Growth Factor Upregulation during Obliterative Bronchiolitis in the Mouse Model

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Abstract
Obliterative bronchiolitis (OB), or chronic allograft rejection, is a major cause of morbidity and mortality after lung transplantation. The goal of these experiments was to determine whether several important growth factors were upregulated during OB in the mouse heterotopic trachea model. Isografts (BALB/c into BALB/c) and allografts (BALB/c into C57BL/6) were implanted in three sets of cyclosporine-treated animals and were harvested from 2 to 10 weeks. Ribonucleic acid was isolated using the cesium chloride-guanidine method and was reverse transcribed and semiquantitated with the polymerase chain reaction using specific primers for platelet-derived growth factor (PDGF)-A and PDGF-B chains, fibroblast growth factor (FGF) isoforms 1 and 2, transforming growth factor-beta, tumor necrosis factor-alpha (TNF-alpha), edothelin-1, (prepro) epidermal growth factor, insulin-like growth factor-1, and beta-actin as a control. Transforming growth factor-beta, TNF-alpha, endothelin-1, and insulin-like growth factor-1 expression were increased 1.5-fold to 5.0-fold (p < or = 0.04 for each) in the allografts compared with the isografts at Weeks 2 through 6. Significantly increased expression of FGF-1, FGF-2, and PDGF-B was noted in the allografts at 4 weeks (p < 0.05 for each), which reversed at 6 and 10 weeks. No differences were found with the PDGF-A chain. The isografts expressed more epidermal growth factor than allografts (p < 0.001). Treatment with a TNF-alpha-soluble receptor (human TNFR:Fc) significantly reduced epithelial injury (p = 0.01) and lumenal obstruction (p = 0.037) in this model. We conclude that increased expression of a large number of growth factors occurs during OB in this model. Growth factor blockade (in particular with regard to TNF-alpha) may be useful in ameliorating OB in this model.