Chronic obstructive pulmonary disease (COPD) is characterised by accelerated aging of the lung. This manifests as a reduction in lung function and increased inflammatory mediators over that observed in age-matched individuals. There is also an increase in senescent cells that produce the senescence associated secretory phenotype (SASP) which closely matches the inflammatory profile of COPD. Senescent cells are thought to be cleared by macrophages but in COPD, these cells may have features of immunosenescence as they are more pro-inflammatory and have defective phagocytic function. Whether COPD macrophages are senescent and are able to clear senescent cells is unknown.
This thesis hypothesises that COPD macrophages are immunosenescent, shown by increased expression of senescence markers and reduced clearance of senescent cells, compared to cells from age-matched non-smoker subjects.
The expression of senescence markers was assessed in age-matched non-smoker and COPD monocyte-derived macrophages (MDM) differentiated in GM-CSF and macrophages isolated from lung resection tissue. Markers of senescence were increased in COPD MDM and tissue macrophages, including SASP components IL-6 and CXCL8.
Next, the ability of MDM to phagocytose senescent cells was examined. To investigate this, a population of senescent BEAS-2B cells were required to use as bait. Repeated treatment with 50nM doxorubicin induced the highest population of senescent cells, compared to cells treated with etoposide or H2O2. These doxorubicin-induced senescent BEAS-2B cells were fluorescently labelled and then incubated with MDM for 4h and phagocytosis was assessed. COPD MDM patients demonstrated reduced phagocytic clearance of senescent cells compared to NS MDM (~17% reduction, p<0.05).
These data indicate that COPD macrophages display features of senescence and show reduced ability to clear senescent cells, compared to NS macrophages. Therefore, the accumulation of senescent cells in COPD may be due to a lack of clearance of senescent cells by immunosenescent-macrophages, but this requires further investigation.