Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

Lerner, Chad; Sundar, Isaac K.; Rahman, Irfan

doi:10.1016/j.biocel.2016.07.026

Cited by 77 publications

(71 citation statements)

References 143 publications

(166 reference statements)

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“…27 The MoA in airway epithelial cells is Ag + -mediated reactive oxygen species (ROS) production, which leads to adverse cellular responses including oxidative stress, mitochondrial dysfunction, inflammation, and cytotoxicity. [28][29][30][31][32][33][34][35][36][37] Asthmatics are possibly a sensitive population to AgNP exposures in occupational settings, as these adverse cellular responses may further modulate innate and adaptive immune responses at the epithelial-immune interface to exacerbate this chronic airway disease. 38 Few previous studies have characterized the effects of interactions between host genetic and acquired factors, or gene × environment interactions (G×E), 39,40 on AgNP toxicity.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Genotype × Phenotype Interactions on Silver Nanoparticle Toxicity in Organotypic Cultures of Murine Tracheal Epithelial Cells

Nicholas

Haick

Workman

et al. 2019

Preprint

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Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. Previous studies have identified AgNP toxicity in airway epithelial cells, but no in vitro studies to date have used organotypic cultures as a high-content in vitro model of the conducting airway to characterize the effects of interactions between host genetic and acquired factors, or gene × phenotype interactions (G×P), on AgNP toxicity. In the present study, we derived organotypic cultures from primary murine tracheal epithelial cells (MTEC) to characterize nominal and dosimetric dose-response relationships for AgNP-induced barrier dysfunction, glutathione (GSH) depletion, reactive oxygen species (ROS) production, lipid peroxidation, and cytotoxicity across two genotypes (A/J and C57BL/6J mice), two phenotypes ("Normal" and "Type 2[T2]-Skewed"), and two exposures (an acute exposure of 24 h and a subacute exposure of 4 hours, every other day, over 5 days [5×4 h]). We characterized the "T2-Skewed" phenotype as an in vitro model of chronic respiratory diseases, which was marked by increased sensitivity to AgNP-induced barrier dysfunction, GSH depletion, ROS production, lipid peroxidation, and cytotoxicity, suggesting that asthmatics are a sensitive population to AgNP exposures in occupational settings. This also suggests that exposure limits, which should be based upon the most sensitive population, should be derived using in vitro and in vivo models of chronic respiratory diseases. This study highlights the importance of considering dosimetry as well as G×P effects when screening and prioritizing potential respiratory toxicants. Such in vitro studies can be used to inform regulatory policy aimed at special protections for all populations.

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Section: Introductionmentioning

confidence: 99%

The Effects of Genotype × Phenotype Interactions on Silver Nanoparticle Toxicity in Organotypic Cultures of Murine Tracheal Epithelial Cells

Nicholas

Haick

Workman

et al. 2019

Preprint

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“…In the lung, cell senescence leads to a decreased regenerative capacity and an increased cytokine production by structural cells (epithelium, fibroblasts) through a senescence‐associated secretome (Amsellem et al, 2011; Dagouassat et al, 2013; Noureddine et al, 2011; Tsuji, Aoshiba, & Nagai, 2010). However, other mechanisms, including mitochondrial dysfunction and defective mitophagy, may also contribute to ROS‐mediated senescence in COPD (Lerner, Sundar, & Rahman, 2016). …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…; and (c) overall, how does this interconnection contribute to age-associated disease phenotypes and aging? Numerous forms of endogenous and environmental stressors may disrupt mitochondrial function by impacting critical processes in mitochondrial homeostasis, such as mitochondrial redox system, oxidative phosphorylation, biogenesis, and mitophagy (Fivenson et al, 2017; Lerner et al, 2016). In this regard, it is intriguing that mitochondrial dysfunction is causally resulted from defects of DNA repair mechanisms which have been identified to accelerate aging process (Fang et al, 2014).…”

Section: Recent Advances – Mitochondrial Dysfunction/damps and Cmentioning

confidence: 99%

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

2018

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Inflammation represents a comprehensive host response to external stimuli for the purpose of eliminating the offending agent, minimizing injury to host tissues and fostering repair of damaged tissues back to homeostatic levels. In normal physiologic context, inflammatory response culminates with the resolution of infection and tissue damage response. However, in a pathologic context, persistent or inappropriately regulated inflammation occurs that can lead to chronic inflammatory diseases. Recent scientific advances have integrated the role of innate immune response to be an important arm of the inflammatory process. Accordingly, the dysregulation of innate immunity has been increasingly recognized as a driving force of chronic inflammatory diseases. Mitochondria have recently emerged as organelles which govern fundamental cellular functions including cell proliferation or differentiation, cell death, metabolism and cellular signaling that are important in innate immunity and inflammation-mediated diseases. As a natural consequence, mitochondrial dysfunction has been highlighted in a myriad of chronic inflammatory diseases. Moreover, the similarities between mitochondrial and bacterial constituents highlight the intrinsic links in the innate immune mechanisms that control chronic inflammation in diseases where mitochondrial damage associated molecular patterns (DAMPs) have been involved. Here in this review, the role of mitochondria in innate immune responses is discussed and how it pertains to the mitochondrial dysfunction or DAMPs seen in chronic inflammatory diseases is reviewed.

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Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD

Cited by 77 publications

References 143 publications

The Effects of Genotype × Phenotype Interactions on Silver Nanoparticle Toxicity in Organotypic Cultures of Murine Tracheal Epithelial Cells

The Effects of Genotype × Phenotype Interactions on Silver Nanoparticle Toxicity in Organotypic Cultures of Murine Tracheal Epithelial Cells

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

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

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