Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

Obliterative bronchiolitis (OB) is the major long-term complication following lung and heart-lung transplantation. In bronchoalveolar lavage fluid samples obtained from patients suffering from OB, a marked increase in the number of neutrophils and elevated expression of transforming growth factor (TGF)-beta(1) had been found. The goal of the study was to evaluate whether TGF-beta(1) is capable of interfering with the expression of the secretory leukoprotease inhibitor (SLPI), the dominating defence of the conducting airways against neutrophil elastase (NE). The authors analysed the effects of TGF-beta(1) on gene expression and protein release of SLPI by cultured human bronchial epithelial (BEAS-2B) cells. SLPI protein levels in the supernatants were quantified with a specific enzyme-linked immunosorbent assay; SLPI messenger ribonucleic acid (mRNA) levels were measured by reverse transcriptase polymerase chain reaction. Incubation with TGF-beta(1) induced a marked decrease in SLPI protein levels (1 ng.mL(-1) TGF-beta(1): stimulation index (SI; protein: relation to SLPI 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) TGF-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 significant 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 upregulation of transforming growth factor-beta(1) in obliterative bronchiolitis may lead to uninhibited neutrophil elastase activity by downregulation of secretory leukoprotease inhibitor, with the consequence of ongoing injury to the epithelium.