Giordano 2018 Am J Respir Cell Mol Biol
|Giordano L, Farnham A, Dhandapani PK, Salminen L, Bhaskaran J, Voswinckel R, Rauschkolb P, Scheibe S, Sommer N, Beisswenger C, Weissmann N, Braun T, Jacobs HT, Bals R, Herr C, Szibor M (2018) Alternative oxidase attenuates cigarette smoke-induced lung dysfunction and tissue damage. Am J Respir Cell Mol Biol [Epub ahead of print].|
Giordano L, Farnham A, Dhandapani PK, Salminen L, Bhaskaran J, Voswinckel R, Rauschkolb P, Scheibe S, Sommer N, Beisswenger C, Weissmann N, Braun T, Jacobs HT, Bals R, Herr C, Szibor M (2018) Am J Respir Cell Mol Biol
Abstract: Cigarette-smoke (CS) exposure is the predominant risk factor for the development of chronic obstructive pulmonary disease (COPD) and the third leading cause of death worldwide. We aimed to elucidate if mitochondrial respiratory inhibition and oxidative stress are triggers in its etiology. In different models of CS exposure, we investigated the effect on lung remodeling and cell signaling of restoring mitochondrial respiratory electron flow, using the alternative oxidase (AOX), which by-passes the cytochrome segment of the respiratory chain. AOX attenuated CS-induced lung tissue destruction and loss of function in mice exposed chronically to CS (for 9 months). It preserved cell viability of isolated mouse embryonic fibroblasts (MEFs) treated with cigarette smoke condensate (CSC), limited the induction of apoptosis and decreased the production of reactive oxygen species (ROS). In contrast, the early-phase inflammatory response induced by acute CS exposure of mouse lung, i.e. infiltration by macrophages and neutrophils and adverse signaling, was unaffected. The use of AOX allowed novel pathomechanistic insights into CS-induced cell damage, mitochondrial ROS production and lung remodeling. Our findings implicate mitochondrial respiratory inhibition as a key pathogenic mechanism of CS toxicity in the lung. We propose AOX as a novel tool to study CS-related lung remodeling and potentially counteract CS-induced ROS production and cell damage.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: COPD Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Fibroblast Preparation: Permeabilized cells
Coupling state: OXPHOS Pathway: N, S, CIV, ROX HRR: Oxygraph-2k