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Pulmonary Neutrophil Infiltration in Murine Sepsis

Role of Inducible Nitric Oxide Synthase

Vascular Biology Group, Lawson Health Research Institute, Division of Respirology, Departments of Medicine, Physiology, and Pharmacology, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada

Correspondence and requests for reprints should be addressed to Sanjay Mehta, M.D., F.R.C.P.C., F.C.C.P., Division of Respirology, London Health Sciences Center South Street Campus, 375 South Street, London, ON, N6A 4G5 Canada. E-mail: sanjay.mehta{at}lhsc.on.ca

Nitric oxide (NO) derived from inducible NO synthase (iNOS) contributes to the pathophysiology of acute lung injury (ALI). The effect of iNOS on pulmonary neutrophil infiltration in ALI is not known. Thus, we assessed pulmonary microvascular neutrophil sequestration through intravital videomicroscopy and pulmonary neutrophil infiltration, reflected by myeloperoxidase activity and lavage neutrophil counts, after induction of sepsis by cecal ligation/perforation in wild-type (iNOS+/+) versus iNOS–/– mice. Pulmonary microvascular neutrophil sequestration was attenuated in septic iNOS–/– versus iNOS+/+ mice (15 ± 1 vs. 20 ± 1 leukocytes per field, p < 0.05), but lavage neutrophil counts were greater in iNOS–/– mice (5.7 ± 1.5% vs. 0.7 ± 0.1%, p < 0.05) between 6 and 18 hours after cecal ligation and perforation. When iNOS+/+ bone marrow was transplanted into bone marrow–depleted iNOS–/– mice (+ to – chimeras; iNOS limited to marrow-derived inflammatory cells), septic pulmonary microvascular neutrophil sequestration and lavage neutrophil counts were restored to levels seen in septic iNOS+/+ mice. In contrast, in – to + chimeras, pulmonary neutrophil trafficking was similar to iNOS–/– mice. In vitro cytokine-stimulated neutrophil transendothelial migration was significantly greater for iNOS–/– versus iNOS+/+ neutrophils (7.9 ± 0.7% vs. 3.8 ± 0.6%, p < 0.05) but was independent of endothelial iNOS. Thus, neutrophil iNOS-derived NO is an important autocrine modulator of pulmonary neutrophil infiltration in murine sepsis.

Key Words: sepsis • acute lung injury • neutrophil infiltration • inducible nitric oxide synthase • reciprocal bone marrow transplant chimeras

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