Distinct effects of systemic infusion of G-CSF vs. IL-6 on lung and liver inflammation and injury in hemorrhagic shock.
Production of pro-inflammatory cytokines, such as granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) occurs at multiple tissue sites in hemorrhagic shock (HS), resulting in elevated circulating plasma levels. The current study was designed to test the hypothesis that circulating G-CSF and IL-6 contribute to polymorphonuclear neutrophilic granulocyte (PMN)-mediated inflammation and organ injury in HS. Sprague-Dawley rats were subjected to decompensated HS (mean arterial blood pressure = 40 mm Hg for 2.5 h), followed by resuscitation with lactated Ringer's solution with or without G-CSF (3 microg/kg) or IL-6 (3 microg/kg). Animals were killed 4 h after resuscitation, and their lungs and livers were assessed quantitatively for PMN infiltration, organ injury, and activation of NF-kappaB and signal transducer and activator or transcription (STAT) 3. Infusion of G-CSF during resuscitation increased PMN infiltration into the lungs by 2.4-fold (P < 0.01) compared with animals resuscitated with lactated Ringer's solution alone. Increased PMN infiltration was accompanied by interstitial edema and pneumocyte swelling, resulting in a 42% increase in lung alveolar wall cross-sectional surface area (P < 0.01) and a 3.7-fold increase in Stat3 activity (P < 0.01). G-CSF infusion did not affect PMN infiltration into the liver and was accompanied by a 68% decrease in focal hepatocellular necrosis (P < 0.01). Infusion of IL-6, in contrast, dramatically decreased inflammation and injury in both the lung and liver; the anti-inflammatory effects of IL-6 may be mediated, in part, by down-modulation of nuclear factor (NF)-kappaB activity. Thus, circulating G-CSF and IL-6 have opposing effects on PMN recruitment and injury in the lung in HS while both protect against hepatic necrosis. The beneficial effect of these cytokines on liver injury in HS appears to be independent of PMN recruitment.
Meng
Z H
ZH
Department of Medicine, Baylor College of Medicine, Houston, Texas, 77030, USA.
Dyer
K
K
Billiar
T R
TR
Tweardy
D J
DJ
D000818:Animals; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000633:toxicity*; D006520:Hepatitis, Animal / Q000209:etiology* / Q000503:physiopathology; D015850:Interleukin-6 / Q000008:administration & dosage / Q000633:toxicity*; D007511:Ischemia / Q000209:etiology*; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology; D011014:Pneumonia / Q000209:etiology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000633:toxicity; D015427:Reperfusion Injury / Q000209:etiology* / Q000503:physiopathology; D012151:Resuscitation; D050796:STAT3 Transcription Factor; D012771:Shock, Hemorrhagic / Q000150:complications* / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D009569:Nitric Oxide