Regulation of the effects of TGF-β1 by activation of latent TGF-β1 and differential expression of TGF-β receptors CTβR-I and TβR-II) in idiopathic Pulmonary fibrosis

Khalil, N.; Parekh, T. V.; O'Connor, R.; Antman, N.; Kepron, W.; Yehaulaeshet, T.; Xu, Y. D.; Gold, L. I.
December 2001
Thorax;Dec2001, Vol. 56 Issue 12, p907
Academic Journal
Background-Idiopathic Pulmonary brosis (IPF) is characterised by subpleural fibrosis that progresses to Involve areas of the lung. The expression of trai forming growth factor-β1 (TGF-β1), potent regulator of connective tissue synthesis, is increased in lung sections patients with IPF. TGF-β1 is general released in a biologically latent for (L-TGF-β1). Before being biologically a five, TGF-β must be converted to its active form and interact with both TGF-β1 receptors type I and II (TβR-I and Tβ1R-II) TGF-β latency binding protein 1 (LTB1-1), which facilitates the release and activation of L-TGF-β1, is also important in the biology of TGF-β1. Methods-Open lung biopsy samples from patients with IPF and normal control were examined to localise TβR-I, TβR-II and LTBP- 1. Alveolar macrophages (AM) and bronchoalveolar lavage (BAL) fluid were examined using the CCL-64 bioassay to determine if TGF-β is present in its active form in the lungs of patients with IPE Results-Immunoreactive L-TGF-β1 was present in all lung cells of patients with IPF except for fibroblasts in the subepithelial regions of honeycomb cysts. LTBP-1 was detected primarily in AM and epithelial cells lining honeycomb cysts in areas of advanced IPF. In normal lungs LTBP-1 immunoreactivity was observed in a few AM. AM from the upper and lower lobes of patients with IPF secreted 1.6 (0.6) fmol and 4.1 (1.9) fmol active TGF-β, respectively, while AM from the lower lobes of control patients secreted no active TGF-β (p ⩽ 0.01 for TGF-β in the conditioned media from AM obtained from the lower lobes of IPF patients v normal controls). The difference in percentage active TGF-β secreted by AM from the lower lobes of patients with IPF and the lower lobes of control patients was significant (p⩽0.01), but the difference between the total TGF-β secreted from these lobes was not significant. The difference in active TGF-β in conditioned media of AM from the Upper and lower lobes of patients with IPF was also not statistically significant. BAL fluid from the upper and lower lobes of patients with IPF contained 0.7 (0.2) fmol and 2.9 (1.2) finol active TGF-β, respectively (p ⩽ 0.03). The percentage of active TGF-β in the upper and lower lobes was 17.6 (1.0)% and 78.4 (1.6)%, respectively (p⩽0.03). In contrast, BAL fluid from control patients contained small amounts of L-TGF-p. Using immunostaining, both TβR-I and TβR-II were present on all cells of normal lungs but TβR-I was markedly reduced in most cells in areas of honeycomb cysts except for interstitial myofibroblasts in lungs of patients with IPE TGF-β1 inhibits epithelial cell proliferation and a lack of TβR-I expression by epithelial cells lining honey-comb cysts would facilitate repair of the alveoli by epithelial cell proliferation. However, the presence of both TβRs on fibroblasts is likely to result in a response to TGF-β1 for synthesis of connective tissue proteins. Our findings show that biologically active TGF-β1 is only present in the lungs of patients with IPF. In addition, the effects of TGF-β1 on cells may be further regulated by the expression of TβRs. Conclusion-Activation of L-TGF-β1 and the differential expression of TβRs may be important in the pathogenesis of remodelling and fibrosis in IPF.


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