Lung mitochondrial DNA copy number, inflammatory biomarkers, gene transcription and gene methylation in vapers and smokers

Mori, Kellie M.; McElroy, Joseph P.; Weng, Daniel; Chung, Sangwoon; Fadda, Paolo; Reisinger, Sarah A.; Ying, Kevin L.; Brasky, Theodore M.; Wewers, Mark D.; Freudenheim, Jo L.; Shields, Peter G.; Song, Min-Ae

doi:10.1016/j.ebiom.2022.104301

Cited by 15 publications

(4 citation statements)

References 74 publications

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“…A previous study has revealed increased mtDNA damage and deletion, as well as decreased mtDNA in macrophages in BALF from smokers compared with that from non-smokers (28). While a number of other studies have demonstrated increased mtDNA levels in blood (16) or cells exposed to cigarette smoke (29,30), the alteration of extracellular mtDNA levels in BALF has not been extensively studied. Although further studies investigating the effect of smoking on BALF-mtDNA are warranted, our data suggest that the increased BALF-mtDNA observed in IPF patients may re ect the pathological mechanisms correlated with disease severity and progression, rather than nonspeci c oxidative stress increased in the lungs of smokers.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a cohort study

Fukihara,

Sakamoto,

Ikeyama

et al. 2024

Preprint

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Background Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. Methods Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. Results mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. Conclusions Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a cohort study

Fukihara,

Sakamoto,

Ikeyama

et al. 2024

Preprint

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“…A previous study has revealed increased mtDNA damage and deletion, as well as decreased mtDNA in macrophages in BALF from smokers compared with that from non-smokers [30]. While a number of other studies have demonstrated increased mtDNA levels in blood [18] or cells exposed to cigarette smoke [31,32], the alteration of extracellular mtDNA levels in BALF has not been extensively studied. Although further studies investigating the effect of smoking on BALF-mtDNA are warranted, our data suggest that the increased BALF-mtDNA observed in IPF patients may reflect the pathological mechanisms correlated with disease severity and progression, rather than non-specific oxidative stress increased in the lungs of smokers.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a single cohort study

Fukihara,

Sakamoto,

Ikeyama

et al. 2024

Respir Res

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Background Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. Methods Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. Results mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. Conclusions Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

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“…Participants, chronologically aged 21–30 years, were recruited (2015–2017) through the Ohio State University (OSU) Study Search and Research Match websites, local print, television media, and Craig’s List [ 12 , 23 , 37 , 64 ]. Participants included EC vapers (EC; n = 14, including 3 never-smoking EC), smokers (SM; n = 16), and non-EC/non-SM (NS; n = 39) (Table 3 ) .…”

Section: Methodsmentioning

confidence: 99%

“…Liquid chromatography–tandem mass spectrometry (LC–MS/MS) was performed as previously described [ 64 , 65 ] for NNAL, nicotine equivalent, and PG.…”

Section: Methodsmentioning

confidence: 99%

Accelerated epigenetic age, inflammation, and gene expression in lung: comparisons of smokers and vapers with non-smokers

Song,

Mori,

McElroy

et al. 2023

Clin Epigenet

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Background Cigarette smoking and aging are the main risk factors for pulmonary diseases, including cancer. Epigenetic aging may explain the relationship between smoking, electronic cigarette vaping, and pulmonary health. No study has examined smoking and vaping-related epigenetic aging in relation to lung biomarkers. Methods Lung epigenetic aging measured by DNA methylation (mAge) and its acceleration (mAA) was assessed in young (age 21–30) electronic cigarette vapers (EC, n = 14, including 3 never-smoking EC), smokers (SM, n = 16), and non-EC/non-SM (NS, n = 39). We investigated relationships of mAge estimates with chronological age (Horvath-mAge), lifespan/mortality (Grim-mAge), telomere length (TL-mAge), smoking/EC history, urinary biomarkers, lung cytokines, and transcriptome. Results Compared to NS, EC and SM had significantly older Grim-mAge, shorter TL-mAge, significantly accelerated Grim-mAge and decelerated TL-mAge. Among SM, Grim-mAA was associated with nicotine intake and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). For EC, Horvath-mAA was significantly correlated with puffs per day. Overall, cytokines (IL-1β, IL-6, and IL-8) and 759 transcripts (651 unique genes) were significantly associated with Grim-mAA. Grim-mAA-associated genes were highly enriched in immune-related pathways and genes that play a role in the morphology and structures of cells/tissues. Conclusions Faster lung mAge for SM is consistent with prior studies of blood. Faster lung mAge for EC compared to NS indicates possible adverse pulmonary effects of EC on biological aging. Our findings support further research, particularly on epigenetic markers, on effects of smoking and vaping on pulmonary health. Given that most EC are former smokers, further study is needed to understand unique effects of electronic cigarettes on biological aging.

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Lung mitochondrial DNA copy number, inflammatory biomarkers, gene transcription and gene methylation in vapers and smokers

Cited by 15 publications

References 74 publications

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a cohort study

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a cohort study

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a single cohort study

Accelerated epigenetic age, inflammation, and gene expression in lung: comparisons of smokers and vapers with non-smokers

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