Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease and the third leading cause of death worldwide. COPD pathogenesis is characterized by chronic inflammation resulting in changes in airway walls with exaggerated repair, i.e., chronic bronchitis, and alveolar lung tissue destruction with lack of alveolar repair, i.e., emphysema. The underlying disease mechanisms are largely unclear, and no effective treatments are available to stop disease progression. Therefore, novel insights into the pathogenesis of COPD and new therapeutic strategies are urgently needed. Cellular senescence, defined as an irreversible cell cycle arrest, has been recognized to play a role in COPD pathogenesis. Increased cellular senescence can lead to chronic inflammation and tissue dysfunction. Recently, I demonstrated higher levels of cellular senescence in parenchymal lung fibroblasts from COPD patients compared to matched non-COPD controls. Lung fibroblasts play an essential role in tissue repair and remodelling, including normal alveolar repair by regulating extracellular matrix (ECM) homeostasis and the production of growth factors for alveolar epithelial cells. The higher level of fibroblast senescence was associated with lower expression of the ECM proteoglycan decorin and higher secretion of pro-inflammatory proteins. Moreover, senescence induction in these fibroblasts resulted in ECM dysregulation, with altered expression of multiple ECM genes, including lower decorin. As both ECM dysregulation and chronic inflammation contribute to impaired alveolar repair in COPD, this increase in fibroblast senescence may contribute to emphysema in COPD patients. Therefore, I hypothesize that fibroblast senescence contributes to the impaired alveolar repair in COPD and that targeting fibroblast senescence may restore alveolar repair. To investigate this, I will assess the role of fibroblast senescence in alveolar repair in COPD, identify the key senescence proteins involved in COPD, and develop therapeutic strategies to target fibroblasts senescence and thereby restore alveolar repair in COPD. These insights are important to understand the pathogenesis of COPD. This project is the first step towards targeting fibroblast senescence as a new therapeutic strategy in COPD.
This news is related to Groningen Research Institute for Asthma and COPD (GRIAC)
