A nitric oxide scavenger protects against pulmonary inflammation following hemorrhagic shock.
Hemorrhagic shock (HS) elicits an inflammatory response characterized by increased cytokine production and recruitment of PMN which we previously found to be iNOS dependent. In this study we attempted to remove excess induced-NO by administration of the NO scavenger, NOX, with the goal of suppressing proinflammatory signaling and reducing organ damage. Rats subjected to HS (MAP = 40 mmHg for 100 min) followed by resuscitation and examined 24 h later demonstrated histological signs of lung injury including pulmonary edema as well as an 8.6-fold increase in MPO-positive PMN. These events were accompanied by a 3.9-fold increase in mRNA levels for IL-6, 3.7-fold for ICAM-1, 3.5-fold for IL-1beta, and 7.3-fold for TNFalpha compared to sham animals. Immunostaining of the lungs of shock animals demonstrated IL-6 protein localized to cells lining the luminal sides of bronchiols. These animals also demonstrated a 2-fold and 5.5-fold increase in activation of NF-kappaB and Stat3 (an IL-6 signaling intermediate), respectively. Administration of NOX (30 mg/kg/h beginning at 60 min of shock for total of 4.5 h) resulted in reduced lung injury as measured by a 46% reduction in PMN infiltration, a 20% decrease in wet-to-dry ratio, and improved arterial blood gases. NOX reduced proinflammatory signaling in the lung as demonstrated by a 62% decrease in NF-kappaB binding, 47% reduction in Stat3 binding, a reduction in mRNA expression of 48% for IL-6, 57% for ICAM-1, 67% for IL-1beta, and 64% for TNFalpha, as well as a marked reduction in the intensity of IL-6 protein staining. These data indicate that NOX prevents lung injury in this HS model, possibly through downmodulation of proinflammatory signaling and the shock-induced inflammatory response.
Hierholzer
Christian
C
Department of Surgery, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
Menezes
John M
JM
Ungeheuer
Andreas
A
Billiar
Timothy R
TR
Tweardy
David J
DJ
Harbrecht
Brian G
BG
D000818:Animals; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D016166:Free Radical Scavengers / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D012771:Shock, Hemorrhagic / Q000150:complications*; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide