American Journal of Respiratory and Critical Care Medicine Vol 165. pp. 1634-1639, (2002)
© 2002 American Thoracic Society
Role of Inducible Nitric Oxide Synthase in Pulmonary Microvascular Protein Leak in Murine Sepsis
Le Feng Wang,
Milan Patel,
Habib Moshref Razavi,
Sean Weicker,
Mariamma G. Joseph,
David G. McCormack and
Sanjay Mehta
Departments of Medicine, Pharmacology/Toxicology, and Pathology, Division of Respirology, Lawson Health Research Institute, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada
Correspondence and requests for reprints should be addressed to Dr. Sanjay Mehta, Division of Respirology, London Health Sciences Center-Victoria South Street Campus, 375 South Street, London, ON, N6A 4G5 Canada. E-mail: sanjay.mehta{at}lhsc.on.ca
The effects of nitric oxide (NO) from calcium-independent NO synthase (iNOS) on microvascular protein leak in acute lung injury (ALI) are uncertain, possibly because of disparate effects of iNOS-derived NO from different cells. We assessed the contribution of iNOS from inflammatory versus parenchymal cells to pulmonary protein leak in murine cecal ligation and perforation-induced ALI. We studied iNOS+/+, iNOS-/-, and two reciprocally bone marrow-transplanted iNOS chimeric mice groups: + to - (iNOS+/+ donor bone marrow-transplanted into iNOS-/- recipient mice) and - to +. Sepsis-induced ALI was characterized by pulmonary leukocyte infiltration, increased pulmonary iNOS activity, and increased pulmonary microvascular protein leak, as assessed by Evans blue (EB) dye. Despite equal neutrophil infiltration, sepsis-induced EB-protein leak was eliminated in iNOS-/- mice and in - to + iNOS chimeras (parenchymal cell-localized iNOS) but was preserved in + to - chimeric mice (inflammatory cell-localized iNOS). EB-protein leak was also prevented by pretreatment with allopurinol and superoxide dismutase. Microvascular protein leak in sepsis-induced ALI is uniquely dependent on iNOS in inflammatory cells with no obvious contribution of iNOS in pulmonary parenchymal cells. Pulmonary protein leak is also dependent on superoxide, suggesting an effect of peroxynitrite rather than NO itself.
Key Words: nitric oxide • acute lung injury • pulmonary circulation • pulmonary edema • peroxynitrite
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Copyright © 2002 American Thoracic Society
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