Abstract
BackgroundInfants born at extremely low gestational age are at high risk for bronchopulmonary dysplasia and continuing lung disease. There are no early clinical biomarkers for pulmonary outcome and limited therapeutic interventions.ObjectivesWe performed global proteomics of premature infant tracheal aspirate (TA) and plasma to determine the composition and source of lung fluid proteins and to identify potential biomarkers of respiratory outcome.MethodsTA samples were collected from intubated infants in the TOLSURF cohort before and after nitric oxide treatment, and plasma was collected from NO CLD infants. Protein abundance was assayed by HPLC/tandem mass spectrometry and Protein Prospector software. mRNA abundance in mid-gestation fetal lung was assessed by RNA sequencing. Pulmonary morbidity was defined as a need for ventilatory support at term and during the first year.ResultsAbundant TA proteins included albumin, hemoglobin, and actin-related proteins. 96 of 137 detected plasma proteins were present in TA (r = 0.69, p<0.00001). Based on lung RNAseq data, ~88% of detected TA proteins in injured infant lung are derived at least in part from lung epithelium with overrepresentation in categories of cell membrane/secretion and stress/inflammation. Comparing 37 infants at study enrollment (7–14 days) who did or did not develop persistent pulmonary morbidity, candidate biomarkers of both lung (eg., annexin A5) and plasma (eg., vitamin D-binding protein) origin were identified. Notably, levels of free hemoglobin were 2.9-fold (p = 0.03) higher in infants with pulmonary morbidity. In time course studies, hemoglobin decreased markedly in most infants after enrollment coincident with initiation of inhaled nitric oxide treatment.ConclusionsWe conclude that both lung epithelium and plasma contribute to the lung fluid proteome in premature infants with lung injury. Early postnatal elevation of free hemoglobin and heme, which are both pro-oxidants, may contribute to persistent lung disease by depleting nitric oxide and increasing oxidative/nitrative stress.
Highlights
tracheal aspirates (TA) samples were collected from intubated infants in the Trial of Late Surfactant (TOLSURF) cohort before and after nitric oxide treatment, and plasma was collected from NO CLD infants
Abundant TA proteins included albumin, hemoglobin, and actin-related proteins. 96 of 137 detected plasma proteins were present in TA (r = 0.69, p
Course studies, hemoglobin decreased markedly in most infants after enrollment coincident with initiation of inhaled nitric oxide treatment. We conclude that both lung epithelium and plasma contribute to the lung fluid proteome in premature infants with lung injury
Summary
Infants born prematurely are at risk for respiratory failure and for bronchopulmonary dysplasia (BPD), a disorder that can continue into childhood and is characterized by hypoxemia, pulmonary hypertension, wheezing and/or later asthma, requiring chronic respiratory medications and hospitalizations. Therapeutic options for the prevention and treatment of BPD are limited and have not substantially affected the incidence of disease that remains high for the very premature infants [3]. Previous studies have analyzed constituents of lung fluid such as cytokines and surfactant components with the goal of identifying potential biomarkers for later respiratory outcome and understanding the pathogenesis of infant lung disease [4, 5]. Infants born at extremely low gestational age are at high risk for bronchopulmonary dysplasia and continuing lung disease. There are no early clinical biomarkers for pulmonary outcome and limited therapeutic interventions
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