F. Jaumann et al., Transforming growth factor-beta(1) is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line, EUR RESP J, 15(6), 2000, pp. 1052-1057
Obliterative bronchiolitis (OB) is the major long-term complication followi
ng lung and heart-lung transplantation. In bronchoalveolar lavage fluid sam
ples obtained from patients suffering from OB, a marked increase in the num
ber of neutrophils and elevated expression of transforming growth factor (T
GF)-beta(1) had been found. The goal of the study was to evaluate whether T
GF-beta(1) is capable of interfering with the expression of the secretory l
eukoprotease inhibitor (SLPI), the dominating defence of the conducting air
ways against neutrophil elastase (NE).
The authors analysed the effects of TGF-beta(1) on gene expression and prot
ein release of SLPI by cultured human bronchial epithelial (BEAS-2B) cells.
SLPI protein levels in the supernatants were quantified with a specific en
zyme-linked immunosorbent assay; SLPI messenger ribonucleic acid (mRNA) lev
els were measured by reverse transcriptase polymerase chain reaction.
Incubation with TGF-beta(1) induced a marked decrease in SLPI protein level
s (1 ng.mL(-1) TGF-beta(1): stimulation index (SI; protein: relation to SLP
I protein release of resting cells) = 0.56; 10 ng.mL(-1) TGF-beta(1): SI =
0.48; 50 ng.mL(-1) TGF-beta(1): SI = 0.37, p<0.01 each) and mRNA expression
(1 ng.mL(-1) TGF-beta(1): SI (SI mRNA: relation to SLPI mRNA expression of
resting cells) = 0.46; 10 ng.mL(-1) TGF-beta(1): SI = 0.31; 50 ng.mL(-1) T
GF-beta(1): SI=0.18, p<0.01 each) in a dose dependent fashion. Simultaneous
incubation of BEAS-2B cells with TGF-beta(1) and NE also caused a signific
ant reduction in SLPI synthesis (10 ng.mL(-1) TGF-beta(1) + 7.5 U.mL(-1) NE
: mRNA SI = 0.61, p<0.05; protein SI = 0.65, p<0.05; 50 ng.mL(-1) TGF-beta(
1) + 7.5 U.mL(-1) NE: mRNA SI = 0.52, p<0.05; protein SI = 0.58, p<0.05; 10
ng.mL(-1) TGF-beta(1): mRNA SI = 0.33, p<0.01; protein SI; = 0.38, p<0.01)
.
In conclusion, the data suggest that the coincidence of neutrophilia and up
regulation of transforming growth factor-beta(1) in obliterative bronchioli
tis may lead to uninhibited neutrophil elastase activity by downregulation
of secretory leukoprotease inhibitor, with the consequence of ongoing injur
y to the epithelium.