Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 116, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2019.105598
Keywords
Fibroblast; Small airway; Cellular senescence; Transforming growth factor-beta; COPD
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Chronic obstructive pulmonary disease (COPD) is characterised by an accelerated decline in airway function with age compared to age-matched non-smokers. There is increasing evidence that this is due to small airway disease rather than from emphysema, especially in the early stages of the disease. Small airways (< 2 mm internal diameter) are narrowed in COPD with thickening and distortion of the airway wall and peribronchiolar fibrosis. In addition, loss of elasticity in alveolar attachments and mucus hypersecretion contribute to the airway narrowing and closure, leading to air trapping. The mechanisms of peribronchiolar fibrosis are poorly understood and small airway fibroblasts have not been characterised. In small airways of COPD patients the fibroblasts are profibrotic, pro-inflammatory and senescent. There is a reduction in the anti-ageing molecules sirtuin-1 and -6, which are regulated by specific microRNAs that are increased in COPD cells. It is plausible that extracellular vesicles from senescent airway epithelium transmit senescent signals to airway fibroblasts to stimulate fibrosis and inflammation. Small airways fibrosis is a target for new drug development that inhibit growth factor receptors, new antioxidants and particularly those that are targeted to mitochondria and inhibitors of cellular senescence or senolytic therapies.
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