title: Endothelial nitric oxide synthase deficient mice are protected from lipopolysaccharide induced acute lung injury.
abstract: Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury.
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Gross
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: P Benson
authors.initials: PB
authors.lastname: Ham
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Mary Louise
authors.initials: ML
authors.lastname: Meadows
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Cherian-Shaw
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Archana
authors.initials: A
authors.lastname: Kangath
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Supriya
authors.initials: S
authors.lastname: Sridhar
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lucas
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000517:prevention & control*; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects*; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency*; D012129:Respiratory Function Tests; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein