title: Time course of nitric oxide synthases, nitrosative stress, and poly(ADP ribosylation) in an ovine sepsis model.
abstract: BACKGROUND
  Different isoforms of nitric oxide synthases (NOS) and determinants of oxidative/nitrosative stress play important roles in the pathophysiology of pulmonary dysfunction induced by acute lung injury (ALI) and sepsis. However, the time changes of these pathogenic factors are largely undetermined.
  
  
  METHODS
  Twenty-four chronically instrumented sheep were subjected to inhalation of 48 breaths of cotton smoke and instillation of live Pseudomonas aeruginosa into both lungs and were euthanized at 4, 8, 12, 18, and 24 hours post-injury. Additional sheep received sham injury and were euthanized after 24 hrs (control). All animals were mechanically ventilated and fluid resuscitated. Lung tissue was obtained at the respective time points for the measurement of neuronal, endothelial, and inducible NOS (nNOS, eNOS, iNOS) mRNA and their protein expression, calcium-dependent and -independent NOS activity, 3-nitrotyrosine (3-NT), and poly(ADP-ribose) (PAR) protein expression.
  
  
  RESULTS
  The injury induced severe pulmonary dysfunction as indicated by a progressive decline in oxygenation index and concomitant increase in pulmonary shunt fraction. These changes were associated with an early and transient increase in eNOS and an early and profound increase in iNOS expression, while expression of nNOS remained unchanged. Both 3-NT, a marker of protein nitration, and PAR, an indicator of DNA damage, increased early but only transiently.
  
  
  CONCLUSIONS
  Identification of the time course of the described pathogenetic factors provides important additional information on the pulmonary response to ALI and sepsis in the ovine model. This information may be crucial for future studies, especially when considering the timing of novel treatment strategies including selective inhibition of NOS isoforms, modulation of peroxynitrite, and PARP.
authors.affiliation: Department of Anesthesiology, Investigational Intensive Care Unit, The University of Texas Medical Branch and Shriners Burns Hospital for Children, 301 University Boulevard, Galveston, Texas 77550, USA. lanm@gmx.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Lange
authors.forename: Rhykka
authors.initials: R
authors.lastname: Connelly
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
authors.forename: Atsumori
authors.initials: A
authors.lastname: Hamahata
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Nakano
authors.forename: Aimalohi
authors.initials: A
authors.lastname: Esechie
authors.forename: Collette
authors.initials: C
authors.lastname: Jonkam
authors.forename: Sanna
authors.initials: S
authors.lastname: von Borzyskowski
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schmalstieg
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D016209:Interleukin-8 / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D008168:Lung / Q000737:chemistry / Q000201:enzymology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism* / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism / Q000502:physiology; D009573:Nitrites / Q000097:blood; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology; D012756:Sheep; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000502:physiology
chemical_list: D016209:Interleukin-8; D009566:Nitrates; D009573:Nitrites; D011064:Poly Adenosine Diphosphate Ribose; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III