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Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema
Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity and impaired innate host defense. One important aspect of innate airway epithelial host defense to non-microbial triggers is the secretion of alarmins such as IL-33 and acti...
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Published in: | American journal of physiology. Lung cellular and molecular physiology 2021-07, Vol.321 (1), p.L144-L158 |
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Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity and impaired innate host defense. One important aspect of innate airway epithelial host defense to non-microbial triggers is the secretion of alarmins such as IL-33 and activation of type 2 inflammation, which were previously found to depend on activation of the NADPH oxidase (NOX) homolog DUOX1, and redox-dependent signaling pathways that promote alarmin secretion. Here, we demonstrate that normal aging of C57BL/6J mice resulted in markedly decreased lung innate epithelial type 2 responses to exogenous triggers such as the airborne allergen, D. pteronyssinus, which was associated with marked downregulation of DUOX1, as well as DUOX1-mediated redox-dependent signaling. DUOX1-deficiency was also found to accelerate age-related airspace enlargement and decline in lung function, but did not consistently affect other features of lung aging such as senescence-associated inflammation. Intriguingly, observations of age-related DUOX1 downregulation and enhanced airspace enlargement due to DUOX1 deficiency in C57BL/6J mice, which lack a functional mitochondrial nicotinamide nucleotide transhydrogenase (NNT), were much less dramatic in C57BL/6NJ mice with normal NNT function, although the latter mice also displayed impaired innate epithelial injury responses with advancing age. Overall, our findings indicate a marked aging-dependent decline in (DUOX1-dependent) innate airway injury responses to external non-microbial triggers, but the impact of aging on DUOX1 downregulation and its significance for age-related senile emphysema development was variable between different C57BL6 substrains, possibly related to metabolic alterations due to differences in NNT function. |
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ISSN: | 1040-0605 1522-1504 |
DOI: | 10.1152/AJPLUNG.00021.2021 |