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首页> 外文期刊>Thorax: The Journal of the British Thoracic Society >Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis.
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Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis.

机译：通过特发性肺纤维化中潜在的TGF-β1的激活和TGF-β受体（TβR-I和TβR-II）的差异表达来调节TGF-β1的作用。

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BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by subpleural fibrosis that progresses to involve all areas of the lung. The expression of transforming growth factor-beta1 (TGF-beta 1), a potent regulator of connective tissue synthesis, is increased in lung sections of patients with IPF. TGF-beta 1 is generally released in a biologically latent form (L-TGF-beta 1). Before being biologically active, TGF-beta must be converted to its active form and interact with both TGF-beta receptors type I and II (T beta R-I and T beta R-II). TGF-beta latency binding protein 1 (LTBP-1), which facilitates the release and activation of L-TGF-beta 1, is also important in the biology of TGF-beta 1. METHODS: Open lung biopsy samples from patients with IPF and normal controls were examined to localise T beta R-I, T beta R-II, and LTBP-1. Alveolar macrophages (AM) and bronchoalveolar lavage (BAL) fluid were examined using the CCL-64 bioassay to determine if TGF-beta is present in its active form in the lungs of patients with IPF. RESULTS: Immunoreactive L-TGF-beta 1 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-beta, respectively, while AM from the lower lobes of control patients secreted no active TGF-beta (p< or =0.01 for TGF-beta in the conditioned media from AM obtained from the lower lobes of IPF patients v normal controls). The difference in percentage active TGF-beta secreted by AM from the lower lobes of patients with IPF and the lower lobes of control patients was significant (p< or =0.01), but the difference between the total TGF-beta secreted from these lobes was not significant. The difference in active TGF-beta 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) fmol active TGF-beta, respectively (p< or =0.03). The percentage of active TGF-beta in the upper and lower lobes was 17.6 (1.0)% and 78.4 (1.6)%, respectively (p< or =0.03). In contrast, BAL fluid from control patients contained small amounts of L-TGF-beta. Using immunostaining, both T beta R-I and T beta R-II were present on all cells of normal lungs but T beta R-I was markedly reduced in most cells in areas of honeycomb cysts except for interstitial myofibroblasts in lungs of patients with IPF. TGF-beta 1 inhibits epithelial cell proliferation and a lack of T beta R-I expression by epithelial cells lining honeycomb cysts would facilitate repair of the alveoli by epithelial cell proliferation. However, the presence of both T beta Rs on fibroblasts is likely to result in a response to TGF-beta 1 for synthesis of connective tissue proteins. Our findings show that biologically active TGF-beta 1 is only present in the lungs of patients with IPF. In addition, the effects of TGF-beta 1 on cells may be further regulated by the expression of T beta Rs. CONCLUSION: Activation of L-TGF-beta 1 and the differential expression of T beta Rs may be important in the pathogenesis of remodelling and fibrosis in IPF.
机译：背景：特发性肺纤维化（IPF）的特征是胸膜下纤维化发展为累及肺的所有区域。 IPF患者的肺切片中，转化生长因子-beta1（TGF-beta 1）（一种有效的结缔组织合成调节剂）的表达增加。 TGF-beta 1通常以生物潜伏形式（L-TGF-beta 1）释放。在具有生物活性之前，必须将TGF-β转化成其活性形式并与I型和II型TGF-β受体（TβR-I和TβR-II）相互作用。 TGF-beta潜伏期结合蛋白1（LTBP-1）有助于L-TGF-beta 1的释放和激活，在TGF-beta 1的生物学中也很重要。方法：从IPF和检查正常对照以定位T beta RI，T beta R-II和LTBP-1。使用CCL-64生物测定法检查了肺泡巨噬细胞（AM）和支气管肺泡灌洗（BAL）液，以确定IPF患者肺部是否以活性形式存在TGF-β。结果：IPF患者的所有肺细胞中均存在免疫反应性L-TGF-β1，除了蜂窝囊肿上皮下区域的成纤维细胞外。 LTBP-1主要在晚期IPF区域的AM和蜂窝细胞内衬的上皮细胞中检测到。在正常肺中，在几个上午观察到LTBP-1免疫反应性。 IPF患者上叶和下叶的AM分别分泌1.6（0.6）fmol和4.1（1.9）fmol的活性TGF-beta，而对照患者下叶的AM不分泌活性TGF-beta（p <或=在条件培养基中，从IPF患者下叶与正常对照获得的AM中，TGF-β的含量为0.01。 IPF患者下叶和对照患者下叶由AM分泌的活性TGF-β百分比差异显着（p <或= 0.01），但这些叶所分泌的总TGF-β差异为不重要。 IPF患者上，下叶的AM条件培养基中活性TGF-beta的差异也无统计学意义。 IPF患者上，下叶的BAL液分别含有0.7（0.2）fmol和2.9（1.2）fmol活性TGF-β（p <或= 0.03）。上叶和下叶中活性TGF-β的百分比分别为17.6（1.0）％和78.4（1.6）％（p <或= 0.03）。相反，来自对照患者的BAL液含有少量的L-TGF-β。使用免疫染色，正常肺的所有细胞上都存在T beta R-1和T beta R-II，但是除IPF患者肺中的间质成纤维细胞外，蜂窝囊肿区域的大多数细胞中T beta R-1均显着降低。 TGF-β1抑制上皮细胞增殖，并且衬有蜂窝状囊肿的上皮细胞缺乏TβR-1表达将促进上皮细胞增殖对肺泡的修复。但是，在成纤维细胞上同时存在两个T beta Rs可能会导致对TGF-beta 1的反应，从而合成结缔组织蛋白。我们的发现表明，具有生物活性的TGF-beta 1仅存在于IPF患者的肺部。另外，TGF-β1对细胞的作用可以通过TβRs的表达来进一步调节。结论：L-TGF-beta 1的激活和T beta Rs的差异表达可能在IPF重塑和纤维化的发病机制中起重要作用。

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