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Increased Lysosomal Membrane Permeabilization in Oxidant-exposed Macrophages of Human Fibrotic Lungs
Hans L Persson1, Linda K Vainikka2
1Division of Pulmonary Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Department of Respiratory Medicine UHL, Centre for Surgery and Oncology, County Council of Östergötland, Linköping, Sweden.
Abstract:
A disrupted balance of reduced glutathione (GSH) and iron (Fe) and subsequent enhanced susceptibility of lysosomes of lung macrophages (LMs) to oxidants may play a role in lung fibrogenesis. We assessed cellular Fe/GSH, lysosomal membrane permeabilization (LMP), and cell death in cultures of oxidant exposed LMs. LMs from 7 lung fibrosis patients and healthy subjects were exposed to a physiologic concentration of H2O2 for 1 h. LMP was assessed with acridine orange green fluorescence, apoptosis/necrosis were estimated by apoptotic DNA and typical morphology, Fe was assessed with Prussian blue staining/atomic absorption spectrophotometry, and GSH was evaluated using a GSH assay kit. Oxidant-induced LMP and cell death were more pronounced in cultures of LMs from patients with lung fibrosis, and these cells contained less GSH and more cytochemically stained Fe. These observations indicate that LMP may be involved in fibrosis development, possibly through activation of the inflammasome complex. Further studies are warranted for a detailed understanding.
Insights
Lung fibrosis involves an imbalance of reduced glutathione (GSH) and iron (Fe), increasing lysosome susceptibility. This study found oxidant-induced cell damage in lung macrophages from fibrosis patients, suggesting a role for lysosomal membrane permeabilization (LMP) in fibrosis.
Area of Science:
- Cell Biology
- Pulmonary Medicine
- Toxicology
Background:
- Lung fibrogenesis may involve disrupted cellular redox balance and lysosomal dysfunction.
- Reduced glutathione (GSH) and iron (Fe) homeostasis are critical for cellular protection against oxidants.
Purpose of the Study:
- To investigate the role of lysosomal membrane permeabilization (LMP) and cell death in lung macrophages (LMs) from patients with lung fibrosis.
- To assess cellular iron (Fe) and GSH levels in relation to oxidant exposure in LMs.
Main Methods:
- Primary lung macrophages (LMs) from lung fibrosis patients and healthy controls were exposed to hydrogen peroxide (H2O2).
- Lysosomal membrane permeabilization (LMP) was measured using acridine orange fluorescence.
- Cell death (apoptosis/necrosis), cellular Fe, and GSH levels were quantified.
Main Results:
- Oxidant-induced LMP and cell death were significantly higher in LMs from lung fibrosis patients compared to controls.
- LMs from fibrosis patients exhibited lower GSH levels and higher iron content.
- These findings suggest a link between altered Fe/GSH balance, increased LMP, and cell death in lung fibrosis.
Conclusions:
- Disrupted GSH and Fe balance may enhance LM susceptibility to oxidants, leading to LMP and contributing to lung fibrosis.
- Lysosomal membrane permeabilization (LMP) is implicated in fibrosis development, potentially via inflammasome activation.
- Further research is needed to elucidate the precise mechanisms involved in fibrosis pathogenesis.
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