Acute G-CSF therapy is not protective during lethal E. coli sepsis.
We investigated whether decreases in circulating polymorphonuclear neutrophils (PMN) during lethal Escherichia coli (E. coli) sepsis in canines are related to insufficient host granulocyte colony-stimulating factor (G-CSF). Two-year-old purpose-bred beagles had intraperitoneal E. coli-infected or -noninfected fibrin clots surgically placed. By 10 to 12 h following clot, both infected survivors and nonsurvivors had marked increases (P = 0.001) in serum G-CSF levels (mean peak G-CSF ng/ml +/- SE, 1,931 +/- 364 and 2,779 +/- 681, respectively) compared with noninfected controls (134 +/- 79), which decreased at 24 to 48 h. Despite increases in G-CSF, infected clot placement caused delayed (P = 0.06) increases in PMN (mean +/- SE change from baseline in cells x 10(3)/mm(3) at 24 and 48 h) in survivors (+3.9 +/- 3.9 and +13.8 +/- 3.6) compared with noninfected controls (+13.1 +/- 2.8 and +9.1 +/- 2.5). Furthermore, infected nonsurvivors had decreases in PMN (-1.4 +/- 1.0 and -1.1 +/- 2.3, P = 0.006 compared with the other groups). We next investigated whether administration of G-CSF immediately after clot placement and continued for 96 h to produce more rapid and prolonged high levels of G-CSF after infection would alter PMN levels. Although G-CSF caused large increases in PMN compared with control protein from 2 to 48 h following clot in noninfected controls, it caused much smaller increases in infected survivors and decreases in infected nonsurvivors (P = 0.03 for the ordered effect of G-CSF comparing the three groups). Thus insufficient host G-CSF is unlikely the cause of decreased circulating PMN in this canine model of sepsis. Other factors associated with sepsis either alone or in combination with G-CSF itself may reduce increases or cause decreases in circulating PMN.
Quezado
Z
Z
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA.
Parent
C
C
Karzai
W
W
Depietro
M
M
Natanson
C
C
Hammond
W
W
Danner
R L
RL
Cui
X
X
Fitz
Y
Y
Banks
S M
SM
Gerstenberger
E
E
Eichacker
P Q
PQ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D006334:Heart Function Tests / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D017211:Treatment Failure
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor