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From the Department of Pathology*
and Internal
Medicine,
Division of Pulmonary and Critical
Care, University of Michigan Medical School, and the Department of
Pathology,
Veterans Affairs Medical Center,
Ann Arbor, Michigan
Recent studies support the concept that pulmonary granulomatous
inflammation directed by interferon (IFN)-
, interleukin
(IL)-12, and nitric oxide usually resolves in the absence of
fibrosis. To determine whether nitric oxide participates in modulating
the fibrotic response during the development of pulmonary granulomas in
response to purified protein derivative (PPD), mice
presensitized to PPD received daily intraperitoneal injections of
NG-nitro-D-arginine-methyl ester
(D-NAME),
NG-nitro-L-arginine-methyl ester
(L-NAME), or aminoguanidine after delivery of
PPD-coated beads to the lungs. Eight days later, morphometric
analysis of lung granulomas revealed that L-NAME-treated
mice when challenged with PPD in vitro for 36 hours had
the largest pulmonary granulomas and the greatest collagen deposition
among the treated groups. In addition, equivalent numbers of
dispersed lung cells from L-NAME- and
aminoguanidine-treated mice produced significantly higher levels of
IL-4, monocyte chemoattractant protein (MCP)-1, and
macrophage inflammatory protein (MIP)-1
and significantly lower
levels of eotaxin compared with D-NAME-treated mice.
Cultures of dispersed lung cells from L-NAME-treated mice
also produced significantly more IL-10 and less IL-12 compared with
similar numbers of dispersed lung cells from D-NAME-treated
mice. Cultures of isolated lung fibroblasts from
L-NAME-treated mice expressed higher levels of C-C
chemokine receptor 2 (CCR2) and CCR3 mRNA and contained less MCP-1 and
eotaxin protein than a similar number of fibroblasts from
D-NAME-treated mice. Thus, nitric oxide appears to
regulate the deposition of extracellular matrix in lung granulomas
through the modulation of the cytokine and chemokine profile of these
lesions. Alterations in the cytokine, chemokine, and
procollagen profile of this lesion may be a direct effect of nitric
oxide on the pulmonary fibroblast and provide an important signal for
regulating fibroblast activity during the evolution of chronic lung
disease.
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