Abstract
A number of inflammatory lung diseases have abnormally low glutathione (GSH) levels in the airway fluids. Lung macrophages are common mediators of inflammation, make up the majority of cells that are found in the airway epithelial lining fluid (ELF), and are commonly elevated in many lung diseases. Several animal models with altered ELF GSH levels are associated with similar alterations in the intracellular GSH levels of bronchoalveolar lavage (BAL) cells. The possible mechanisms and outcomes for this association between ELF GSH levels and intracellular BAL cell GSH are unknown. To investigate these issues, macrophages were grown in media supplemented with 500 µM GSH. GSH supplementation resulted in a 2–3 fold increase in macrophage intracellular GSH levels. The increase in macrophage intracellular GSH levels was associated with a significant reduction in NF-κB nuclear translocation and tumor necrosis factor α (TNFα) release upon LPS stimulation. Furthermore, co-treatment of macrophages with GSH and inhibitors of GSH breakdown or synthesis did not block GSH accumulation. In contrast, treatment with cytochalasin D, an inhibitor of actin dependent endocytosis, and amiloride, an inhibitor of macropinocytosis blocked, at least in part, GSH uptake. Furthermore, using two cigarette smoke exposure paradigms that result in two different GSH levels in the ELF and thus in the BAL cells resulted in modulation of cytokine release when stimulated with LPS ex vivo. These data suggest that macrophages are able to utilize extracellular GSH which can then modulate inflammatory signaling in response to proinflammatory stimuli. This data also suggests the lung can modulate inflammatory responses triggered by proinflammatory stimuli by altering ELF GSH levels and may help explain the dysregulated inflammation associated with lung diseases that have low ELF GSH levels.
Highlights
The epithelial lining fluid (ELF) of the lung is a heterogeneous mixture of cells, proteins, and low molecular weight antioxidants [1,2]
A correlation between bronchoalveolar lavage cell GSH levels and ELF GSH levels The bronchoalveolar lavage (BAL) cells, which are predominately Alveolar macrophages (AMs), reside within the ELF, and many of the nutrients for them to survive are derived from the ELF
When the ELF GSH increases to 272 mM in response to cigarette smoke (CS) the AM GSH increased to 9.9 nmol/ mg
Summary
The epithelial lining fluid (ELF) of the lung is a heterogeneous mixture of cells, proteins, and low molecular weight antioxidants [1,2]. There are several lung diseases that have been shown to have characteristically low ELF GSH levels. These lung disorders include chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), cystic fibrosis (CF), and not typically thought of as a disease, aging [7,8,9]. Under conditions of decreased GSH, patients typically exhibit decreased pathogen clearance leading to chronic inflammation [10]. This is especially important since many of these lung disease have high levels of airway inflammation and recurrent exacerbations [11]
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