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A6971 - Loss of IL-6 Preserves Surfactant Protein Expression and Enables Lung Growth in Newborn Mice Exposed to Prolonged Hyperoxia
Author Block: D. Hirani1, K. Dinger1, B. Darvishan1, J. Mohr1, C. Vohlen1, F. Klein1, M. Odenthal2, J. Dötsch3, M. Alejandre Alcazar1; 1Department of Pediatrics, Translational Experimental Pediatrics - Experimental Pulmonology, University Hospital Cologne, Cologne, Germany, 2Institute of Pathology, University Hospital Cologne, Cologne, Germany, 3Department of Pediatrics, University Hospital Cologne, Cologne, Germany.
Rationale: Premature infants exposed to increased oxygen (O2) are often afflicted with bronchopulmonary dysplasia (BPD), a debilitating disorder marked by reduced formation of alveoli and microvessels as well as perturbed matrix remodeling. It is well recognized that inflammation contributes to the pathogenesis of BPD; human studies show that Interleukin-6 (IL-6) is increased in lungs of infants evolving BPD. Since IL-6 is known to regulate inflammation and cell homeostasis, we hypothesized that hyperoxia-induced lung growth arrest in newborn mice is linked to activation of IL-6 signaling; in contrast, IL-6 deficiency is protective and enables lung growth in newborn mice exposed to hyperoxia.
Methods: The functional role of IL-6 signaling in aberrant lung development was studied in C57Bl/6N as well as IL-6-deficient mice (IL-6-/-) and its wildtype controls (WT). Newborn mice were exposed to either hyperoxia (85% O2) or normoxia (21% O2) from postnatal day 1 (P1) to P28. Lung function tests were performed at P28; at the end of the experiments lungs were excised and snap-frozen or pressure-fixed in paraformaldehyde and paraffin embedded for quantitative morphometric analyses.
Results: 1) Exposure to 85% O2 induced a 10-fold increase of IL-6 expression and a marked activation of Stat3-SOCS3 signaling in lungs of newborn mice. Activation of pulmonary IL-6 signaling was related to previously shown impaired alveolarization and decreased dynamic compliance. 2) To investigate the functional role of IL-6 we exposed IL-6-/- and its controls to hyperoxia or normoxia. Quantitative histomorphometric analyses of the lungs revealed reduced radial alveolar count, increased mean linear intercept and alveolar surface area, as well as less microvascular formation (vWF staining) in lungs after hyperoxia, indicating impaired alveolarization. In contrast, IL-6-/- pups were significantly protected from blocked alveolarization and impaired angiogenesis. Moreover, assessment of elastic fibers showed that IL-6 deficiency partially attenuated the significant increase of elastic fibers; collagen Iα1 mRNA, however, was increased in lungs of IL-6-/- after hyperoxia when compared to WT. Further analysis revealed that hyperoxia reduced gene expression of surfactant proteins (SP-A, SP-C, and SP-D) in the lungs of WT, but not of IL-6-/- mice.
Conclusion: Our study demonstrates that activation of pulmonary IL6-signaling is intimately linked to hyperoxia-induced lung growth arrest. Loss of IL-6, however, enabled lung growth in newborn mice exposed to prolonged hyperoxia, offering thereby a new potential target to treat preterm infants evolving BPD.