Distinct effects of systemic infusion of G-CSF vs. IL-6 on lung and liver inflammation and injury hemorrhagic shock

Production of pro-inflammatory cytokines, such as granulocyte colony-stimul ating factor (G-CSF) and interleukin-8 (IL-6) occurs at multiple tissue sit es in hemorrhagic shock (HS), resulting in elevated circulating plasma leve ls. The current study was designed to test the hypothesis that circulating G-CSF and IL-6 contribute to polymorphonuclear neutrophilic granulocyte (PM N)-mediated inflammation and organ injury in HS. Sprague-Dawley rats were s ubjected to decompensated HS (mean arterial blood pressure = 40 mm Hg for 2 .5 h), followed by resuscitation with lactated Ringer's solution with or wi thout G-CSF (3 mu g/kg) or IL-6 (3 mu g/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-kappa B and signal tra nsducer and activator or transcription (STAT) 3. infusion of G-CSF during r esuscitation increased PMN infiltration into the lungs by 2.4-fold (P < 0.0 1) compared with animals resuscitated with lactated Ringer's solution alone . Increased PMN infiltration was accompanied by interstitial edema and pneu mocyte swelling, resulting in a 42% increase in lung alveolar wall cross-se ctional 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 an d was accompanied by a 68% decrease in focal hepatocellular necrosis (P < 0 .01). Infusion of IL-6, in contrast, dramatically decreased inflammation an d 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)-kappa B activity. Thus, circulating G-CSF and IL-6 have opposing effects on PMN re cruitment and injury in the lung in HS while both protect against hepatic n ecrosis. The beneficial effect of these cytokines on liver injury in HS app ears to be independent of PMN recruitment.