Altered iron metabolism and elevated cellular senescence in COPD small airway epithelial cells

Abstract

Background: Altered iron metabolism is associated with COPD pathogenesis, and elevated iron levels are observed in the COPD lung. COPD is also associated with elevated levels of senescent cells that contain increased intracellular iron. Whether this is a cause or consequence of senescence is unknown. Aim: To examine the relationship between excess intracellular iron and senescence in COPD. Methods: Total intracellular iron was detected in small airway epithelial cells (SAEC) from non-smokers (NS) and COPD patients by atomic absorbance spectrometry. Heme iron was measured using absorbance at 400 nM. SAEC were treated with ferric ammonium iron citrate (FAC) or the iron chelator, deferoxamine. Iron and senescence markers were detected by western blot. Results: Intracellular iron was increased 1.7-fold (p=0.002) and heme iron 2.1-fold in COPD SAEC compared NS cells (n=6 p=0.008). Treatment of NS and COPD SAEC with FAC induced a 3.65 (p=0.4) and 4.8-fold (p=0.02) increase in iron respectively, with COPD SAEC accumulating significantly more iron than NS cells (n=6 p=0.04). Iron chelation significantly reduced intracellular iron in COPD, but not NS SAEC (n=4 p=0.02). Elevated expression of transferrin heavy chain and transferrin receptor were detected in COPD SAEC compared to NS, correlating with alterations in senescence markers p21 and Sirtuin-1/-6 (n=6). Conclusion: Elevated levels of intracellular iron were observed in COPD SAEC compared to NS, with COPD SAEC having increased capacity to accumulate extracellular iron, possibly via increased transferrin receptor. Altered senescence markers were also seen in COPD, but whether altered iron metabolism regulates this requires further investigation.