Asbestos-Induced Pulmonary Fibrosis Is Augmented in 8-Oxoguanine DNA Glycosylase Knockout Mice

Cheresh, Paul; Morales‐Nebreda, Luisa; Kim, Seok Jo; Yeldandi, Anjana V.; Williams, David B.; Cheng, Yuan; Mutlu, Gökhan M.; Budinger, G. R. Scott; Ridge, Karen M.; Schumacker, Paul T.; Bohr, Vilhelm A.; Kamp, David W.

doi:10.1165/rcmb.2014-0038oc

Cited by 47 publications

(83 citation statements)

References 62 publications

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“…Male and female 8- to 10- week old C57Bl/6 J wild-type (WT) mice (Jackson Labs, Bar Harbor, ME) and MCAT (C57Bl/6 J background; kindly provided by Peter S. Rabinovitch; [18]) were used for lung fibrosis studies [16,27,28]. Using a Mitochondria Isolation kit (Thermo Fisher Scientific Inc., Rockford, IL) according to the manufacturer’s recommendations as we previously described [6], we obtained mitochondrial protein from lung and heart to show the mitochondrial catalase protein.…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage

Kim

Cheresh

Jablonski

et al. 2016

Free Radical Biology and Medicine

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Rationale Alveolar epithelial cell (AEC) injury and mitochondrial dysfunction are important in the development of lung fibrosis. Our group has shown that in the asbestos exposed lung, the generation of mitochondrial reactive oxygen species (ROS) in AEC mediate mitochondrial DNA (mtDNA) damage and apoptosis which are necessary for lung fibrosis. These data suggest that mitochondrial-targeted antioxidants should ameliorate asbestos-induced lung. Objective To determine whether transgenic mice that express mitochondrial-targeted catalase (MCAT) have reduced lung fibrosis following exposure to asbestos or bleomycin and, if so, whether this occurs in association with reduced AEC mtDNA damage and apoptosis. Methods Crocidolite asbestos (100 μg/50 μL), TiO2 (negative control), bleomycin (0.025 units/50 μL), or PBS was instilled intratracheally in 8–10 week-old wild-type (WT - C57Bl/6 J) or MCAT mice. The lungs were harvested at 21 d. Lung fibrosis was quantified by collagen levels (Sircol) and lung fibrosis scores. AEC apoptosis was assessed by cleaved caspase-3 (CC-3)/Surfactant protein C (SFTPC) immunohistochemistry (IHC) and semi-quantitative analysis. AEC (primary AT2 cells from WT and MCAT mice and MLE-12 cells) mtDNA damage was assessed by a quantitative PCR-based assay, apoptosis was assessed by DNA fragmentation, and ROS production was assessed by a Mito-Sox assay. Results Compared to WT, crocidolite-exposed MCAT mice exhibit reduced pulmonary fibrosis as measured by lung collagen levels and lung fibrosis score. The protective effects in MCAT mice were accompanied by reduced AEC mtDNA damage and apoptosis. Similar findings were noted following bleomycin exposure. Euk-134, a mitochondrial SOD/catalase mimetic, attenuated MLE-12 cell DNA damage and apoptosis. Finally, compared to WT, asbestos-induced MCAT AT2 cell ROS production was reduced. Conclusions Our finding that MCAT mice have reduced pulmonary fibrosis, AEC mtDNA damage and apoptosis following exposure to asbestos or bleomycin suggests an important role for AEC mitochondrial H2O2-induced mtDNA damage in promoting lung fibrosis. We reason that strategies aimed at limiting AEC mtDNA damage arising from excess mitochondrial H2O2 production may be a novel therapeutic target for mitigating pulmonary fibrosis.

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Section: Methodsmentioning

confidence: 99%

“…Intratracheal instillation of asbestos or TiO 2 to induce pulmonary fibrosis was performed as described [16]. Stock solutions (2 mg/mL) of crocidolite asbestos was prepared in Phosphate Buffered Saline (PBS) and 15 mM HEPES (Sigma, St. Louis, MO) and sonicated at 40% power (Sonicator: Branson, Danbury, CT) for 8 min to disrupt fiber clumps.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage

Kim

Cheresh

Jablonski

et al. 2016

Free Radical Biology and Medicine

Self Cite

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“…A more general approach to determine how inhibition of autophagy modulates the fibrotic response has used mice deficient enzyme that hydrolyzes oxidized guanine residues that are modified as a result of excessive ROS production, and deficiency of OGG1 increases susceptibility to pulmonary fibrosis induced by asbestos (89,(92)(93)(94). Accumulation of mutations and the deletion of mtDNA can accelerate aging.…”

