Neutrophil stimulation with granulocyte colony-stimulating factor worsens ventilator-induced lung injury and mortality in rats.
BACKGROUND
Based on the association between the neutrophil and ventilator-induced lung injury, the authors hypothesized that neutrophil inhibition with fucoidin would be beneficial and stimulation with granulocyte colony-stimulating factor (G-CSF) would be harmful in a rat model of lethal ventilator-induced lung injury.


METHODS
Animals (n = 111) were randomly assigned to be pretreated with fucoidin, G-CSF, or placebo (control) before 4 h of low-tidal-volume (10 ml/kg) or high-tidal-volume (40 ml/kg) mechanical ventilation.


RESULTS
All low-volume animals survived. With high volumes, compared with controls, fucoidin did not improve survival (3 of 20 control animals and 5 of 20 fucoidin animals died; P = 0.51) but G-CSF significantly worsened it (18 of 22 animals died; P < 0.001). Circulating neutrophils were increased early with G-CSF and late with fucoidin with low and high tidal volumes (P < 0.05 for each treatment and tidal volume). Fucoidin decreased lung neutrophils, but these were only significant with high tidal volumes, whereas G-CSF increased lung neutrophils but only significantly with low tidal volumes (P < or = 0.01 for each). Fucoidin did not alter any cardiopulmonary measure significantly. Compared with control, G-CSF increased airway pressures with high tidal volumes and worsened lung edema and arterial oxygen with both tidal volumes (P < 0.05 for each).


CONCLUSIONS
In this model, neutrophil stimulation by G-CSF increased lung dysfunction and with high tidal volumes worsened survival rates. Extrapolated clinically, neutrophil stimulation either by agents such as G-CSF or conditions such as sepsis may aggravate ventilator-induced lung injury.
Karzai
Waheedullah
W
Department of Anesthesiology and Critical Care Medicine, Friedrich-Schiller-University Hospital, Jena, Germany. ana@zentralklinik-bad-berka.de
Cui
Xizhong
X
Heinicke
Norbert
N
Niemann
Christian
C
Gerstenberger
Eric P
EP
Correa
Rosaly
R
Banks
Steven
S
Mehlhorn
Bjoern
B
Bloos
Frank
F
Reinhart
Konrad
K
Eichacker
Peter Q
PQ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002404:Catheterization; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D010243:Paralysis / Q000139:chemically induced; D011134:Polysaccharides / Q000494:pharmacology; D011654:Pulmonary Edema / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000401:mortality*; D012129:Respiratory Function Tests; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D012122:Ventilators, Mechanical / Q000009:adverse effects*
D000900:Anti-Bacterial Agents; D015850:Interleukin-6; D011134:Polysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; C007789:fucoidan