title: Role of inducible nitric oxide synthase in pulmonary microvascular protein leak in murine sepsis.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Respirology, Lawson Health Research Institute, London Health Sciences Center, University of Western Ontario, London, Canada.
authors.forename: Le Feng
authors.initials: le F
authors.lastname: Wang
authors.forename: Milan
authors.initials: M
authors.lastname: Patel
authors.forename: Habib Moshref
authors.initials: HM
authors.lastname: Razavi
authors.forename: Sean
authors.initials: S
authors.lastname: Weicker
authors.forename: Mariamma G
authors.initials: MG
authors.lastname: Joseph
authors.forename: David G
authors.initials: DG
authors.lastname: McCormack
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mehta
mesh_terms: D000493:Allopurinol / Q000627:therapeutic use; D000818:Animals; D016026:Bone Marrow Transplantation; D019559:Capillary Leak Syndrome / Q000201:enzymology* / Q000209:etiology*; D002678:Chimera; D004396:Coloring Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D005070:Evans Blue / Q000008:administration & dosage; D016166:Free Radical Scavengers / Q000627:therapeutic use; D008168:Lung / Q000098:blood supply* / Q000473:pathology*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000502:physiology* / Q000528:radiation effects; D052247:Nitric Oxide Synthase Type II; D010538:Peritonitis / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D010865:Pilot Projects; D011092:Polyethylene Glycols / Q000627:therapeutic use; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000209:etiology; D018805:Sepsis / Q000150:complications / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000627:therapeutic use
chemical_list: D004396:Coloring Agents; D016166:Free Radical Scavengers; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D005070:Evans Blue; D000493:Allopurinol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase