Composition and origin of lung fluid proteome in premature infants and relationship to respiratory outcome

Background 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. Objectives We 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. Methods TA 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. Results Abundant 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. Conclusions We 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.

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Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00073.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. L858-L869 ◽

Cited By ~ 9

Author(s):

Dara G. Torgerson ◽

Philip L. Ballard ◽

Roberta L. Keller ◽

Sam S. Oh ◽

Scott Huntsman ◽

...

Keyword(s):

Nitric Oxide ◽

High Risk ◽

Lung Disease ◽

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Genome Wide Association Study ◽

African Ancestry ◽

Inhaled Nitric Oxide ◽

Race Ethnicity ◽

Hispanic White

Bronchopulmonary dysplasia in premature infants is a common and often severe lung disease with long-term sequelae. A genetic component is suspected but not fully defined. We performed an ancestry and genome-wide association study to identify variants, genes, and pathways associated with survival without bronchopulmonary dysplasia in 387 high-risk infants treated with inhaled nitric oxide in the Trial of Late Surfactant study. Global African genetic ancestry was associated with increased survival without bronchopulmonary dysplasia among infants of maternal self-reported Hispanic white race/ethnicity [odds ratio (OR) = 4.5, P = 0.01]. Admixture mapping found suggestive outcome associations with local African ancestry at chromosome bands 18q21 and 10q22 among infants of maternal self-reported African-American race/ethnicity. For all infants, the top individual variant identified was within the intron of NBL1, which is expressed in midtrimester lung and is an antagonist of bone morphogenetic proteins ( rs372271081 , OR = 0.17, P = 7.4 × 10−7). The protective allele of this variant was significantly associated with lower nitric oxide metabolites in the urine of non-Hispanic white infants ( P = 0.006), supporting a role in the racial differential response to nitric oxide. Interrogating genes upregulated in bronchopulmonary dysplasia lungs indicated association with variants in CCL18, a cytokine associated with fibrosis and interstitial lung disease, and pathway analyses implicated variation in genes involved in immune/inflammatory processes in response to infection and mechanical ventilation. Our results suggest that genetic variation related to lung development, drug metabolism, and immune response contribute to individual and racial/ethnic differences in respiratory outcomes following inhaled nitric oxide treatment of high-risk premature infants.

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Plasma Biomarkers of Oxidative Stress: Relationship to Lung Disease and Inhaled Nitric Oxide Therapy in Premature Infants

PEDIATRICS ◽

10.1542/peds.2007-2479 ◽

2008 ◽

Vol 121 (3) ◽

pp. 555-561 ◽

Cited By ~ 37

Author(s):

P. L. Ballard ◽

W. E. Truog ◽

J. D. Merrill ◽

A. Gow ◽

M. Posencheg ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Lung Disease ◽

Premature Infants ◽

Inhaled Nitric Oxide ◽

Plasma Biomarkers ◽

Nitric Oxide Therapy ◽

Biomarkers Of Oxidative Stress

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Ancestry and Genetic Associations with Bronchopulmonary Dysplasia in Preterm Infants

10.1101/263814 ◽

2018 ◽

Cited By ~ 1

Author(s):

Dara G. Torgerson ◽

Philip L. Ballard ◽

Roberta L. Keller ◽

Sam S. Oh ◽

Scott Huntsman ◽

...

Keyword(s):

Nitric Oxide ◽

High Risk ◽

Lung Disease ◽

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Genome Wide Association Study ◽

African Ancestry ◽

Inhaled Nitric Oxide ◽

Race Ethnicity ◽

Hispanic White

ABSTRACTBronchopulmonary dysplasia in premature infants is a common and often severe lung disease with long term sequelae. A genetic component is suspected but not fully defined. We performed an ancestry and genome-wide association study to identify variants, genes and pathways associated with survival without bronchopulmonary dysplasia in 387 high-risk infants treated with inhaled nitric oxide in the Trial of Late Surfactant study. Global African genetic ancestry was associated with increased survival without bronchopulmonary dysplasia among infants of maternal self-reported Hispanic White race/ethnicity (OR=4.5, p=0.01). Admixture mapping found suggestive outcome associations with local African ancestry at 18q21 and 10q22 among infants of maternal self-reported African American race/ethnicity. For all infants, the top individual variant identified was within the intron of NBL1, which is expressed in mid-trimester lung and is an antagonist of bone morphogenetic proteins (rs372271081, OR=0.17, p=7.4 × 10−7). The protective allele of this variant was significantly associated with lower nitric oxide metabolites in the urine of non-Hispanic white infants (p= 0.006), supporting a role in the racial differential response to nitric oxide. Interrogating genes upregulated in bronchopulmonary dysplasia lungs indicated association with variants in CCL18, a cytokine associated with fibrosis and interstitial lung disease, and pathway analyses implicated variation in genes involved in immune/inflammatory processes in response to infection and mechanical ventilation. Our results suggest that genetic variation related to lung development, drug metabolism, and immune response contribute to individual and racial/ethnic differences in respiratory outcomes following inhaled nitric oxide treatment of high-risk premature infants.

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LUNG FLUID PROTEOME IN PREMATURE INFANTS AND RESPIRATORY OUTCOME

Journal of Paediatrics and Child Health ◽

10.1111/jpc.14409_13 ◽

2019 ◽

Vol 55 (S1) ◽

pp. 8-8

Keyword(s):

Premature Infants ◽

Lung Fluid ◽

Respiratory Outcome

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Prediction of Abnormal Pulmonary Follow-up in Premature Infants

PEDIATRICS ◽

10.1542/peds.82.4.670 ◽

1988 ◽

Vol 82 (4) ◽

pp. 670-671

Author(s):

EDUARDO BANCALARI

Keyword(s):

Mechanical Ventilation ◽

Respiratory Failure ◽

Lung Disease ◽

Premature Infants ◽

Chronic Lung Disease ◽

Oxygen Therapy ◽

Prolonged Mechanical Ventilation ◽

Respiratory Outcome ◽

Definition Of

The article by Shennan and collaborators1 raises some interesting questions concerning the diagnosis of chronic lung disease and the predictability of respiratory outcome in early infancy. The first question addressed by the authors relates to the definition of bronchopulmonary dysplasia. This term was introduced by Northway et al2 in 1967 to describe a group of infants in whom severe chronic lung changes developed after prolonged mechanical ventilation and oxygen therapy. Most of these were infants with birth weights greater than 1000 g in whom chronic respiratory failure developed and whose chest radiographs appeared abnormal. In recent years, there has been an increase in the survival rate of infants with birth weights less than 1000 g, which has resulted in an increase in the population at risk for the development of chronic lung disease.

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