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Am J Physiol Lung Cell Mol Physiol 296: L480-L488, 2009. First published December 12, 2008; doi:10.1152/ajplung.90201.2008
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Septic pulmonary microvascular endothelial cell injury: role of alveolar macrophage NADPH oxidase

K. S. Farley, L. Wang, and S. Mehta

Centre for Critical Illness Research, Division of Respirology, Lawson Health Research Institute, London Health Sciences Center and Departments of Medicine and Physiology/Pharmacology, Schulich Faculty of Medicine and Dentistry, University Of Western Ontario, London, Ontario, Canada

Submitted 12 February 2008 ; accepted in final form 8 December 2008

A significant role for alveolar macrophages (AM) in the pathophysiology of sepsis-induced acute lung injury (ALI) has been shown; however, the mechanisms behind AM-related lung injury remain relatively uncertain. We examined the role of AM nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in pulmonary endothelial cell septic injury. NADPH oxidase is one of the major sources of cellular reactive oxygen species and has been implicated in endothelial injury in ALI. Pulmonary microvascular endothelial cells (PMVEC) monolayers were grown on Transwell inserts and incubated with wild-type and NADPH oxidase-deficient AM in the presence or absence of cytomix (equimolar TNF-{alpha}, IL-1β, and IFN-{gamma}). Injury to the monolayers was assessed by trans-PMVEC Evans blue (EB)-labeled albumin flux. We found AM under cytomix stimulation caused significant EB-albumin flux across the PMVEC monolayers, and this effect was attenuated by the genetic deletion of AM NADPH oxidase. The pharmacological inhibition of AM NADPH oxidase with apocynin and PR-39 also significantly reduced AM-dependent PMVEC injury. In the AM-PMVEC cocultures, we also assessed PMVEC injury through measurement of protein oxidation and lipid peroxidation. AM were shown to cause a significant increase in these markers of PMVEC injury, which was also attenuated by the inhibition of NADPH oxidase or through the use of NADPH oxidase-deficient AM. PMVEC NADPH oxidase was shown not to significantly contribute to PMVEC injury in our studies. From our findings we have concluded that AM NADPH oxidase is crucial for the septic increase in pulmonary vascular permeability.

alveolar macrophages; endothelial cells; oxidative stress


Address for reprint requests and other correspondence: S. Mehta, Division of Respirology, E2.635 Professional Block, London Health Sciences Center-Victoria Hospital, 800 Commissioner's Road East, London, ON, Canada N6A 5W9 (e-mail: sanjay.mehta{at}lhsc.on.ca)






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