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Human Lung Macrophages Challenged to Oxidants ex vivo: Lysosomal Membrane Sensitization is Associated with
Hans Lennart Persson1,2, Apostolos Sioutas1,2, Petra Jacobson1,2
1Department of Respiratory Medicine in Linköping, Linköping University, Linköping, Sweden.
Background:
The lung macrophage (LM) is involved in most inflammatory processes of the human lung by clearance of dying cells and by wound repair. Upon cellular stress by oxidant challenge in vivo lysosomes may rupture in LMs and leakage of cellular content and cell debris may trigger airway inflammation and fibrosis, which may lead to chronic airflow limitation (CAL).
Objective:
The aim of this study was to determine whether lysosomal membrane permeabilization (LMP) in LMs challenged to oxidants ex vivo is associated with airway inflammation and CAL, the latter assessed as the reduced forced expiratory volume in one second (FEV1) expressed as % of predicted.
Materials And Methods:
Twenty-eight subjects were investigated; 13 lung-healthy subjects and 15 subjects with a variety of inflammatory disorders, demonstrating CAL on dynamic spirometry (defined as an FEV1/FVC ratio < 0.70). LMs were harvested by broncho-alveolar lavage (BAL) and challenged ex vivo by oxidants. LMP in oxidant-exposed LMs was assessed as the emitted acridine orange (AO) green fluorescence from oxidant-exposed LMs (using macrophage-like murine J774 cells as positive controls). Inflammatory cells in BAL were counted and lung volumes were recorded.
Results:
Oxidant-induced LMP in LMs was significantly greater among subjects with CAL and particularly among those with ongoing inflammation. Previous tobacco history did not influence LMP. Among subjects with CAL, oxidant-induced LMP correlated negatively with FEV1% of predicted.
Conclusion:
Lysosomes of LMs harvested from patients with CAL demonstrate an increased sensitivity to oxidants, which may trigger mechanisms behind CAL, eg, chronic airway inflammation and fibrotic re-modelling. The study suggests a mechanistic role for LMP in LMs on airway inflammation, suggesting an anti-inflammatory effect by drugs that prevent increased LMP.
Insights
Lysosomal membrane permeabilization in lung macrophages is heightened in chronic airflow limitation (CAL). This increased sensitivity to oxidants may drive airway inflammation and fibrosis, suggesting therapeutic targets for CAL.
Area of Science:
- Pulmonary Medicine
- Immunology
- Cell Biology
Background:
- Lung macrophages (LMs) are key players in lung inflammation, cell clearance, and repair.
- Oxidant stress can cause lysosomal rupture in LMs, releasing contents that promote airway inflammation and fibrosis, potentially leading to chronic airflow limitation (CAL).
Purpose of the Study:
- To investigate the association between lysosomal membrane permeabilization (LMP) in LMs challenged with oxidants and the presence of airway inflammation and CAL.
- To assess CAL by measuring forced expiratory volume in one second (FEV1) as a percentage of predicted values.
Main Methods:
- Investigated 28 subjects (13 healthy, 15 with CAL).
- Collected LMs via broncho-alveolar lavage (BAL) and exposed them to oxidants ex vivo.
- Assessed LMP by measuring acridine orange fluorescence in oxidant-exposed LMs.
Main Results:
- Oxidant-induced LMP was significantly higher in subjects with CAL, especially those with active inflammation.
- No correlation was found between LMP and previous tobacco use.
- In CAL subjects, higher LMP correlated with lower FEV1% predicted.
Conclusions:
- LMs from CAL patients exhibit increased oxidant sensitivity, potentially driving chronic airway inflammation and fibrotic remodeling.
- LMP in LMs appears to play a mechanistic role in airway inflammation.
- Drugs preventing increased LMP may offer anti-inflammatory benefits for CAL.
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