Nitric oxide in the development of obliterative bronchiolitis in a heterotopic pig model

  • Salminen U
  • Maasilta P
  • Harjula A
 et al. 
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Abstract

Background. Inflammation, epithelial cell injury,
and development of fibrosis and airway obliteration
are the major histological features of posttransplant
obliterative bronchiolitis (OB). The expression of in-
ducible nitric oxide synthase (iNOS) in the damaged
epithelium, accompanied by peroxynitrite, suggests
that endogenous nitric oxide (NO) mediates the epi-
thelial destruction preceding obliteration. To eluci-
date the role of NO in this cascade, heterotopic bron-
chial allografts were studied in pigs.
Methods. Allografts or autografts were harvested se-
rially 3–90 days after transplantation and processed
for histology and immunocytochemistry for iNOS, ni-
trotyrosine, a marker of peroxynitrite formation, and
superoxide dismutase (SOD).
Results. During initial ischemic damage to the epi-
thelium, iNOS, nitrotyrosine, and SOD were found to
be strongly expressed in the epithelium of all implants
as well as later, after partial recovery, parallel to onset
of epithelial destruction and subsequent airway oblit-
eration in allografts. The levels of expression of iNOS
in fibroblasts during the early phase of obliteration
paralleled the onset of fibrosis. Constant expression of
iNOS and SOD, but not nitrotyrosine, occurred in au-
tografts and allografts with blocked alloimmune
response.
Conclusions. These findings suggest that an exces-
sive amount of NO promotes posttransplant oblitera-
tive bronchiolitis by destroying airway epithelium
and stimulating fibroblast activity. SOD may provide
protection by binding reactive molecules and prevent-
ing peroxynitrite formation.

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Authors

  • Ulla Stina Salminen

  • Paula K. Maasilta

  • Ari L.J. Harjula

  • Hanna M. Romanska

  • Anne E. Bishop

  • Julia M. Polak

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