title: Endothelial nitric oxide synthase inhibits the development of autoimmune-mediated vasculitis in mice.
abstract: OBJECTIVE
  Many different genes or mediators have been implicated in promoting the development of vasculitis, although little is known regarding the mechanisms that normally act to suppress lesion formation. Endothelial nitric oxide synthase (eNOS) has been shown to inhibit vascular inflammation in many different model systems, but its roles in the pathogenesis of vasculitis have not been elucidated. This study was undertaken to determine the functions of eNOS in the initiation and progression of vasculitic lesion formation.
  
  
  METHODS
  MRL/MpJ-Fas(lpr)  mice lacking the gene for eNOS (Nos3(-/-) ) were generated and comprehensively evaluated and compared to controls with regard to the development of autoimmune disease, including vasculitic lesion formation and glomerulonephritis.
  
  
  RESULTS
  Nos3(-/-)  MRL/MpJ-Fas(lpr)  mice exhibited accelerated onset and increased incidence of renal vasculitis compared to Nos3(+/+)  controls. In contrast, no significant differences in severity of glomerulonephritis were observed between groups. Vasculitis was also observed in other organs of eNOS-deficient mice, including in the lungs of several of these animals. Ultrastructural analyses of renal lesions revealed the presence of electron-dense deposits in affected arteries, and IgG, IgA, and C3 deposition was observed in some vessels in the kidneys of Nos3(-/-)  mice. In addition, Nos3(-/-)  MRL/MpJ-Fas(lp)  mice showed increased levels of circulating IgG-IgA immune complexes at 20 weeks of age, compared to Nos3(+/+)  MRL/MpJ-Fas(lpr)  and Nos3(-/-)  C57BL/6 mice.
  
  
  CONCLUSIONS
  These findings strongly indicate that eNOS serves as a negative regulator of vasculitis in MRL/MpJ-Fas(lpr)  mice and further suggest that NO produced by this enzyme may be critical for inhibiting lesion formation and vascular damage in human vasculitic diseases.
authors.affiliation: University of Alabama at Birmingham, 720 South 20th Street, Birmingham, AL 35294, USA.
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.forename: Tambi
authors.initials: T
authors.lastname: Jarmi
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.forename: Scott
authors.initials: S
authors.lastname: Henke
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Zarjou
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Philip
authors.initials: P
authors.lastname: Kramer
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Bullard
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D003176:Complement C3 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005921:Glomerulonephritis / Q000473:pathology / Q000503:physiopathology; D007070:Immunoglobulin A / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D014657:Vasculitis / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*
chemical_list: D003176:Complement C3; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D052250:Nitric Oxide Synthase Type III