Cyclooxygenase-2 expression in experimental post-transplant obliterative bronchiolitis.
Epithelial cell injury, inflammation, progressive fibrosis, and airway obliteration are histological features of post-transplant obliterative bronchiolitis (OB). Cyclooxygenase (COX)-2 is expressed in acute and chronic inflammatory responses. Our aim was to elucidate the possible role of COX-2 in post-transplant OB by using a heterotopic bronchial porcine model. Bronchial allografts from non-related donors were transplanted subcutaneously into 24 random-bred domestic pigs, each weighing about 20 kg. Groups studied had grafts, non-treated allografts, allografts given cyclosporine A (CsA), methylprednisolone (MP), and azathioprine (Aza), and allografts given CsA, MP, and everolimus. Grafts were serially harvested during a follow-up period of 21 days for histology (H&E) and immunohistochemistry. Immunostaining was performed with monoclonal IgG against human COX-2 peptide, and histological alterations and immunohistochemical positivity were graded on a scale from 0 to 5. Epithelial COX-2 index was calculated by multiplying the percentage of positive cells by grade of epithelial COX-2 intensity. Ischaemic epithelial loss, evident in all implants, recovered rapidly in autografts, and bronchi remained patent. Epithelial loss in non-treated allografts preceded fibroblast proliferation, resulting in total luminal obliteration. In CsA-, MP-, and Aza-treated allografts epithelial destruction and luminal obliteration were delayed, and these were prevented in CsA-, MP-, and everolimus-treated allografts. COX-2 expression due to operative ischaemia was evident in all implants on day 2. Thereafter, the epithelial COX-2 index preceded epithelial injury and obliteration. During the inflammatory response and fibroblast proliferation, COX-2 expression occurred in macrophages and fibroblasts. In conclusion, in the early stage of OB development, COX-2 induction occurred in airway epithelial cells prior to luminal obliteration. In addition, the observation that COX-2 expression in macrophages and fibroblasts paralleled the onset of inflammation and fibroblast proliferation indicates a role in OB development, but the causal relationships need further study.
Department of Surgery, Helsinki University Hospital, Finland.
Outi E
OE
Päiväniemi
Paula K
PK
Maasilta
Hanni S
HS
Alho
C Henrik J
CH
Wolff
Ulla-Stina
US
Salminen
D000818:Animals; D001379:Azathioprine / Q000627:therapeutic use; D001980:Bronchi / Q000473:pathology / Q000637:transplantation*; D001989:Bronchiolitis Obliterans / Q000201:enzymology* / Q000473:pathology; D019902:Chondrocytes / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D000068338:Everolimus; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007527:Isoenzymes / Q000032:analysis*; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008775:Methylprednisolone / Q000627:therapeutic use; D011184:Postoperative Period; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013552:Swine
D007166:Immunosuppressive Agents; D007527:Isoenzymes; D016572:Cyclosporine; D000068338:Everolimus; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D001379:Azathioprine; D020123:Sirolimus; D008775:Methylprednisolone