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d in IgG Immune Complex-Induced Rat Lung Injury1 ,2
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and ICOS Corporation, Bothwell, WA 98021
d is a newly cloned adhesion molecule that forms a heterodimer
with CD18. The requirement for
d in IgG immune complex-induced lung
injury in rats has been evaluated by the use of blocking polyclonal and
monoclonal antibodies to rat
d. Using whole lung extracts, Northern
and Western blot analyses have revealed up-regulation of mRNA and
d
protein in inflamed lungs. Immunostaining has revealed the presence of
d in lung tissue and in alveolar macrophages as early as 1 h
after initiation of the inflammatory reaction. When polyclonal rabbit
Ab to rat
d was coinstilled into lung together with Ab to BSA, lung
injury (as determined by leakage of [125I]albumin into
lung parenchyma) was significantly diminished. In parallel, there was
reduced accumulation of neutrophils recoverable in bronchoalveolar
lavage (BAL) fluids. These findings were associated with reduced levels
of TNF-
as well as
NO2-/NO3- in BAL
fluids. A hamster mAb to rat
d was also protective in this lung
injury model. Anti-
d inhibited in vitro production of
NO2-/NO3- by rat
alveolar macrophages (stimulated with LPS and IFN-
) by approximately
60%. These data suggest that, in the lung inflammatory model employed,
d up-regulation occurs in lung macrophages and is necessary for
expression of TNF-
, recruitment of neutrophils, and full development
of lung injury.
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