Nitric oxide in the development of obliterative bronchiolitis in a heterotopic pig model.
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 inducible nitric oxide synthase (iNOS) in the damaged epithelium, accompanied by peroxynitrite, suggests that endogenous nitric oxide (NO) mediates the epithelial destruction preceding obliteration. To elucidate the role of NO in this cascade, heterotopic bronchial allografts were studied in pigs.


METHODS
Allografts or autografts were harvested serially 3-90 days after transplantation and processed for histology and immunocytochemistry for iNOS, nitrotyrosine, a marker of peroxynitrite formation, and superoxide dismutase (SOD).


RESULTS
During initial ischemic damage to the epithelium, 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 obliteration 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 autografts and allografts with blocked alloimmune response.


CONCLUSIONS
These findings suggest that an excessive amount of NO promotes posttransplant obliterative bronchiolitis by destroying airway epithelium and stimulating fibroblast activity. SOD may provide protection by binding reactive molecules and preventing peroxynitrite formation.
Salminen
Ulla-Stina
US
Tissue Engineering Centre, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, UK.
Maasilta
Paula K
PK
Harjula
Ari L J
AL
Romanska
Hanna M
HM
Bishop
Anne E
AE
Polak
Julia M
JM
D000818:Animals; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D002455:Cell Division; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology; D016040:Lung Transplantation / Q000009:adverse effects* / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D013552:Swine; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase