Reduced hepatic transcription factor activation and expression of IL-6 and ICAM-1 after hemorrhage by NO scavenging.
BACKGROUND
Hemorrhagic shock (HS) elicits an inflammatory response characterized by increased cytokine production and recruitment of polymorphonucleated neutrophilic granulocytes (PMN) that we reported to be inducible nitric oxide synthase (iNOS) dependent. In a previous study, we demonstrated that removing excess induced nitric oxide (NO) by administration of the NO scavenger NOX resulted in reduced PMN infiltration, attenuated liver injury, and improved survival. In this study, we examined the role of NOX treatment in down-modulating the inflammatory response in the liver following HS.


METHODS
Rats ( n=5) were subjected to severe HS with mean arterial blood pressure (MAP) of 40 mmHg for 100 min followed by resuscitation and killing at 24 h.


RESULTS
Shock animals demonstrated increased mRNA levels of interleukin (IL)-6 and intercellular adhesion molecule (ICAM)-1 and increased activation of the transcription factors nuclear factor kappa B (NF-kappa B) and signal transducers and activators of transcription 3 (Stat3). Treatment with NOX (30 mg/kg/h) infused 60 min following the onset of shock over 4 h resulted in significant reduction in cytokine mRNA expression and transcriptional factor activation. These results suggest that excessive NO contributes to hemorrhage-induced tissue inflammation and that reducing the bioavailability of NO using NOX may be beneficial in HS.


CONCLUSIONS
These data indicate that NOX prevents liver injury in this HS model, possibly through down-modulation of proinflammatory signaling and the shock-induced inflammatory response.
Hierholzer
C
C
Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. chrishierholzer@yahoo.com
Billiar
T R
TR
Tweardy
D J
DJ
Harbrecht
B
B
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D012771:Shock, Hemorrhagic / Q000188:drug therapy / Q000503:physiopathology*; D013012:Sorbitol / Q000031:analogs & derivatives; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; C404528:nitric oxide scavenger 100; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D013012:Sorbitol