Loss of interleukin-6 enhances the inflammatory response associated with hyperoxia‑induced lung injury in neonatal mice

Abstract

In bronchopulmonary dysplasia (BPD), decreased angiogenesis and alveolarization is associated with pulmonary cell death and inflammation. It is commonly observed in premature infants who required mechanical ventilation and oxygen therapy. Since enhanced interleukin-6 (IL-6) expression has been reported in infants with BPD, it was hypothesized that a decrease in IL-6 may enhance lung inflammation and decrease hyperoxia-induced neonatal lung injury in mice. In the current study, newborn wild-type (WT) and IL-6 null mice were treated with 85% O 2 (hyperoxia) or 21% O 2 (normoxia) for 96 h. Although the increased volume and decreased quantity of alveoli was triggered by hyperoxia in WT and IL-6 null mice, transcription and translation of proinflammatory cytokines (monocyte chemoattractant protein-1, IL-10, IL-12 and tumor necrosis factor- α ) and pulmonary cell death (caspase stimulation and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling staining) were significantly enhanced in IL-6 null mice compared with WT mice. These results suggest that the crosstalk between inflammation and cell death may be involved in hyperoxia-induced lung injury in BPD. Future treatment approaches for bronchopulmonary dysplasia should be based on the suppression of cytokine expression.

Inhibition of microRNA-451 is associated with increased expression of Macrophage Migration Inhibitory Factor and mitigation of the cardio-pulmonary phenotype in a murine model of Bronchopulmonary Dysplasia

“…IL-6 in addition to having pro-inflammatory activities, also plays an important role in antiinflammatory and regenerative processes [61]. When NB IL-6 transgenic mice were studied in a model of hyperoxia-induced lung injury, absence of IL-6 was found to be associated with higher levels of proinflammatory cytokines and increased apoptosis in comparison to WT controls [62]. IL-6 is also known to act via hypoxia-inducible factor (HIF)-1α to increase VEGF expression [63] and this process has been shown to be inhibited by miR-451 mediated regulation of IL-6R expression in colorectal cancer cells [16].…”

Bacterial Colonization within the First Six Weeks of Life and Pulmonary Outcome in Preterm Infants <1000 g

“…Therefore, modulation of the inflammatory cytokine response and thereby NFκB in either direction puts the lung at risk for increased lung damage. BPD has been recently demonstrated to evolve from either inhibition or overstimulation of the pathways of classical pro-inflammatory cytokine response including TNF-α and IL-6 [ 49 , 50 , 51 , 52 , 53 ]. It is well accepted that pre- and postnatal bacterial infections aggravate lung injury via pro-inflammatory cytokine production [ 4 , 5 , 26 , 27 , 54 ].…”

Hyperoxia-induced bronchopulmonary dysplasia: better models for better therapies

“…IL-6 is elevated in tracheal aspirates of human neonates, who subsequently developed BPD ( von Bismarck et al, 2009 ). Elevated IL-6 concentrations are associated with BPD progression, which suggests that IL-6 expression may be used as a reliable biomarker of BPD ( Li et al, 2019 ). When BPD is modeled in IL-6 knockout mice, the animals demonstrate a decreased severity of lung injury ( Aziz et al, 2020 ).…”