Section: Cellular Perturbations In the Ipf Lungmentioning

confidence: 99%

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mora¹,

Bueno²,

Rojas³

2017

Journal of Clinical Investigation

183

169

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One of the most remarkable medical accomplishments in the last century has been the increasing longevity of the human population. A decrease in birth rates, accompanied by a reduction in mortality among the elderly population, has collectively increased the percentage of the aged population, particularly in developed countries. Globally, it is estimated that the proportion of the population over the age of 60 will increase from 11% to 22% by 2050, and 28% by 2100. Currently, 18% of the US population is over 60 years of age (57 million), which is predicted to rise to 27% (107 million) in 2050 and up to 31% (149 million) by 2100 (1). The aging population has propelled an increase in the overall prevalence of chronic conditions. Several lung diseases, including acute lung injury and asthma, and some infectious diseases, such as pneumonia, increase in severity and mortality with age. Additionally, there has been a significant increase in incidence of chronic lung diseases -including chronic obstructive pulmonary disease, most forms of lung cancer, and idiopathic pulmonary fibrosis (IPF) -resulting in aging-related increases in prevalence.IPF is the most common form of idiopathic interstitial lung diseases. Its overall incidence in the US is 7 to 17 per 100,000 persons with a prevalence between 13.2 and 63 per 100,000 persons (2). A 1996 study initially demonstrated a higher incidence and prevalence of IPF in patients over 65 (3). These observations were confirmed more recently by Raghu et al. (4) and others, using both broad and narrow case-finding criteria for IPF diagnosis. These studies estimated that in the US, the prevalence of IPF increases with age, ranging from 4 per 100,000 for population aged between 18 and 34 years old to 227.2 per 100,000 among those 75 or older (4). This aging-related increase in cumulative incidence and prevalence of IPF has been corroborated by several studies that include populations in Europe and Asia (5-9). Accordingly, the median age at diagnosis of sporadic IPF ranges between 50 and 85 years old, and patients younger than 50 are more commonly associated with familial, rather than sporadic, forms of the disease (2). Mortality rates from IPF are steadily increasing worldwide, and a positive association has also been observed with advanced age (10). Examination of US government health insurance data for people aged 65 and older shows an increasing prevalence of IPF among older age groups (11). These studies confirm the growing concern that aging, and consequently age-related diseases, will drive up health care expenditures. As the elderly population in developed countries is expected to double in the next 25 years, there is an urgent need to understand the pathogenesis of IPF and develop interventions to attenuate or reverse lung fibrosis. The physiology of aging and the lungEvolutionary theories of aging include the concept of selection shadow that permits the accumulation of mutations with late deleterious effects, and the theory of antagonistic pleiotropy, which supports the sele...

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“…In accord with this notion, the hypoxic environment at the alveolar level that ensues following acute lung injury has been shown to trigger enhanced mitochondrial ROS generation by alveolar cells, which plays a key role in modulating TGFβ signaling and onset of fibrosis (Zhou, et al, 2009, Na, et al, 2010, Panduri, Weitzman, Chandel, & Kamp, 2004, Chandel, et al, 2000and Song, et al, 2014. Similar observations have been made in animals treated with bleomycin (Song, et al, 2014), asbestos (Song, et al, 2014), asbestos (Cheresh, et al, 2015 andPanduri, et al, 2009) or particulate matter air pollution . Consistent with this idea, lung tissue from IPF patients display elevated lactate levels, which synergizes with TGF-beta to induce myofibroblast differentiation under hypoxic conditions providing a direct link between perturbed glycolysis and modulation of a key pathway implicated in lung remodeling (Kottmann, et al, 2012).…”

Section: E) Diffuse Parenchymal Lung Diseasesmentioning

confidence: 56%

Mitochondria dysfunction: A novel therapeutic target in pathological lung remodeling or bystander?

Rowlands¹

2016

Pharmacology & Therapeutics

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Asbestos-Induced Pulmonary Fibrosis Is Augmented in 8-Oxoguanine DNA Glycosylase Knockout Mice

Cited by 47 publications

References 62 publications

Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage

Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

Mitochondria dysfunction: A novel therapeutic target in pathological lung remodeling or bystander?

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