Failure of Alveolar Type 2 Cell Maintenance Links Neonatal Distress with Adult Lung Disease

Vaughan, Andrew E.; Chapman, Harold A.

doi:10.1165/rcmb.2016-0411ed

Cited by 2 publications

(2 citation statements)

References 22 publications

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“…Alveolar regeneration is primarily directed by ATII, which have the capacity for self-renewal and give rise to ATI after lung injury [6]. Disruption of ATII homeostasis is involved in the pathogenesis of various chronic lung diseases, including BPD [7,8]. Hyperoxia reduces survival and induces epithelial mesenchymal transition in ATII [9,10].…”

Section: Introductionmentioning

confidence: 99%

Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia

et al. 2021

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RationalePremature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD.Methods and resultsFirst, transcriptomic analysis with in silico cellular deconvolution identified a lung-intrinsic M1-like-driven cytokine pattern in newborn mice after hyperoxia. These findings were confirmed by gene expression of macrophage-regulating chemokines (Ccl2, Ccl7, Cxcl5) and markers (Il6, Il17A, Mmp12). Secondly, hyperoxia-activated interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signalling was measured in vivo and related to loss of alveolar epithelial type II cells (ATII) as well as increased mesenchymal marker. Il6 null mice exhibited preserved ATII survival, reduced myofibroblasts and improved elastic fibre assembly, thus enabling lung growth and protecting lung function. Pharmacological inhibition of global IL-6 signalling and IL-6 trans-signalling promoted alveolarisation and ATII survival after hyperoxia. Third, hyperoxia triggered M1-like polarisation, possibly via Krüppel-like factor 4; hyperoxia-conditioned medium of macrophages and IL-6-impaired ATII proliferation. Finally, clinical data demonstrated elevated macrophage-related plasma cytokines as potential biomarkers that identify infants receiving oxygen at increased risk of developing BPD. Moreover, macrophage-derived IL6 and active STAT3 were related to loss of epithelial cells in BPD lungs.ConclusionWe present a novel IL-6-mediated mechanism by which hyperoxia activates macrophages in immature lungs, impairs ATII homeostasis and disrupts elastic fibre formation, thereby inhibiting lung growth. The data provide evidence that IL-6 trans-signalling could offer an innovative pharmacological target to enable lung growth in severe neonatal chronic lung disease.

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Section: Introductionmentioning

confidence: 99%

Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia

et al. 2021

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“…If they were, this would provide strategies to modulate senescence induced by hyperoxia through alterations in metabolism. Type II (ATII) cells are progenitor to ATI cells, the alveolar cells that are responsible for gas exchange, and therefore provide an important regenerative function in response to stress in the lung (Nova et al, 2019; Olajuyin et al, 2019; Vaughan & Chapman, 2017). However, ATII cell numbers decrease in response to hyperoxia (O'Reilly et al, 1998), thereby preventing lung repair.…”

Section: Introductionmentioning

confidence: 99%

Hyperoxia causes senescence and increases glycolysis in cultured lung epithelial cells

et al. 2021

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Failure of Alveolar Type 2 Cell Maintenance Links Neonatal Distress with Adult Lung Disease

Cited by 2 publications

References 22 publications

Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia

Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia

Hyperoxia causes senescence and increases glycolysis in cultured lung epithelial cells

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