ICAM-1 and CD11b inhibition worsen outcome in rats with E. coli pneumonia.
We investigated whether inhibiting an endothelial adhesion molecule [intracellular adhesion molecule 1 (ICAM-1)] would alter outcome and lung injury in a similar fashion to inhibition of a leukocyte adhesion molecule (integrin CD11b) in a rat model of gram-negative pneumonia. Inhibition of ICAM-1 with monoclonal antibody (MAb) 1A29 (1 mg/kg sc or 0.2 or 2 mg/kg iv, q 12 h x 3) or of CD11b with MAb 1B6 (1 mg/kg sc, q 12 h x 3) were compared against similarly administered placebo proteins in rats challenged with intrabronchial Escherichia coli. After challenge, all animals were treated with antibiotics. ICAM-1 MAb (6 mg/kg, iv, total dose) increased mortality vs. control (P = 0.03). CD11b MAb (3 mg/kg, sc, total dose) did not significantly (P = 0.16) increase mortality rates, but this was not in a range of probability to exclude a harmful effect. All other doses of MAb had no significant effect on survival rates. ICAM-1 and CD11b MAbs had significantly different effects on the time course of lung injury, circulating white cells and lymphocytes, and lung lavage white cells and neutrophils (P = 0.04-0.003). CD11b MAb decreased, whereas ICAM-1 MAb increased these measures compared with control from 6 to 12 h after E. coli. However, from 144 to 168 h after E. coli both MAbs increased these measures compared with control rats but to a greater level with CD11b MAb. Thus both ICAM-1 and CD11b appear to be necessary for survival during E. coli pneumonia. Although these adhesion molecules may participate differently in early lung injury, with CD11b increasing and ICAM-1 decreasing inflammation and injury, both are important for the resolution of later injury. During gram-negative pneumonia the protective roles of ICAM-1 and CD11b may make their therapeutic inhibition difficult.
Zeni
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F
Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892-1662, USA.
Parent
C
C
Correa
R
R
Natanson
C
C
Freeman
B
B
Fontana
J
J
Quezado
M
M
Danner
R L
RL
Fitz
Y
Y
Richmond
S
S
Gerstenberger
E
E
Banks
S M
SM
Eichacker
P Q
PQ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D004927:Escherichia coli Infections / Q000209:etiology / Q000276:immunology* / Q000628:therapy; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008168:Lung / Q000276:immunology; D055370:Lung Injury; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008297:Male; D018410:Pneumonia, Bacterial / Q000209:etiology / Q000276:immunology* / Q000628:therapy; D011379:Prognosis; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D016177:Macrophage-1 Antigen; D018799:Intercellular Adhesion Molecule-1