Rationale Cellular senescence is observed in the lungs of patients with COPD and may contribute to the disease pathogenesis. Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor β superfamily and was recently reported to be a circulating protein that may have rejuvenating effects in mice. We aimed to investigate the amounts of GDF11 in the plasma and the lungs of patients with COPD and elucidate the possible roles of GDF11 in cellular senescence.
Methods The plasma levels of GDF11 were investigated in two separate cohorts by western blotting. The localisation and expression of GDF11 in the lungs were investigated by immunohistochemistry and quantitative reverse transcription PCR, respectively. The effects of GDF11 on both cigarette smoke extract (CSE)-induced cellular senescence in vitro and on elastase-induced cellular senescence in vivo were investigated.
Results The levels of plasma GDF11 in the COPD group were decreased compared with the control groups in the two independent cohorts. The levels of plasma GDF11 were significantly positively correlated with pulmonary function data. The mRNA expression of GDF11 in mesenchymal cells from the COPD group was decreased. Chronic exposure to CSE decreased the production of GDF11. Treatment with GDF11 significantly inhibited CSE-induced cellular senescence and upregulation of inflammatory mediators, partly through Smad2/3 signalling in vitro. Daily GDF11 treatment attenuated cellular senescence and airspace enlargement in an elastase-induced mouse model of emphysema.
Conclusions The decrease in GDF11 may be involved in the cellular senescence observed in COPD.
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Contributors KO: cell culture, biochemical studies, immunohistochemical analysis, interpretation of results. HS: design of the study, interpretation of results, technical advice, writing of the manuscript. MY: design of the study, quantification of mRNAs, technical advice, interpretation of results. AK, NF, SY, YH, TO and TT: technical advice, interpretation of results. RT, TN, KS, YK, SK, MY, MM, YH, YO and SS: recruitment of patients, informed consent of patients. ST: preparation of rat tail tendon collagen, technical advice. MI: design of the study, interpretation of results, writing of the manuscript.
Funding This study was supported by grants from the Japan Society for the Promotion of Science (grant number: #26293195, #16H05307, #16K15453) and the Japan Agency for Medical Research and Development (grant number: #16ek0410018h0002, #16ek0410036h001, #17ek0410036h0002).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics committee of Tohoku University Graduate School of Medicine, Tohoku Rosai Hospital, and Japanese Red Cross Ishinomaki Hospital
Provenance and peer review Not commissioned; externally peer reviewed.
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