Journal
JOURNAL OF MOLECULAR CELL BIOLOGY
Volume 13, Issue 2, Pages 128-140Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjaa079
Keywords
testosterone replacement therapy; COPD; NRF1; NF-kappa B; transcriptional regulation; endothelia
Categories
Funding
- National Natural Science Foundation of China [31671206, 81702874, 81873924, 81971131]
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Testosterone deficiency is common in male COPD patients and may worsen the disease. Testosterone replacement therapy has been shown to slow COPD progression by inhibiting NRF1-derived NF-kappa B signaling and phosphorylation of p65 in pulmonary epithelial inflammation.
Testosterone deficiency is common in male patients with chronic obstructive pulmonary disease (COPD) and may correlate with the deterioration of COPD. Clinical research suggests that testosterone replacement therapy may slow the COPD progression, but the specific biological pathway remains unclear. In this study, we explored the effect of testosterone on pulmonary inflammation in male COPD rats. The animals were co-treated with lipopolysaccharide (LPS) and cigarette to induce COPD. In COPD rats, nuclear respiratory factor 1 (NRF1) and NF-kappa B p65 were upregulated. In cigarette smoke extract (CSE)-, LPS-, or the combination of CSE and LPS-treated L132 cells, NRF1 and p65 were also upregulated. Silencing NRF1 resulted in the downregulation of p65. ChIP-seq, ChIP-qPCR, and luciferase results showed that NRF1 transcriptionally regulated p65. Both male and female COPD rats showed an upregulated NRF1 level and similar pulmonary morphology. But NRF1 was further upregulated in male castrated rats. Further supplementing testosterone in castrated male rats significantly reduced NRF1, pulmonary lesions, and inflammation. Supplementation of testosterone also reduced the phosphorylation of p65 and IKK beta induced by LPS or CSE in L132 cells. Our results suggest that testosterone plays a protective role in pulmonary epithelial inflammation of COPD through inhibition of NRF1-derived NF-kappa B signaling and the phosphorylation of p65.
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