Yehualaeshet T, O'Connor R, Begleiter A, Murphy-Ullrich J E, Silverstein R, Khalil N
Departments of Internal Medicine and Pathology, and the Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Mannitoba, British Columbia, Canada.
Am J Respir Cell Mol Biol. 2000 Aug;23(2):204-12. doi: 10.1165/ajrcmb.23.2.4089.
Transforming growth factor (TGF)-beta1 is an important regulator of inflammation and fibrosis. TGF-beta1 is usually secreted as a biologically latent protein called latent TGF-beta1 (L-TGF-beta1). L-TGF-beta1 has no biologic effect unless L-TGF-beta1 is converted to its active form. Using a well-recognized model of lung injury induced by the antineoplastic antibiotic bleomycin (Blm), we demonstrated that 7 d after intratracheal Blm administration, total lung TGF-beta was maximally increased. This induction was due to TGF-beta1 production by alveolar macrophages that, when explanted, generated increased quantities of L-TGF-beta1 complexed with the glycoprotein thrombospondin (TSP)-1. The TSP-1/L-TGF-beta1 complex was associated with CD36, a receptor for TSP-1. The association of TSP-1/L-TGF-beta1 to CD36 was critical for plasmin-mediated release of mature TGF-beta1. In this paper we show that, compared with administration of Blm by itself, when a synthetic peptide of CD36 between amino acids 93 and 110 is given concomitantly with Blm to rats, alveolar macrophages generate markedly less active TGF-beta1, the rats gain weight more rapidly, and there is less inflammation, collagen I and III, and fibronectin synthesis. These findings demonstrate a novel in vivo mechanism of activation of L-TGF-beta1 in lung injury and the importance of alveolar macrophage- derived active TGF-beta1 in the pathogenesis of pulmonary inflammation and fibrosis.
转化生长因子（TGF）-β1是炎症和纤维化的重要调节因子。TGF-β1通常以一种称为潜伏性TGF-β1（L-TGF-β1）的生物学潜伏蛋白形式分泌。L-TGF-β1没有生物学效应，除非它转化为其活性形式。使用一种公认的由抗肿瘤抗生素博来霉素（Blm）诱导的肺损伤模型，我们证明在气管内给予Blm后7天，肺组织中总的TGF-β含量最大程度增加。这种诱导是由于肺泡巨噬细胞产生TGF-β1，当将这些肺泡巨噬细胞移出体外时，会产生与糖蛋白血小板反应蛋白（TSP）-1复合的L-TGF-β1的量增加。TSP-1/L-TGF-β1复合物与TSP-1的受体CD36相关联。TSP-1/L-TGF-β1与CD36的结合对于纤溶酶介导的成熟TGF-β1的释放至关重要。在本文中我们表明，与单独给予Blm相比，当将氨基酸93至110之间的CD36合成肽与Blm同时给予大鼠时，肺泡巨噬细胞产生的活性TGF-β1明显减少，大鼠体重增加更快，并且炎症、I型和III型胶原蛋白以及纤连蛋白的合成减少。这些发现证明了肺损伤中L-TGF-β1激活的一种新的体内机制，以及肺泡巨噬细胞衍生的活性TGF-β1在肺部炎症和纤维化发病机制中的重要性。
