A model of the aged lung epithelium in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is an age-related disorder that carries a universally poor prognosis and is thought to arise from repetitive micro injuries to the alveolar epithelium. To date, a major factor limiting our understanding of IPF is a deficiency of disease models, particularly in vitro models that can recapitulate the full complement of molecular attributes in the human condition. In this study, we aimed to develop a model that more closely resembles the aberrant IPF lung epithelium. By exposing mouse alveolar epithelial cells to repeated, low doses of bleomycin, instead of usual one-time exposures, we uncovered changes strikingly similar to those in the IPF lung epithelium. This included the acquisition of multiple phenotypic and functional characteristics of senescent cells and the adoption of previously described changes in mitochondrial homeostasis, including alterations in redox balance, energy production and activity of the mitochondrial unfolded protein response. We also uncovered dramatic changes in cellular metabolism and detected a profound loss of proteostasis, as characterized by the accumulation of cytoplasmic protein aggregates, dysregulated expression of chaperone proteins and decreased activity of the ubiquitin proteasome system. In summary, we describe an in vitro model that closely resembles the aberrant lung epithelium in IPF. We propose that this simple yet powerful tool could help uncover new biological mechanisms and assist in developing new pharmacological tools to treat the disease.

Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis

“…Briefly, 1 × 10 6 MLE-12 cells were incubated with short (4 h) or chronic (6 day; 2 hit) bleomycin (10 μg/ml) exposures as previously described. 60 In chronic bleomycin exposure, cells were challenged to two, 24h exposures of low-dose bleomycin on days 1 and 4, followed by 48 hr post-exposure incubation periods (6 days, two 24 h exposures on days 1 and 4). After short or chronic exposures, MLE-12 cells were harvested for downstream experiments.…”

The Role of Mitochondrial Dysfunction in Idiopathic Pulmonary Fibrosis: New Perspectives for a Challenging Disease

“…Despite extensive research, the underlying mechanisms driving the pathogenesis of IPF remain unanswered. However, emerging evidence suggests that mitochondrial dysfunction, a disruption in the normal functioning of cellular powerhouses known as mitochondria, plays a crucial role in the development and progression of IPF [ 2 ].…”

“…Mitochondria are key regulators of cellular energy production, apoptosis, and redox balance, and their dysfunction has been associated with implications in various diseases. Perturbed mitochondrial function contributes to altered metabolic processes, increased oxidative stress, and impaired cell survival mechanisms, all of which are hallmark features observed in IPF [ 2 , 3 , 4 ]. Understanding the relationship between IPF and mitochondrial dysfunction is crucial for identifying novel therapeutic targets and developing targeted interventions.…”