Plasmin regulates the activation of cell-associated latent TGF-beta(1) secreted by rat alveolar macrophages after in vivo bleomycin injury
Plasmin regulates the activation of cell-associated latent TGF-beta(1) secreted by rat alveolar macrophages after in vivo bleomycin injury
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DOI：
10.1165/ajrcmb.15.2.8703482
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发表时间：
1996-08-01
影响因子：
6.4
通讯作者：
Yacyshyn, H
中科院分区：
文献类型：
--
作者：
Khalil, N;Corne, S;Yacyshyn, H
转化生长因子β（TGF-β）是调节炎症和结缔组织合成的25-kD多功能蛋白质。除了极少数例外，TGF-β（1）分泌时与潜伏相关肽（LTP）非共价结合，使成熟的TGF-β（1）失去生物活性。控制TGF-β（1）作用的一个重要机制是调节翻译后加工，该加工从成熟肽中去除β 2并使其具有生物活性。在一个由抗生素博莱霉素诱导的肺部炎症和纤维化模型中，我们已经证明，肺泡巨噬细胞分泌的TGF-β（1）的生物活性形式的数量逐渐增加，在博莱霉素给药后7天分泌量达到最大。此后，TGF-β（1）活性形式的分泌迅速下降，而潜伏形式的分泌量继续增加。纤溶酶是一种丝氨酸蛋白酶，由相同的博来霉素激活的肺泡巨噬细胞瞬时产生，并抑制活性TGF-β的升高（1）。当α（2）-抗纤溶酶（纤溶酶的抑制剂）加入肺泡巨噬细胞培养物中时，L-TGF-β（1）的翻译后激活被完全消除。当将纤溶酶添加到培养物中的肺泡巨噬细胞中时，培养期间分泌的L-TGF-β（1）完全激活。然而，在无细胞条件培养基中，纤溶酶对相同的肺泡巨噬细胞来源的L-TGF-β（1）没有影响。我们的研究结果表明，肺泡巨噬细胞分泌活性形式的TGF-β（1）是由纤溶酶的产生来调节的，并且需要肺泡巨噬细胞的存在。由于活性TGF-β（1）的减少与炎症的消退一致，这表明纤溶酶的可用性调节TGF-β（1）的生物活性形式，因此，在博来霉素诱导的肺损伤后观察到的炎症。
Transforming growth factor beta s (TGF-beta s) are 25-kD multifunctional proteins that regulate inflammation and connective tissue synthesis. With rare exception TGF-beta(1) is secreted noncovalently bound to a latency-associated peptide (LAP) that renders the mature TGF-beta(1), biologically inactive. An important mechanism for the control of TGF-beta(1) action is the regulation of the post-translational processing that removes the LAP from the mature peptide and renders it biologically active. In a model of pulmonary inflammation and fibrosis induced by the antineoplastic antibiotic, bleomycin, we have demonstrated that explanted alveolar macrophages secrete progressively increasing quantities of a biologically active form of TGF-beta(1), the secretion of which was maximal 7 days after bleomycin administration. Thereafter, there was a rapid decline in the secretion of the active form of TGF-beta(1) whereas the latent form continued to be secreted in elevated quantities. Plasmin, a serine protease, was transiently generated by the same bleomycin-activated alveolar macrophages and paralleled the rise in active TGF-beta(1). When alpha(2)-antiplasmin, an inhibitor of plasmin, was added to cultures of alveolar macrophages, the post-translational activation of L-TGF-beta(1) was totally abrogated. When plasmin was added to alveolar macrophages in culture, there was complete activation of the L-TGF-beta(1) that had been secreted during the culture period. However, there was no effect of plasmin on the same alveolar macrophage-derived L-TGF-beta(1) in cell-free conditioned media. Our findings suggest that the secretion of an active form of TGF-beta(1) by alveolar macrophages is regulated by the generation of plasmin and requires that the alveolar macrophages be present. Because the diminution of active TGF-beta(1) coincides with the resolution of inflammation, this suggests that the availability of plasmin regulates the biologically active form of TGF-beta(1), and thus, the inflammation seen after bleomycin-induced lung injury.