Biomarkers in Pediatric ARDS: Future Directions

Orwoll, Benjamin E.; Sapru, Anil

Lipid biomarkers comprise a heterogeneous group of hydrophobic molecules that have multiple and varied roles in normal bodily functions. One group of these that has been investigated in more detail in the setting of ARDS is the eicosanoids, which are generated through metabolism of 20-carbon fatty acids, such as arachidonic acid. These include prostaglandins (PGs), leukotrienes (LTs), thromboxane (TXA), and others, many of which have potential effects involving vascular, endothelial, platelet, and leukocyte function. Thromboxane A2 (TXA2) and prostacyclin (PGI2) (also known as prostaglandin I2) are produced in the lung and have effects on pulmonary vascular resistance, with TXA2 promoting pulmonary vasoconstriction and PGI2 vasodilation (166) . In several studies of at risk adults (167) (168) (169) , TXA levels were elevated in patients who developed ARDS, as was the TXA to prostaglandin ratio. Indeed, elevations in BAL fluid TXA B2, an active metabolite of TXA2, are associated with progression to BPD in infants with lung inflammation and RDS (57) , while elevations in PGI2 seem to have a beneficial relationship (73) . An early study of RDS also reported elevations in plasma prostaglandin E (PGE) and prostaglandin F (PGF) with a low PGE:PGF ratio (54) . Elevated levels of LT B4, C4, and D4 have been detected in the blood and BAL fluid from adult patients with ARDS (170, 171) , and leukotriene B4 has been associated with mortality (81, 172) . In children, these molecules have largely been studied in the setting of neonatal RDS and the development of BPD. Elevations of urinary leukotriene E4 have been associated with ARDS in adults (173) and development of BPD in infants (174, 175) , though variations observed may be highly affected by gestational age and maturity (176) . Several studies of neonates have demonstrated alterations in the levels of markers of oxidative stress and DNA damage in RDS (175, 177) , and one study of BAL fluid in children with ALI found alterations in the concentrations of multiple cell surface lipids indicative of alveolar-capillary membrane damage (21) . Eicosanoids and other lipid-derived and small molecules may serve as useful biomarkers, especially of vascular physiology, oxidative damage, and inflammation, in future studies of children with ARDS. Advances in genetic science and technology have enabled research into the feasibility of using nucleic acid-based biomarker assays in acute illness. Major targets have been small RNA molecules, such as micro-RNAs (miRNAs), which, due to their abundance in the blood and other body fluids as well as their relative resistance to degradation, may have utility as biomarkers (178) . miRNAs have a predictable structure and have variable expression patterns depending on the body site and physiologic conditions. miRNAs perform important functional roles in cellular function through their ability to regulate translation of specific gene products at the mRNA level, and a single miRNA species may have multiple gene targets (178) . Another notable feature of miRNAs is that they have potential as therapeutic targets due to their ability to be regulated by antisense versions of themselves, or antagomiRs. Though many miRNAs have been identified as possible contributors to or markers of lung diseases, clinical data in humans with ARDS are extremely limited (179, 180) . This is a fertile area for further study in children with ARDS.