Human breast milk‐derived exosomes through inhibiting AT II cell apoptosis to prevent bronchopulmonary dysplasia in rat lung

Abstract

Human breast milk (HBM) effectively prevents and cures neonatal bronchopulmonary dysplasia (BPD). Exosomes are abundant in breast milk, but the function of HBM‐derived exosomes (HBM‐Exo) in BPD is still unclear. This study was to investigate the role and mechanism of HBM‐Exo in BPD. Overall lung tissue photography and H&E staining showed that HBM‐Exo improved the lung tissue structure collapse, alveolar structure disorder, alveolar septum width, alveolar number reduction and other injuries caused by high oxygen exposure. Immunohistochemical results showed that HBM‐Exo improved the inhibition of cell proliferation and increased apoptosis caused by hyperoxia. qPCR and Western blot results also showed that HBM‐Exo improved the expression of Type II alveolar epithelium (AT II) surface marker SPC. In vivo study, CCK8 and flow cytometry showed that HBM‐Exo improved the proliferation inhibition and apoptosis of AT II cells induced by hyperoxia, qPCR and immunofluorescence also showed that HBM‐Exo improved the down‐regulation of SPC. Further RNA‐Seq results in AT II cells showed that a total of 88 genes were significantly different between the hyperoxia and HBM‐Exo with hyperoxia groups, including 24 up‐regulated genes and 64 down‐regulated genes. KEGG pathway analysis showed the enrichment of IL‐17 signalling pathway was the most significant. Further rescue experiments showed that HBM‐Exo improved AT II cell damage induced by hyperoxia through inhibiting downstream of IL‐17 signalling pathway (FADD), which may be an important mechanism of HBM‐Exo in the prevention and treatment of BPD. This study may provide new approach in the treatment of BPD.

ILC2 regulates hyperoxia-induced lung injury via an enhanced Th17 cell response in the BPD mouse model

“…Apart from higher concentrations of leukotriene, endothelin-1[ 32 ], IL-6[ 33 ], and IL-17 A [ 34 , 35 ], newborns destined for BPD also exhibit an increase in the number of circulating neutrophils and macrophages. During the alveolar phase (lung development is not mature), the increase in IL-17 A activates the IL-17 signaling pathway, causing inflammation, which may further affect lung development and lead to the occurrence of BPD [ 36 ].…”

“…During the alveolar phase (lung development is not mature), the increase in IL-17 A activates the IL-17 signaling pathway, causing inflammation, which may further affect lung development and lead to the occurrence of BPD [ 36 ]. Recent studies have found that IL-17 A level is significantly upregulated and the IL-17 signaling pathway is significantly activated in the external circulation of children with BPD [ 10 , 34 , 35 ]. In the BPD mouse model, the expression of Th17 cells was enhanced in lung, demonstrating strong pro-inflammatory properties and resistance to Treg mediated inhibition [ 13 , 37 , 38 ].…”

Breast-feeding as protective factor against bronchopulmonary dysplasia in preterm infants

“…Antioxidant activity may be the main mechanism by which breast milk decreases the risk of BPD (42) . Although BPD is multifactorial in origin, it has been suggested that the association between breast-feeding and BPD is related to the presence of antioxidant components such as the exosomes in breast milk, which exert a protective role on the type II alveolar epithelium (43) . From an epidemiological standpoint, the prevalence of late sepsis and NEC is reported to be lower in VLBW infants fed with breast milk (44,45) , due to the shorter period spent in the neonatal intensive care unit, with fewer days of mechanical ventilation and oxygen therapy (46) , and hence a lower risk of BPD, observations in line with our results.…”

Monitoring the Use of Human Milk, the Ideal Food for Very Low-Birth-Weight Infants—A Narrative Review

“…This is particularly relevant considering that BPD is an increasingly common respiratory adverse outcome that prolongs NICU stays and particularly impacts rehospitalization, as well as long-term lung and neurological outcomes. In a study conducted on rats [ 28 ], the role of HBM-Exo in the protective action of breast milk on BPD was investigated, and the results were also encouraging about the possibility of a new therapeutic approach to BPD. HBM-Exo histochemically promoted the proliferation of AT II cells and inhibited their apoptosis through IL-17 regulation, and in the overall picture, it improved the appearance of structural lesions in the lung tissue.…”