Cigarette Smoke Induces Human Airway Epithelial Senescence via Growth Differentiation Factor 15 Production.
Cigarette smoke (CS)-induced airway epithelial senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), although the underlying mechanisms remain largely unknown. Growth differentiation factor (GDF) 15 is increased in airway epithelium of smokers with COPD and CS-exposed human airway epithelial cells, but its role in CS-induced airway epithelial senescence is unclear. In this study, we first analyzed expression of GDF15 and cellular senescence markers in airway epithelial cells of current smokers and nonsmokers. Second, we determined the role of GDF15 in CS-induced airway epithelial senescence by using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9 genome editing approach. Finally, we examined whether exogenous GDF15 protein promoted airway epithelial senescence through the activin receptor-like kinase 1/Smad1 pathway. GDF15 up-regulation was found in parallel with increased cellular senescence markers, p21, p16, and high-mobility group box 1 in airway epithelial cells of current smokers compared with nonsmokers. Moreover, CS extract induced cellular senescence in cultured human airway epithelial cells, represented by induced senescence-associated β-galactosidase activity, inhibited cell proliferation, increased p21 expression, and increased release of high-mobility group box 1 and IL-6. Disruption of GDF15 significantly inhibited CS extract-induced airway epithelial senescence. Lastly, GDF15 protein bound to the activin receptor-like kinase 1 receptor and promoted airway epithelial senescence via activation of the Smad1 pathway. Our findings highlight an important contribution of GDF15 in promoting airway epithelial senescence upon CS exposure. Senescent airway epithelial cells that chronically accumulate in CS-exposed lungs could contribute substantially to chronic airway inflammation in COPD development and progression.
1 Department of Medicine and.
Qun
Q
Wu
1 Department of Medicine and.
Di
D
Jiang
2 Mouse Genetics Core Facility, National Jewish Health, Denver, Colorado.
Jennifer L
JL
Matsuda
2 Mouse Genetics Core Facility, National Jewish Health, Denver, Colorado.
Kristina
K
Ternyak
2 Mouse Genetics Core Facility, National Jewish Health, Denver, Colorado.
Bicheng
B
Zhang
1 Department of Medicine and.
Hong Wei
HW
Chu
D030301:Activin Receptors, Type II / Q000378:metabolism; D000368:Aged; D064113:CRISPR-Cas Systems / Q000235:genetics; D016922:Cellular Senescence; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*
C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D051898:Smad1 Protein; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II
airway epithelial cells; cellular senescence; cigarette smoke; growth differentiation factor 15