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Published ahead of print on April 24, 2008, doi:10.1164/rccm.200710-1602OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 2, July 2008, 168-179

A more recent version of this article appeared on July 15, 2008
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Submitted on October 30, 2007
Accepted on April 24, 2008

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

Jaroslaw W Zmijewski1, Emmanuel Lorne2, Xia Zhao3, Yuko Tsuruta3, Yonggang Sha3, Gang Liu3, Gene P Siegal4, and Edward Abraham1*

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

* To whom correspondence should be addressed. 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 NF-{kappa}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-{kappa}B activation in neutrophils and neutrophil dependent acute lung injury. Measurements and Main Results: Inhibition of complex I with either rotenone or the anti-hyperglycemic agent metformin was associated with increased intracellular levels of both superoxide and hydrogen peroxide, as well as inhibition of LPS-induced I{kappa}B-{alpha} degradation, NF-{kappa}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 TLR4-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, respiratory complex I




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