Controlled trials of rG-CSF and CD11b-directed MAb during hyperoxia and E. coli pneumonia in rats.
We studied the effects of inhibiting and augmenting neutrophil function by using an immunocompetent rat model of infectious and hyperoxic lung injury. After intrabronchial Escherichia coli challenge at all fractional inspired O2 (FIO2) values studied (FIO2 = 0.21, 0.60, and 0.95) and after lethal O2 exposure alone (FIO2 = 0.90), lung injury, as measured by histological and physiological changes, was reduced by a CD11b/CD18-directed monoclonal antibody (MAb 1B6, P < 0.05 vs. controls) but was increased by recombinant granulocyte colony-stimulating factor (rG-CSF; P < 0.05 vs. control; MAb 1B6 vs. rG-CSF, P < 0.004). Pulmonary neutrophil counts were reduced by MAb 1B6 (P < 0.04) and increased by rG-CSF (P < 0.0004) compared with control animals. However, despite antibiotics, MAb 1B6 and rG-CSF both significantly increased the relative risk of death, independent of O2 concentration, during E. coli pneumonia (1.74 [symbol: see text] 1.20 and 2.39 [symbol: see text] 1.19, respectively, each P < 0.01). During lethal hyperoxia, MAb 1B6 increased the relative risk of death (1.76 [symbol: see text] 1.28, P < 0.16), whereas rG-CSF had no effect on survival (0.97 [symbol: see text] 1.28, P = 0.89). Thus inhibition of neutrophil function attenuated and enhancement worsened lung injury in response to infectious and hyperoxic challenges, supporting a pathophysiological role of the neutrophil in these processes. However, it is problematic that MAb 1B6 therapy, despite preventing lung damage, ultimately worsened host defenses and survival. Furthermore, rG-CSF also adversely affected survival during infectious lung injury, demonstrating the inherent risks of inhibiting or augmenting neutrophil function in an immunocompetent host during infection.
Freeman
B D
BD
Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892-1662, USA.
Correa
R
R
Karzai
W
W
Natanson
C
C
Patterson
M
M
Banks
S
S
Fitz
Y
Y
Danner
R L
RL
Wilson
L
L
Eichacker
P Q
PQ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004926:Escherichia coli; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D016023:Integrins / Q000276:immunology*; D055370:Lung Injury; D008297:Male; D010100:Oxygen / Q000633:toxicity*; D011014:Pneumonia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D016023:Integrins; D016179:Granulocyte Colony-Stimulating Factor; D010100:Oxygen