Loss of IL-6 enables lung growth in newborn mice exposed to prolonged hyperoxia

Abstract

Background: Prolonged exposure to increased oxygen induces inflammation, matrix remodeling, and alveolar arrested in lungs of preterm infants, leading to Bronchopulmonary dysplasia (BPD). Interleukin 6 (IL-6) has been shown to be increased in tracheal aspirates of infants evolving BPD. Aim: We hypothesized that activation of IL-6 signaling is linked to impaired alveolarization; loss of IL-6 protects from neonatal hyperoxia-induced lung injury. Methods: (1) Wildtype and IL-6 deficient newborn mice (IL-6-/-) or (2) cultured macrophages and lung epithelial cells were exposed to 85% O2 (HYX) or 21% O2 (NOX). Results: (1) HYX increased IL-6 mRNA and activates Stat3/SOCS3 signaling in lungs of WT mice. Quantitative lung morphometry showed increased mean linear intercept, alveolar surface area, and septal thickness, and reduced radial alveolar count, indicating impaired alveolar formation. Furthermore, microvessels (20-100µm) were reduced in lungs after HYX. In contrast, IL-6-/- were partially protected from these structural changes. Elastic fibers, elastin protein, and collagen Iα1 mRNA were significantly increased after HYX in IL-6-/- when compared to WT. Moreover, IL-6 deficiency protected from decreased lung expression of surfactant protein A (SP-A) and SP-C, and increased SP-D mRNA. (2) HYX induced the release of IL-6 from cultured macrophages; conditioned media of hyperoxia-exposed macrophages reduced survival of lung epithelial cells. Conclusion: Here, we do not only show that loss of IL-6 partially protects from neonatal hyperoxia-induced lung injury, but also the antiproliferative effect of macrophage secretome. This could offer novel therapeutic approaches for BPD.