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Mitochondrial Respiratory Complex I Regulates Neutrophil Activation and Severity of Lung Injury

¹ Department of Medicine, and ² Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama; ³ Pole Anesthésie Réanimation, CHU d'Amiens and INSERM, ERI-12, Amiens, France; and ⁴ Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama

Correspondence and requests for reprints should be addressed to Edward Abraham, M.D., Department of Medicine, University of Alabama at Birmingham School of Medicine, BDB 420, 1530 Third Avenue S, Birmingham, AL 35294-0012. E-mail: eabraham{at}uab.edu

Rationale: Mitochondria have important roles in intracellular energy generation, modulation of apoptosis, and redox-dependent intracellular signaling. Although reactive oxygen species (ROS) participate in the regulation of intracellular signaling pathways, including activation of nuclear factor (NF)-B, there is only limited information concerning the role of mitochondrially derived ROS in modulating cellular activation and tissue injury associated with acute inflammatory processes.

Objectives: To examine involvement of the mitochondrial electron transport chain complex I on LPS-mediated NF-B activation in neutrophils and neutrophil-dependent acute lung injury.

Methods: Neutrophils incubated with rotenone or metformin were treated with bacterial lipopolysaccharide (LPS) to determine the effects of mitochondrial complex I inhibition on intracellular concentrations of reactive oxygen species, NF-B activation, and proinflammatory cytokine expression. Acute lung injury was produced by intratracheal injection of LPS into control, metformin, or rotenone-treated mice.

Measurements and Main Results: Inhibition of complex I with either rotenone or the antihyperglycemic agent metformin was associated with increased intracellular levels of both superoxide and hydrogen peroxide, as well as inhibition of LPS-induced IB- degradation, NF-B nuclear accumulation, and proinflammatory cytokine production. Treatment of LPS-exposed mice with rotenone or metformin resulted in inhibition of complex I in the lungs, as well as diminished severity of lung injury.

Conclusions: These results demonstrate that mitochondrial complex I plays an important role in modulating Toll-like receptor 4–mediated neutrophil activation and suggest that metformin, as well as other agents that inhibit mitochondrial complex I, may be useful in the prevention or treatment of acute inflammatory processes in which activated neutrophils play a major role, such as acute lung injury.

Key Words: acute lung injury • neutrophil • mitochondria • reactive oxygen species • nuclear factor-B

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Little is known about how mitochondria participate in neutrophil activation and neutrophil-driven inflammation. What This Study Adds to the Field These results demonstrate that mitochondrial complex I plays an important role in modulating Toll-like receptor 4–mediated neutrophil activation and suggest that metformin, as well as other agents that inhibit mitochondrial complex I, may be useful in the prevention or treatment of acute inflammatory processes in which activated neutrophils play a major role, such as acute lung injury.

 

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