Cigarette smoke induces pulmonary arterial dysfunction through an imbalance in the guanylyl cyclase redox status

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Feb. 21, 2022

ABSTRACT Chronic obstructive pulmonary disease (COPD), whose main risk factor is cigarette smoking (CS), one of the most common diseases globally. Many COPD patients also develop hypertension (PH), a severe complication that leads to premature death. Evidence suggests reactive oxygen species (ROS) involvement in and PH, especially regarding artery smooth muscle cells (PASMC) dysfunction. However, effects CS on vasculature are not completely understood. Herein we provide evidence extract (CSE) exposure PASMC ROS production, antioxidant response its consequences vascular tone dysregulation. Our results indicate CSE promotes mitochondrial fission, membrane depolarization increased superoxide levels. increase did parallel counterbalancing human (PA) cells. Interestingly, chelator mitoTEMPO reduced fission potential caused by CSE. As have previously shown, reduces PA vasoconstriction vasodilation. In this respect, prevented impaired nitric oxide-mediated vasodilation, while remained reduced. Finally, observed CSE-driven downregulation Cyb5R3 enzyme, which prevents soluble guanylyl cyclase oxidation PASMC. This might explain CSE-mediated decrease These there be connection between altered vasodilation responses PH secondary COPD, strongly support strategies specifically targeting mitochondria as new therapy for these diseases. Graphical abstract

Language: Английский

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Bronchioalveolar organoids as a tool to study transforming growth factor-β and cigarette smoke–induced lung pathology

Organoid, Journal Year: 2021, Volume and Issue: 1, P. e12 - e12

Published: Nov. 15, 2021

Respiratory medicine has high barriers to new drug development, with fewer approved treatments and candidate drugs a higher failure rate than other common disease fields. Most of the major identified in preclinical animal studies fail clinical setting because differences between models humans. Therefore, rapid development 3-dimensional (3D) organoid-based that recapitulate human pathological attracted increasing attention personalized medicine. In present study, we generated bronchoalveolar organoids (BAOs) from pluripotent stem cells (hPSCs) assessed their potential as pulmonary model. Derived BAOs contained expected spectrum differentiated cells, including alveolar progenitors, type 1 2 epithelial basal secretory ciliated mesenchymal cells. When were exposed transforming growth factor-beta, both fibrosis- inflammation-related transcripts significantly upregulated compared control. addition, exposure cigarette smoking extract induced increased levels nitric oxide dose-dependent manner, well upregulating oxidative stress-related pro-inflammatory genes. These findings suggest hPSC-derived could be promising platform for modeling fibrosis chronic obstructive testing efficacy.

Language: Английский

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Time to Shift Focus from Oxidative Stress to Redox Regulation in COPD

Antioxidants, Journal Year: 2022, Volume and Issue: 11(2), P. 237 - 237

Published: Jan. 26, 2022

Chronic obstructive pulmonary disease (COPD) is a non-communicable chronic that top-ranking with respect to mortality and morbidity rates, posing an enormous burden on patients, caregivers societies at large [...].

Language: Английский

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