title: Vicious inducible nitric oxide synthase-mitochondrial reactive oxygen species cycle accelerates inflammatory response and causes liver injury in rats.
abstract: OBJECTIVE
  Increasing evidences suggest that, apart from activation of guanylyl cyclase, intracellular nitric oxide (NO) signaling is associated with an interaction between NO and reactive oxygen species (ROS) to modulate physiological or pathophysiological processes. The aim of this study was to understand the contribution of mitochondrial ROS (mtROS) to NO-mediated signaling in hepatocytes on inflammation.
  
  
  RESULTS
  In rats treated with lipopolysaccharide (LPS), mitochondria-targeted antioxidants (mtAOX) (mitoTEMPO and SkQ1) reduced inducible nitric oxide synthase (iNOS) gene expression in liver, NO levels in blood and plasma, and markers of organ damage (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase). In cultured hepatocytes, treated with inflammatory mediators, generated ex vivo by incubation of white blood cells with LPS, we observed an increase in NO and mtROS levels. l-NG-monomethyl arginine citrate, a NOS inhibitor, decreased both NO and mtROS levels. mtAOX reduced mtROS, cytoplasmic ROS levels, and expression of iNOS and interleukin (IL)-6. These data suggest that NO, generated by iNOS, elevates mtROS, which, in turn, diffuse into the cytoplasm and upregulate iNOS and IL-6.
  
  
  METHODS
  Here, for the first time, we show that intracellular signaling pathways mediated by NO and ROS are linked to each other via mtROS and form an iNOS-mtROS feed-forward loop which aggravates liver failure on acute inflammation.
  
  
  CONCLUSIONS
  Our results provide a mechanistic explanation of how NO and mtROS cooperate to conduct inflammatory intracellular signals. We anticipate our results to be the missing mechanistic link between acute systemic inflammation and liver failure.
authors.affiliation: 1 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology , Vienna, Austria .
authors.forename: Adelheid
authors.initials: A
authors.lastname: Weidinger
authors.forename: Andrea
authors.initials: A
authors.lastname: Müllebner
authors.forename: Jamile
authors.initials: J
authors.lastname: Paier-Pourani
authors.forename: Asmita
authors.initials: A
authors.lastname: Banerjee
authors.forename: Ingrid
authors.initials: I
authors.lastname: Miller
authors.forename: Lothar
authors.initials: L
authors.lastname: Lauterböck
authors.forename: J Catharina
authors.initials: JC
authors.lastname: Duvigneau
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Skulachev
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kozlov
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010971:Plastoquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; D000975:Antioxidants; D015415:Biomarkers; D008070:Lipopolysaccharides; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D010971:Plastoquinone