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 3 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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Temporal Dynamics of Oxidative Stress and Inflammation in Bronchopulmonary Dysplasia

Teng,

Wu,

Jing

et al. 2024

IJMS

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Bronchopulmonary dysplasia (BPD) is the most common lung complication of prematurity. Despite extensive research, our understanding of its pathophysiology remains limited, as reflected by the stable prevalence of BPD. Prematurity is the primary risk factor for BPD, with oxidative stress (OS) and inflammation playing significant roles and being closely linked to premature birth. Understanding the interplay and temporal relationship between OS and inflammation is crucial for developing new treatments for BPD. Animal studies suggest that OS and inflammation can exacerbate each other. Clinical trials focusing solely on antioxidants or anti-inflammatory therapies have been unsuccessful. In contrast, vitamin A and caffeine, with antioxidant and anti-inflammatory properties, have shown some efficacy, reducing BPD by about 10%. However, more than one-third of very preterm infants still suffer from BPD. New therapeutic agents are needed. A novel tripeptide, N-acetyl-lysyltyrosylcysteine amide (KYC), is a reversible myeloperoxidase inhibitor and a systems pharmacology agent. It reduces BPD severity by inhibiting MPO, enhancing antioxidative proteins, and alleviating endoplasmic reticulum stress and cellular senescence in a hyperoxia rat model. KYC represents a promising new approach to BPD treatment.

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

Cited by 3 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

Temporal Dynamics of Oxidative Stress and Inflammation in Bronchopulmonary Dysplasia

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