Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

Abstract

Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by an irreversible proliferation arrest associated with secretion of inflammatory mediators. ROS production, known to induce senescence, is increased in COPD fibroblasts and mitochondria dysfunction participates in this process. Among the battery of cellular responses against oxidative stress damage, heme oxygenase (HO)‐1 plays a critical role in defending the lung against oxidative stress and inflammation. Therefore, we investigated whether pharmacological induction of HO‐1 by chronic hemin treatment attenuates senescence and improves dysfunctional mitochondria in COPD fibroblasts. Fibroblasts from smoker controls (S‐C) and COPD patients were isolated from lung biopsies. Fibroblasts were long‐term cultured in the presence or absence of hemin, and/or ZnPP or QC‐15 (HO‐1 inhibitors). Lung fibroblasts from smokers and COPD patients displayed in long‐term culture a senescent phenotype, characterized by a reduced replicative capacity, an increased senescence and inflammatory profile. These parameters were significantly higher in senescent COPD fibroblasts which also exhibited decreased mitochondrial activity (respiration, glycolysis, and ATP levels) which led to an increased production of ROS, and mitochondria biogenesis and impaired mitophagy process. Exposure to hemin increased the gene and protein expression level of HO‐1 in fibroblasts and diminished ROS levels, senescence, the inflammatory profile and simultaneously rescued mitochondria dysfunction by restoring mitophagy in COPD cells. The effects of hemin were abolished by a cotreatment with ZnPP or QC‐15. We conclude that HO‐1 attenuates senescence in COPD fibroblasts by protecting, at least in part, against mitochondria dysfunction and restoring mitophagy.

Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort

“…In at least 1 study, exogenous mtDNA given intravascularly to rodents did not increase circulating mtDNA but increased u-mtDNA (26). U-mtDNA may also originate from renal cells, including glomerular or tubular epithelial cells (56), endothelial cells (44), and immune cells (6,12), as well as lung-derived cell sources (5)(6)(7)(8)(9)(10)(11)16) or muscle (65); further mechanistic studies are needed to identify the source of extracellular mtDNA in COPD. Whether u-mtDNA in COPD is a marker of disease or is pathogenic in itself remains to be determined.…”

“…One underlying biological mechanism that may provide insight into COPD pathogenesis and progression is mitochondrial dysfunction, which is consistently observed in cells derived from COPD subjects (5)(6)(7)(8)(9)(10)(11)(12)(13), as well as in experimental COPD models (11,14). Such mitochondrial dysfunction is associated with the leakage of mitochondrial DNA (mtDNA) (15)(16)(17)(18)(19), a mitochondrial derived danger-associated molecular pattern (mtDAMP) (20,21).…”

Exposure to Air Pollution Exacerbates Inflammation in Rats with Preexisting COPD

“…Mediators of Inflammation severity of COPD [33,34]. We evaluated the protein levels of Nrf2 and its major downstream factor HO-1 in the lungs of rats by Western blot.…”

MiR‐21‐5p/dual‐specificity phosphatase 8 signalling mediates the anti‐inflammatory effect of haem oxygenase‐1 in aged intracerebral haemorrhage rats

“…HO‐1 signal activation exerts a protective effect by preventing oxidative stress damage by accelerating catabolism of pro‐oxidant haem and oxygen‐free radicals (Lin et al, ). HO‐1 is expressed at low physiological levels, which can be increased via external stimulation, such as hypoxia, oxidative stress, inflammatory reactions, haem, endotoxins and heavy metals (Even et al, ). Our group found that increased HO‐1 expression begins 6 hr after ICH and that this change is consistent with the peak time of brain oedema (Yin, Chen, Zhou, Wu, & Bao, ).…”