TRANSFORMING GROWTH FACTOR-BETA(1) AND LUNG ALLOGRAFT FIBROSIS

Objectives: Transforming growth factor beta(1) (TGF-beta(1)) is a pote nt immunosuppressive cytokine that promotes fibrosis by enhancing the synthesis of extracellular matrix components. The repair process follo wing lung allograft injury is due to rejection or infection replaces l une parenchyma by fibrotic tissue; leading to pulmonary dysfunction. T he role of TGF-beta(1) in this excessive healing process and increasin g the risk of infection is unknown. Methods: We analysed our patient d ata to investigate the relevance of different factors on allograft fib rosis and its correlation with TGF-beta(1). Fibrosis was graded in H a nd E stained sections. TGF-beta(1) genotype was determined in all pati ents. Results: Patients were aged between 16 and 62 years (mean age of 39.6 years). Procedures were heart/lung (n = 32), double lung (n = 18 ), and SLT (n = 41). A total of 46 patients had lung allograft fibrosi s diagnosed in transbronchial biopsies sections. Patients who had deve loped interstitial fibrosis had significantly more acute rejection epi sodes (mean 3.4 +/- 2.8) compared with patients without fibrosis (mean 2.1 +/- 2.2) (P = 0.024). The presence of eosinophils in the intersti tium preceded and were associated with the development of fibrosis reg ardless of the rejection grade (P = 0.0001). TGF-beta(1) was heavily e xpressed in sections with fibrosis with a mean score of 6.8 +/- 2.9 co mpared with 2.4 +/- 0.6 in sections with no fibrosis (P<0.0001). TGF-b eta(1) expression correlated positively with fibrosis grades (P<0.0001 ). The mean survival for patients with a fibrosis score > 6 is 892.4 /- 73 days compared with mean survival 427 +/- 78 in patients with sco res < 6 (P = 0.0001). Patients who developed fibrosis had homozygous T GF-beta(1) genotype that correlates with excessive TGF-beta(1) express ion (P = 0.01). The use of cardiopulmonary bypass was associated with the development of excessive fibrosis (P = 0.02), and 7 patients who h ad severe fibrosis died of septicaemia (17.5%). FEVI (Forced expirator y volume) was significantly higher in patients without fibrosis (1870 +/- 111 ml versus 1590 +/- 160; P = 0.02). Conclusions: The risks of l ung allograft fibrosis increases with recurrent rejection, tissue eosi nophilia, homozygous TGF-beta(1) genotype and the use of bypass machin e, Fibrosis was associated with higher mortality and morbidity might b e explained by the TGF-beta(1) immunosuppressive and fibrotic properti es. Immunological strategies to down-regulate TGF-beta(1), production might improve survival and function of lung allografts, (C) 1998 Elsev ier Science B.V, All rights reserved.