Division of Pulmonary and Critical Care Medicine, Northwestern University, 240 East Huron St., Chicago, IL 60611, USA.
Proc Am Thorac Soc. 2010 Feb;7(1):77-83. doi: 10.1513/pats.200906-055JS.
It is estimated that, combined, 400,000 people are diagnosed with idiopathic pulmonary fibrosis (IPF) or acute lung injury/acute respiratory distress syndrome annually in the United States, and both diseases are associated with an unacceptably high mortality rate. Although these disorders are distinct clinical entities, they share pathogenic mechanisms that may provide overlapping therapeutic targets. One example is fibroblast activation, which occurs concomitant with acute lung injury as well as in the progressive fibrosis of IPF. Both clinical entities are characterized by elevations of the profibrotic cytokine, transforming growth factor (TGF)-beta1. Protein degradation by the ubiquitin-proteasomal system modulates TGF-beta1 expression and signaling. In this review, we highlight the effects of proteasomal inhibition in various animal models of tissue fibrosis and mechanisms by which it may regulate TGF-beta1 expression and signaling. At present, there are no effective therapies for fibroproliferative acute respiratory distress syndrome or IPF, and proteasomal inhibition may provide a novel, attractive target in these devastating diseases.
据估计，在美国，每年有 40 万人被诊断患有特发性肺纤维化（IPF）或急性肺损伤/急性呼吸窘迫综合征，这两种疾病的死亡率都高得令人无法接受。尽管这些疾病是不同的临床实体，但它们具有相似的发病机制，这可能为重叠的治疗靶点提供了依据。例如成纤维细胞的激活，它既发生在急性肺损伤中，也发生在 IPF 的进行性纤维化中。这两种临床实体的特点是促纤维化细胞因子转化生长因子（TGF）-β1 的升高。泛素-蛋白酶体系统对蛋白质的降解调节 TGF-β1 的表达和信号转导。在这篇综述中，我们强调了蛋白酶体抑制在各种组织纤维化动物模型中的作用，以及它可能调节 TGF-β1 表达和信号转导的机制。目前，尚没有有效的治疗方法可用于治疗纤维增生性急性呼吸窘迫综合征或 IPF，而蛋白酶体抑制可能为这些毁灭性疾病提供一个新颖而有吸引力的靶点。
