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Protection from Lipopolysaccharide-induced Lung Injury by Augmentation of Airway S-Nitrosothiols

¹ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and ² Division of Neonatal Medicine, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina

Correspondence and requests for reprints should be addressed to Harvey E. Marshall, M.D., Room 201, MSRB, Box 2613, Duke University Medical Center, Durham, NC 27710. E-mail: marsh015{at}mc.duke.edu

Rationale: S-Nitrosothiols (SNO) inhibit immune activation of the respiratory epithelium and airway SNO levels are decreased in inflammatory lung disease. Ethyl nitrite (ENO) is a gas with chemical properties favoring SNO formation. Augmentation of airway SNO by inhaled ENO treatment may decrease lung inflammation and subsequent injury by inhibiting activation of the airway epithelium.

Objectives: To determine the effect of inhaled ENO on airway SNO levels and LPS-induced lung inflammation/injury.

Methods: Mice were treated overnight with inhaled ENO (10 ppm) or air, followed immediately by exposure to aerosolized LPS or saline. Parameters of inflammation and lung injury were quantified 1 hour after completion of the aerosol exposure and correlated to lung airway and tissue SNO levels.

Measurements and Main Results: Aerosolized LPS induced a decrease in airway and lung tissue SNO levels including S-nitrosylated NF-B. The decrease in lung SNO was associated with an increase in lung NF-B activity, cytokine/chemokine expression (keratinocyte-derived chemokine, tumor necrosis factor-, and IL-6), airway neutrophil influx, and worsened lung compliance. Pretreatment with inhaled ENO restored airway SNO levels and reduced LPS-mediated NF-B activation thereby inhibiting the downstream inflammatory response and preserving lung compliance.

Conclusions: Airway SNO serves an antiinflammatory role in the lung. Inhaled ENO can be used to augment airway SNO and protect from LPS-induced acute lung injury.

Key Words: ethyl nitrite • NF-B • nitric oxide • S-nitrosylation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject S-Nitrosothiols are endogenously produced, antiinflammatory compounds that are present in the lung airway and are known to be deficient in inflammatory lung disease. What This Study Adds to the Field Increasing airway S-nitrosothiol levels by treatment with inhaled ethyl nitrite inhibits the pulmonary inflammatory response to lipopolysaccharide. Ethyl nitrite may have therapeutic value in the prevention and treatment of acute lung injury and other inflammatory lung diseases.