Abstract
Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O2) and infections. We hypothesized that dysregulated macrophage (MФ) activation is a key feature leading to inflammation-mediated development of bronchopulmonary dysplasia (BPD) in preterm infants. Therefore, we aimed to determine age-dependent differences in immune responses of monocyte-derived MФ comparing cord blood samples derived from preterm (n=14) and term (n=19) infants as well as peripheral blood samples from healthy adults (n=17) after lipopolysaccharide (LPS) exposure. Compared to term and adult MФ, LPS-stimulated preterm MФ showed an enhanced and sustained pro-inflammatory immune response determined by transcriptome analysis, cytokine release inducing a RORC upregulation due to T cell polarization of neonatal T cells, and TLR4 surface expression. In addition, a double-hit model was developed to study pulmonary relevant exposure factors by priming MФ with hyperoxia (O2 = 65%) or hypoxia (O2 = 3%) followed by lipopolysaccharide (LPS, 100ng/ml). When primed by 65% O2, subsequent LPS stimulation in preterm MФ led to an exaggerated pro-inflammatory response (e.g. increased HLA-DR expression and cytokine release) compared to LPS stimulation alone. Both, exposure to 65% or 3% O2 together with subsequent LPS stimulation, resulted in an exaggerated pro-inflammatory response of preterm MФ determined by transcriptome analysis. Downregulation of two major transcriptional factors, early growth response gene (Egr)-2 and growth factor independence 1 (Gfi1), were identified to play a role in the exaggerated pro-inflammatory response of preterm MФ to LPS insult after priming with 65% or 3% O2. Preterm MФ responses to LPS and hyperoxia/hypoxia suggest their involvement in excessive inflammation due to age-dependent differences, potentially mediated by downregulation of Egr2 and Gfi1 in the developing lung.
Highlights
Preterm infants are faced with the challenge of encountering the exutero environment with a premature immune system and a premature lung [1,2,3,4]
Of note, following differentiation with macrophage colonystimulating factor (M-CSF) for 6 days, there were no differences in viability, morphology, or protein expression of CD14, CD68 and CD11b between monocyte-derived MФ from preterm infants, term infants, and adults
The enhanced and sustained proinflammatory response of preterm MФ was exaggerated after exposure to key factors that are strongly associated with the development of bronchopulmonary dysplasia (BPD) in a clinical setting
Summary
Preterm infants are faced with the challenge of encountering the exutero environment with a premature immune system and a premature lung [1,2,3,4]. Recent animal models have investigated lung immunity and development after birth using a sequential double-hit model that mimics inflammation and hyperoxia [17,18,19,20]. In those models, the pro-inflammatory immune response and the disruption of lung development were exaggerated after double-hit exposure. We hypothesize that MФ are important cellular components that mediate the development of lung disease in preterm infants This notion is supported by a study from Blackwell et al describing reduced branching in embryonic lung explants due to NFkB-activated MФ [22]
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