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Published on: August 7, 2017
Monocyte signature as a predictor of chronic lung disease in the preterm infant
Anita C Windhorst1, Motaharehsadat Heydarian2, Maren Schwarz2,3
1Institute of Medical Informatics, Justus-Liebig-University Giessen, Giessen, Germany.
Insights
Early changes in monocyte subtypes, specifically nonclassical and intermediate monocytes, are key indicators of bronchopulmonary dysplasia (BPD) development in preterm infants. These findings highlight TNF-α as a critical regulator and may inform future diagnostic and treatment strategies.
Area of Science:
- Neonatal Immunology
- Innate Immunity
- Respiratory Medicine
Background:
- Inflammation significantly contributes to morbidity in preterm infants, leading to chronic lung disease like bronchopulmonary dysplasia (BPD).
- Early changes in innate immunity associated with BPD development are not fully understood.
Purpose of the Study:
- To investigate early changes in monocyte subtypes and their association with BPD development in preterm infants.
- To identify molecular signatures in cord blood that predict BPD and disease severity.
Main Methods:
- Flow cytometry was used to identify monocyte subtypes and intracellular TNF expression in preterm infants.
- Cytokine, growth factor, and gene expression profiles were analyzed from cord blood samples.
- Multivariate modeling was employed to identify predictors of BPD.
Main Results:
- Preterm infants showed distinct monocyte subtype abundances at birth, with elevated nonclassical and intermediate monocytes correlating with BPD development.
- Lung injury was associated with increased intermediate monocytes postnatally.
- Protein and transcriptome analyses revealed inflammatory pathways, including TNF-α, IL-6, and interferon α, as critical regulators, with ROS synthesis linked to more severe BPD.
Conclusions:
- The early postnatal presence of specific monocyte subtypes is a critical characteristic of BPD development.
- Identified molecular signatures provide pathophysiological insights and highlight TNF-α as a key regulator.
- These findings may guide future diagnostic and therapeutic strategies targeting monocytes in BPD.
Introduction:
Inflammation is a key driver of morbidity in the vulnerable preterm infant exposed to pre- and postnatal hazards and significantly contributes to chronic lung disease, i.e. bronchopulmonary dysplasia (BPD). However, the early changes in innate immunity associated with BPD development are incompletely understood.
Methods:
In very immature preterm infants below 32 weeks gestational age (GA; n=30 infants), monocyte subtypes were identified by Flow Cytometry at birth and throughout the postnatal course including intracellular TNF expression upon LPS stimulation. Complementing these measurements, cytokine end growth factor expression profiles (Luminex® xMAP®; n=110 infants) as well as gene expression profiles (CodeLinkTM Human I Bioarray; n=22) were characterized at birth.
Results:
The abundance of monocyte subtypes differed between preterm and term neonates at birth. Specifically, CD14++CD16+ (intermediate) monocytes demonstrated a dependency on PMA and elevated levels of nonclassical (CD14+CD16++) monocytes characterized preterm infants with developing BPD. Postnatally, lung injury was associated with an increase in intermediate monocytes, while high levels of nonclassical monocytes persisted. Both subtypes were revealed as the main source of intracellular TNF-α expression in the preterm infant. We identified a cytokine and growth factor expression profile in cord blood specimen of preterm infants with developing BPD that corresponded to the disease-dependent regulation of monocyte abundances. Multivariate modeling of protein profiles revealed FGF2, sIL-2 Rα, MCP-1, MIP1a, and TNF-α as predictors of BPD when considering GA. Transcriptome analysis demonstrated genes predicting BPD to be overrepresented in inflammatory pathways with increased disease severity characterized by the regulation of immune and defense response pathways and upstream regulator analysis confirmed TNF-α, interleukin (IL) -6, and interferon α as the highest activated cytokines in more severe disease. Whereas all BPD cases showed downstream activation of chemotaxis and activation of inflammatory response pathways, more severe cases were characterized by an additional activation of reactive oxygen species (ROS) synthesis.
Discussion:
In the present study, we identified the early postnatal presence of nonclassical (CD14+CD16++) and intermediate (CD14++CD16+) monocytes as a critical characteristic of BPD development including a specific response pattern of monocyte subtypes to lung injury. Pathophysiological insight was provided by the protein and transcriptome signature identified at birth, centered around monocyte and corresponding granulocyte activation and highlighting TNFα as a critical regulator in infants with developing BPD. The disease severity-dependent expression patterns could inform future diagnostic and treatment strategies targeting the monocytic cell and its progeny.
