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to Rat Lung Induces Severe Pulmonary Inflammation and Patchy Interstitial Fibrogenesis with Induction of Transforming Growth Factor-ß1 and Myofibroblasts
From the Rayne Laboratory,*
Respiratory Medicine Unit,
University of Edinburgh, Edinburgh, Scotland, and Departments of
Biology
and
Pathology,
McMaster University, Hamilton,
Ontario, Canada
Tumor necrosis factor-
is up-regulated in a variety of different
human immune-inflammatory and fibrotic pulmonary pathologies.
However, its precise role in these pathologies and, in
particular, the mechanism(s) by which it may induce
fibrogenesis are not yet elucidated. Using a replication-deficient
adenovirus to transfer the cDNA of tumor necrosis factor- to rat
lung, we have been able to study the effect of transient but
prolonged (7 to 10 days) overexpression of tumor necrosis factor- in
normal adult pulmonary tissue. We have demonstrated that local
overexpression resulted in severe pulmonary inflammation with
significant increases in neutrophils, macrophages, and
lymphocytes and, to a lesser extent,
eosinophils, with a peak at day 7. By day 14, the
inflammatory cell accumulation had declined, and fibrogenesis
became evident, with fibroblast accumulation and deposition of
extracellular matrix proteins. Fibrotic changes were patchy but
persisted to beyond day 64. To elucidate the mechanism underlying this
fibrogenesis, we examined bronchoalveolar fluids for the
presence of the fibrogenic cytokine transforming growth factor-ß1 and
tissues for induction of -smooth muscle actin-rich myofibroblasts.
Transforming growth factor-ß1 was transiently elevated from day 7
(peak at day 14) immediately preceding the onset of fibrogenesis.
Furthermore, there was a striking accumulation of
myofibroblasts from day 7, with the most extensive and intense
immunostaining at day 14, ie, coincident with the
up-regulation of transforming growth factor-ß1 and onset of
fibrogenesis. Thus, we have provided a model of tumor necrosis
factor--mediated pulmonary inflammation and fibrosis in normal adult
lung, and we suggest that the fibrogenesis may be mediated by
the secondary up-regulation of transforming growth factor-ß1 and
induction of pulmonary myofibroblasts.
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