Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia

Abstract

Lung failure is responsible for significant morbidity and is a frequent cause of death in ataxia-telangiectasia (A-T). Disturbance in the redox balance of alveolar epithelial cells must be considered as a causal factor for respiratory disease in A-T. To investigate bronchoalveolar sensitivity to reactive oxygen species (ROS) and ROS-induced DNA damage, we used bleomycin (BLM) to induce experimental inflammation and fibrotic changes in the Atm-deficient mouse model.BLM or saline was administered by oropharyngeal instillation into the lung of Atm-deficient mice and wild-type mice. Mice underwent pulmonary function testing at days 0, 9, and 28, and bronchoalveolar lavage (BAL) was analysed for cell distribution and cytokines. Lung tissue was analysed by histochemistry.BLM administration resulted in a tremendous increase in lung inflammation and fibrotic changes in the lung tissue of Atm-deficient mice and was accompanied by irreversible deterioration of lung function. ATM (ataxia telangiectasia mutated) deficiency resulted in reduced cell viability, a delay in the resolution of γH2AX expression and a significant increase in intracellular ROS in pulmonary epithelial cells after BLM treatment. This was confirmed in the human epithelial cell line A549 treated with the ATM-kinase inhibitor KU55933.Our results demonstrate high bronchoalveolar sensitivity to ROS and ROS-induced DNA damage in the Atm-deficient mouse model and support the hypothesis that ATM plays a pivotal role in the control of oxidative stress-driven lung inflammation and fibrosis.

Tracking of Infused Mesenchymal Stem Cells in Injured Pulmonary Tissue in Atm-Deficient Mice

“…Although tissue damage and inflammation are hard to detect in Atm-deficient mice without exogenous trigger, our present data showed signs of lung disease and damage in Atm-deficient mice [3,4]. These findings are underlined by our in vivo imaging and qPCR results, which demonstrated increased retention of MSCs into the lung parenchyma of Atm-deficient mice compared to wild-type.…”

“…A direct connection between the ATM protein (A-T Mutated) and TGF-β 1 , one of the key mediators responsible for fibrotic changes in the lung, has been described [2]. In addition, we provided evidence for reduced lung function and increased inflammation in the lung of Atm-deficient mice displaying the human pulmonary A-T phenotype [3]. Therefore, inhibition of inflammation and fibrosis might open new avenues in the treatment of the lung disorder in A-T.…”

“…Aside from the immunodeficiency, it has been proposed that ongoing low grade inflammation and oxidative stress might be responsible for the clinical pathogenesis causing lung failure [1,16]. Recent studies further demonstrated restricted lung function, high sensitivity to inflammatory agents, and a significant amount of oxidative DNA damage in the lung parenchyma of Atm-deficient mice, especially after triggering inflammation [3,11].…”

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

“…Similarly, ATM-induced phosphorylation of the receptor for advanced glycation endproducts (RAGE) was recently shown to be integral for efficient DSB/R to prevent DNA DSB accumulation, induction of cellular senescence, and tissue fibrosis ( 53 ). Of interest, RAGE-knockout mice, ATM-deficient mice, and other mouse models with persistent DSB signaling have been shown to develop pulmonary fibrosis ( 54 , 55 ), suggesting that DSB accumulation may be a trigger of profibrotic pathways. In the same direction, accumulation of mitochondrial DNA damage in alveolar epithelial cells or myofibroblasts has been shown to promote the development of pulmonary fibrosis ( 56 , 57 ).…”

ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

“…Atm −/− mice succumb to lymphomas before the development of any spontaneous lung disease. But Atm-deficient alveolar epithelial cells have higher oxidative stress levels and oropharyngeal administration of bleomycin, a chelating agent that generates free radicals, induces severe inflammation, fibrosis and eventually irreversible damage in the lung of Atm −/− mice (Duecker et al 2018). Since the ability for oxidative damage to trigger DNA-strand breaks, it remains challenging to determine how much of the lung or even neurological phenotype of A-T patients can be attributed to defects in oxidative stresses responses alone.…”