Abstracts Division 3
72. Smoking-associated exposure to aldehydes disrupts the molecular regulation of mitochondrial metabolism in primary human bronchial epithelial cells
C.B.M. Tulen1, H.W.J.M. Cremers2, E. Duistermaat2, P.H.B. Fokkens2, W.N.M. Klerx2, N. Weibolt2, P.J.J. Jessen1, E.J.C. Koene1, L. Maas1, M.A. Dentener3,4, Y.C.M. Staal2, F.J. van Schooten1, A. Opperhuizen1,5, A.H.V. Remels1
1Department of Pharmacology and Toxicology, 3Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
2Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
4PLUC facility, Maastricht University Medical Center+, Maastricht, the Netherlands
5Netherlands Food and Consumer Product Safety Authority, Utrecht, the Netherlands
Inhalation of cigarette smoke (CS) is the primary risk factor for developing devastating lung diseases such as Chronic Obstructive Pulmonary Disease. During the pyrolysis and combustion of tobacco, the chemical class of aldehydes is generated which includes acetaldehyde, acrolein and formaldehyde. These short-chain aldehydes belong to the most hazardous toxicants and are known to induce cellular mechanisms underlying respiratory toxicity. Although impaired mitochondrial morphology and function have been described in CS- and acrolein-exposed human airway epithelial cells, the impact of CS and short-chain aldehydes on the molecular pathways regulating mitochondrial content and quality control are incompletely understood. Therefore, air-liquid interface-differentiated human primary bronchial epithelial cells (PBEC; PLUC facility MUMC+4) of non-COPD subjects (n=4) were acutely exposed to CS (1 Marlboro Red cigarette), a mixture of aldehydes (acetaldehyde, acrolein, formaldehyde; at concentrations as present in 1 Marlboro Red cigarette) or air (control) according to the Health Canadian Intense Regime (8 puffs) using a Vitrocell modular exposure system. After recovery for 6 or 24 hours following exposure, we assessed cell viability (LDH assay), and transcript and protein abundance of key constituents of mitochondrial metabolic pathways. PBEC exposure to CS or an aldehyde mixture revealed no impact on cell viability (cytotoxicity ≤5%). Moreover, CS exposure resulted in decreased protein levels of subunits of the electron transport chain, and constituents controlling mitochondrial biogenesis or mitophagy as well as elevated transcript and protein abundance of molecules associated with autophagy. Furthermore, mRNA levels of anti-oxidant markers and the glycolytic marker Hexokinase 2 were increased following CS exposure. The alterations in expression of regulators involved in mitochondrial metabolism were largely similar but less pronounced in aldehydes exposed PBEC. Collectively, these data show that aldehydes, as components of CS, disrupt the molecular regulation of mitochondrial metabolism in epithelial cells of the human airways.
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