Matrix metalloproteinase induction in post-transplant obliterative bronchiolitis.
BACKGROUND
Epithelial cell injury, inflammation, fibrosis, and airway obliteration are associated in post-transplant obliterative bronchiolitis. Fibrosis is a consequence of fibroblastic activity and of collagen deposition after disturbances in the balance of protein formation and degradation. Proteolytic enzymes such as the matrix metalloproteinases mediate degradation. To assess matrix metalloproteinases during obliterative bronchiolitis development, we studied porcine, heterotopic bronchial allografts.


METHODS
A total of 119 allografts or autografts were harvested serially at 3 to 60 days after transplantation and processed for histology and in situ hybridization for matrix metalloproteinases 2 and 9. Immunocytochemistry for vimentin and alpha-smooth-muscle-cell actin was performed with specific antibodies.


RESULTS
Implants had initial ischemic injury to airway epithelium and to the bronchial wall. Recovery was rapid in autografts and in immunosuppressed allografts. In matrix metalloproteinase-2 mRNA activity in fibroblasts, correlation with endothelial expression and expression in macrophages occurred during intense fibroproliferation. We observed intense matrix metalloproteinase-9 positivity during onset of inflammation and fibroproliferation in endothelial cells (p < 0.01), fibroblasts (p < 0.05), macrophages (p < 0.05), and lymphocytes (p < 0.05). Matrix metalloproteinase-9 mRNA activity in fibroblasts correlated with that in endothelial and inflammatory cells and also proved predictive of early obliteration.


CONCLUSIONS
Matrix metalloproteinase-2, and especially matrix metalloproteinase-9, gene activity was associated with onset of inflammation and fibroblastic proliferation in allografts, predicting early obliteration. Although this may be the case in the model described, its role in human-allograft post-transplant obliterative bronchiolitis requires further supportive data.
Eerola
Leena M
LM
Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
Alho
Hanni S
HS
Maasilta
Paula K
PK
Inkinen
Kaija A
KA
Harjula
Ari L J
AL
Litmanen
Sisko H
SH
Salminen
Ulla-Stina
US
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001980:Bronchi / Q000201:enzymology / Q000473:pathology / Q000637:transplantation; D001989:Bronchiolitis Obliterans / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016040:Lung Transplantation / Q000009:adverse effects* / Q000473:pathology; D008214:Lymphocytes / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000473:pathology; D013552:Swine
D015415:Biomarkers; D012333:RNA, Messenger; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9