Human Lung Macrophages Challenged to Oxidants ex vivo: Lysosomal Membrane Sensitization is Associated with Inflammation and Chronic Airflow Limitation

Abstract

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 (FEV ₁) 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 FEV ₁/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 FEV ₁% 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.