Transforming growth factor-beta1 and lung allograft fibrosis.
OBJECTIVE
Transforming growth factor beta1 (TGF-beta1) is a potent immunosuppressive cytokine that promotes fibrosis by enhancing the synthesis of extracellular matrix components. The repair process following lung allograft injury is due to rejection or infection replaces lung parenchyma by fibrotic tissue, leading to pulmonary dysfunction. The role of TGF-beta1 in this excessive healing process and increasing the risk of infection is unknown.


METHODS
We analysed our patient data to investigate the relevance of different factors on allograft fibrosis and its correlation with TGF-beta1. Fibrosis was graded in H and E stained sections. TGF-beta1 genotype was determined in all patients.


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 fibrosis diagnosed in transbronchial biopsies sections. Patients who had developed interstitial fibrosis had significantly more acute rejection episodes (mean 3.4 +/- 2.8) compared with patients without fibrosis (mean 2.1 +/- 2.2) (P = 0.024). The presence of eosinophils in the interstitium preceded and were associated with the development of fibrosis regardless of the rejection grade (P = 0.0001). TGF-beta1 was heavily expressed in sections with fibrosis with a mean score of 6.8 +/- 2.9 compared with 2.4 +/- 0.6 in sections with no fibrosis (P < 0.0001). TGF-beta1 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 scores < 6 (P = 0.0001). Patients who developed fibrosis had homozygous TGF-beta1 genotype that correlates with excessive TGF-beta1 expression (P = 0.01). The use of cardiopulmonary bypass was associated with the development of excessive fibrosis (P = 0.02), and 7 patients who had severe fibrosis died of septicaemia (17.5%). FEV1 (forced expiratory volume) was significantly higher in patients without fibrosis (1870 +/- 111 ml versus 1590 +/- 160; P = 0.02).


CONCLUSIONS
The risks of lung allograft fibrosis increases with recurrent rejection, tissue eosinophilia, homozygous TGF-beta1 genotype and the use of bypass machine. Fibrosis was associated with higher mortality and morbidity might be explained by the TGF-beta1 immunosuppressive and fibrotic properties. Immunological strategies to down-regulate TGF-beta1 production might improve survival and function of lung allografts.
El-Gamel
A
A
Cardiothoracic Transplant Unit, Wythenshawe Hospital, Manchester, UK. aelgamel@aol.com
Awad
M
M
Sim
E
E
Hasleton
P
P
Yonan
N
N
Egan
J
J
Deiraniya
A
A
Hutchinson
I V
IV
D000293:Adolescent; D000328:Adult; D015342:DNA Probes; D005355:Fibrosis; D005838:Genotype; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology*; D016040:Lung Transplantation / Q000473:pathology* / Q000502:physiology; D008875:Middle Aged; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous
D015342:DNA Probes; D016212:Transforming Growth Factor beta