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Granulocyte-macrophage colony-stimulating factor induces neutrophil
adhesion to pulmonary vascular endothelium in vivo: role of beta 2
integrins
KL Yong, PM Rowles, KG Patterson and DC Linch
Department of Haematology, University College and Middlesex School of
Medicine, London, UK.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) causes
upregulation of neutrophil surface CD11b/CD18 expression, and enhances the
adhesion of neutrophils to cultured human endothelial cells in vitro.
Systemic administration of GM-CSF results in a rapid, transient decrease in
circulating phagocyte numbers. Using a nonhuman primate model (Cynomolgus),
we provide histologic evidence that this transient leukopenia is associated
with the margination of neutrophils in the pulmonary microcirculation. In
four animals receiving 2 to 15 micrograms/kg recombinant human GM-CSF
(rhGM-CSF), light microscopic sections of lung contained 36 +/- 8, 17 +/-
7, 21 +/- 6, and 15 +/- 8 (mean +/- SD, n = 20) neutrophils within a
graticule grid, as compared with two control animals receiving saline
injections whose lung sections contained 2.1 +/- 1.6 and 3.1 +/- 2.1 (mean
+/- SD, n = 20) neutrophils within the same grid. Scanning electron
microscopy shows activated leukocytes adherent to pulmonary vascular
endothelium, but no morphologic evidence of endothelial damage, and no
migration of cells into the extravascular space. Margination is associated
with an increase in surface expression of CD11b/CD18 on circulating
phagocytes, which could contribute to the adhesion to capillary endothelial
cells, but CD11b/CD18 levels remain elevated even when demargination is
complete. In vitro, monoclonal antibodies (MoAbs) to CD18 and CD11b were
able to inhibit neutrophil aggregation and adhesion to endothelium.
FMLP-induced neutrophil aggregation was inhibited by 39.8% +/- 11.5% and
44.8% +/- 12.3%, respectively, by MoAbs to CD18 and CD11b (P less than
.0005, n = 4 for both); a similar effect was demonstrated on TPA-induced
aggregation. MoAb CD18 reduced the adhesion of unstimulated neutrophils to
endothelium by 44% (P less than .01, n = 7), and inhibited the amount of
GM-CSF-stimulated adhesion by 74% (P less than .001, n = 7), while MoAb to
CD11b produced a reduction of unstimulated neutrophil adhesion by 30%, and
of GM-CSF-stimulated adhesion by 40% (P less than .01, n = 5, for both).
However, when administered in vivo, MoAb CD18 produced only a small, albeit
significant, amelioration of GM-CSF-induced margination in vivo, while MoAb
CD11b was without effect. These results show that GM-CSF-induced transient
leukopenia is associated with enhanced neutrophil adherence to pulmonary
vascular endothelium, but suggest that the beta 2 leukocyte integrins
CD11/CD18 play only a minor role in this process.
Volume 80,
Issue 6,
pp. 1565-1575,
09/15/1992
Copyright © 1992 by The American Society of Hematology
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