RESUMO
Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and <30 days old. We identified CD14+CD16+ (double-positive) and CD14+CD16- (single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at day of life (DOL) 7, DOL 14, and DOL 28 compared with those collected at DOL 3. This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.
Assuntos
Displasia Broncopulmonar/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Monócitos/imunologia , RNA Mensageiro/genética , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Displasia Broncopulmonar/imunologia , Displasia Broncopulmonar/patologia , Feminino , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação da Expressão Gênica , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Masculino , Monócitos/patologia , Projetos Piloto , Estudos Prospectivos , RNA Mensageiro/imunologia , Receptores de IgG/deficiência , Receptores de IgG/genética , Receptores de IgG/imunologia , Análise de Sequência de RNA , Transdução de Sinais , Traqueia/imunologia , Traqueia/patologiaRESUMO
Inflammation in response to oxygen exposure is a major contributing factor in neonatal lung injury leading to bronchopulmonary dysplasia. Although increased levels of proinflammatory cytokines are seen in airway samples and blood from bronchopulmonary dysplasia patients, the innate immune responses in this common neonatal lung condition have not been well characterized. We previously reported that depletion of murine CD11b-expressing mononuclear phagocytes at birth led to severe acute hyperoxia-induced lung injury (HILI) and significant mortality. In this study, we further define the mononuclear phagocyte populations that are present in the neonatal lung and characterize their responses to hyperoxia exposure. We used myeloid depleter mice (CD11b-DTR and CCR2-DTR) to contrast the effects of depleting different monocyte/macrophage subpopulations on the innate immune response to hyperoxia. Using RNA sequencing and subsequent data analysis, we identified an IFN-γ-mediated role for interstitial monocytes/macrophages in acute HILI, in which decreased IFN-γ expression led to increased disease severity and increased Mmp9 mRNA expression. Importantly, intranasal administration of rIFN-γ largely rescued CD11b-DTR+ mice from severe HILI and decreased Mmp9 mRNA expression in Ly-6Clo and Ly-6Chi interstitial monocyte/macrophages. We conclude that the proinflammatory effects of hyperoxia exposure are, at least in part, because of the modulation of effectors downstream of IFN-γ by pulmonary monocytes/macrophages.