Date: Monday, November 6, 2017
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Recent data have implemented reactive oxygen species (ROS) in the etiology of interstitial lung disease (ILD) in systemic sclerosis. Recent data from bleomycin mice have suggested a role of large-scale somatically acquired mutations in mitochondrial DNA (mtDNA) and consecutive respiratory chain dysfunction as a trigger of ROS formation and lung fibrosis.
Lung biopsies from patients with idiopathic interstitial pneumonitis and systemic sclerosis (n=31) were analyzed for mitochondrial functions and compared with biopsies from 13 healthy controls (HC). From 17 patients we had simultaneous biopsies from the upper and lower lung.
Malondialdehyde as a marker of ROS formation was increased in ILD (p=0.007). The median proportion of mtDNA containing the pathogenic common deletion was 22.5% in ILD patients, compared to 0% in HC. This translated into a 3.8-fold diminishment of mtDNA-encoded cytochrome c-oxidase (COX2), but not nucleus-encoded (COX4) respiratory chain subunits in ILD compared to controls (p<0.0001) and a 33% diminishment of mtDNA-encoded cytochrome c-oxidase activity (p=0.001 vs. controls). In all patients, the more fibrotic lower lungs had significantly more malondialdehyde (p=0.0004), mtDNA deletions (p=0.0006), and cytochrome c-oxidase dysfunction (p=0.0003) than the less-fibrotic upper lung counterparts. Conversely, lower lungs had significantly less (p=0.0003) mtDNA-encoded COX2 subunits in comparison to non-mtDNA-encoded COX4 subunits (Figure). There was no association of any mitochondrial parameter with smoking status or age, and no difference between biopsies from patients with systemic sclerosis and non-specific interstitial pneumonitis.
Our data support a role of mtDNA-mutations and consecutive respiratory chain dysfunction as a trigger and perpetuator of ROS formation in both, idiopathic interstitial pneumonitis and ILD of patients with systemic sclerosis.
To cite this abstract in AMA style:Jaeger VK, Lebrecht D, Nicholson AG, Wells AU, George S, Gazdhar A, Tamm M, Venhoff N, Geiser T, Walker UA. Mitochondrial DNA Mutations and Respiratory Chain Dysfunction in Lung Fibrosis of Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/mitochondrial-dna-mutations-and-respiratory-chain-dysfunction-in-lung-fibrosis-of-systemic-sclerosis/. Accessed September 25, 2021.
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