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* Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612; and
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109
NO is a crucial mediator of the inflammatory response, but its in
vivo role as a determinant of lung inflammation remains unclear. We
addressed the in vivo role of NO in regulating the activation of
NF-
B and expression of inflammatory proteins using an in vivo mouse
model of sepsis induced by i.p. injection of Escherichia
coli. We observed time-dependent degradation of IB and
activation of NF-B accompanied by increases in inducible NOS,
macrophage inflammatory protein-2 (MIP-2), and ICAM-1 expression after
E. coli challenge, which paralleled the ability of lung
tissue to produce high-output NO. To determine the role of NO in this
process, mice were pretreated with the NO synthase (NOS) inhibitor
NG-methyl-L-arginine. Despite having
relatively modest effects on NF-B activation and ICAM-1 or inducible
NOS expression, the NOS inhibitor almost completely inhibited
expression of MIP-2 in response to E. coli challenge.
These responses were associated with the inhibition of migration of
neutrophils in lung tissue and increased permeability induced by
E. coli. In mice pretreated with
NG-methyl-L-arginine, coadministration of
E. coli with the NO donor
(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate
substantially restored MIP-2 expression but decreased ICAM-1
expression. The results suggest that NO generated after administration
of E. coli serves as an important proinflammatory signal
to up-regulate MIP-2 expression in vivo. Thus, NO production in high
quantities may be important in the mechanism of amplification of the
lung inflammatory response associated with
sepsis.
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