, and Ca2+
entry into the lung microvasculature.
The association between gestational age and expressions of these lipid metabolites suggests that the pathways responsible for their production are regulated through processes during intrauterine growth. The developmental regulation of lipid metabolism could be especially significant in the extremely preterm infant that is more likely to develop morbidities such as BPD. Deficiencies in biologically active lipids in extremely preterm infants may contribute to inappropriate responses to inflammation, inflammatory stimuli, or tissue repair, resulting in further or permanent tissue injury.
The prostaglandin product 8-iso-PGF2α
, a product of free radical oxidation, has previously been measured in infants at risk for the development of BPD. Cord blood plasma levels of 8-iso-PGF2α
were higher in preterm infants than in term infants and directly correlated with poor outcomes (24
). Studies by Ahola et al. (25
) indicated that plasma 8-iso-PGF2α
levels at day of life 3 and 7 were highest in the extremely low birth weight infants that developed BPD and correlated with oxygen support at 7 and 14 days. Unlike the present study, however, Ahola et al. did not correct for gestational age. Following correction for gestational age, our data indicated no correlation between 8-iso-PGF2α
and BPD development but did indicate a positive correlation with gestational age. While our unadjusted results are in agreement with Ahola et al., the loss of significance following adjustment for confounders highlights the importance of appropriately powered studies that enable such adjustments.
The strengths of this study include the prospective study design, the relatively large sample size, the statistical analyses, and the specificity of the analyses enabled by the use of mass spectrometry. Limitations worth noting include the lack of sensitivity to detect some plasma lipid metabolites as evidenced by the number of candidate biomarkers that were below the limits of detection. Secondly, while 0–72 hours were chosen for sample collection, later time points may have been more informative and may have better correlated with disease outcomes. The present studies involved a greater number of patients than in previously published studies allowing us to control for multiple confounding variables in the statistical analyses; however, the use of even more sophisticated statistical modeling was still limited by the cohort size.
Though we were unable to identify correlations between plasma lipid metabolites and the development of BPD, we did identify significant associations with gestational age indicating that pathways governing lipid metabolism are likely to be developmentally regulated in prematurely born infants. These data represent the first attempt to assess lipid metabolites in a relatively large cohort of preterm infants which incorporated the use of statistical analyses adjusting for confounders. While our unadjusted analyses might have led us to conclude that plasma lipid products are associated with the development of BPD, the prospective nature of our study and our ability to account for patient characteristics led to an entirely different and admittedly less exciting conclusion. Nonetheless, we speculate that plasma lipid mediators likely contribute to altered responses in extremely premature infants and highlight the need for focused studies to identify the events that underlie developmental maturation of lipid metabolic pathways and their contribution toward the development of BPD.