Intracellular glutathione in stretch-induced cytokine release from alveolar type-2 like cells
Behrouz Jafari,
Bin Ouyang,
Li-Fu Li,
Charles A. Hales,
Deborah A. Quinn,
Behrouz Jafari
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorBin Ouyang
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorLi-Fu Li
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorCharles A. Hales
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorDeborah A. Quinn
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorBehrouz Jafari,
Bin Ouyang,
Li-Fu Li,
Charles A. Hales,
Deborah A. Quinn,
Behrouz Jafari
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorBin Ouyang
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorLi-Fu Li
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorCharles A. Hales
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorDeborah A. Quinn
Pulmonary & Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
Search for more papers by this authorDeborah A. Quinn, Pulmonary & Critical Care Unit, Massachusetts General Hospital, 55 Fruit Street, Bulfinch-148, Boston, MA 02114, USA. Email: [email protected]
Abstract
Objective: Ventilator-induced lung injury (VILI) is characterized by release of inflammatory cytokines, but the mechanisms are not well understood. We hypothesized that stretch-induced cytokine production is dependent on oxidant release and is regulated by intracellular glutathione (GSH) inhibition of nuclear factor κB (NF-κB) and activator protein-1 (AP-1) binding.
Methodology: Type 2-like alveolar epithelial cells (A549) were exposed to cyclic stretch at 15% strain for 4 h at 20 cycles/min with or without N-acetylcysteine (NAC) or glutathione monoethylester (GSH-e) to increase intracellular GSH, or buthionine sulfoximine (BSO), to deplete intracellular GSH.
Results: Cyclic stretch initially caused a decline in intracellular GSH and a rise in the levels of isoprostane, a marker of oxidant injury. This was followed by a significant increase in intracellular GSH and a decrease in isoprostane. Stretch-induced IL-8 and IL-6 production were significantly inhibited when intracellular GSH was further increased by NAC or GSH-e (P < 0.0001). Stretch-induced IL-8 and IL-6 production were augmented when intracellular GSH was depleted by BSO (P < 0.0001). NAC blocked stretch-induced NF-κB and AP-1 binding and inhibited IL-8 mRNA expression.
Conclusions: We conclude that oxidant release may play a role in lung cell stretch-induced cytokine release, and antioxidants, which increase intracellular GSH, may protect lung cells against stretch-induced injury.
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