Chiang Hou-Yu, Chu Pao-Hsien, Lee Ting-Hein
Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
PLoS One. 2017 Oct 2;12(10):e0185811. doi: 10.1371/journal.pone.0185811. eCollection 2017.
Circulating fibrocytes play a key role in the pathogenesis of pulmonary fibrosis. Fibrocytes are bone marrow-derived leukocytes, which enter the lungs in response to their chemoattractant CXCL12 and differentiate into fibroblasts or myofibroblasts, leading to excess deposition of the collagen-rich extracellular matrix. Matrix metalloproteinase (MMP)-9 and MMP-2, secreted by fibrocytes, degrade the subendothelial basement membrane and promote fibrocyte influx into the lungs. Here, we demonstrate that R1R2, a novel peptide derived from the bacterial adhesin SFS, attenuates pulmonary fibrosis by preventing the differentiation of fibrocytes into myofibroblasts and by reducing the invasion of fibrocytes through basement membrane-like proteins. Moreover, our findings reveal dual regulation of R1R2 on MMP-9 through reduced enzymatic activity on gelatin and increased cleavage of CXCL12. These data suggest that R1R2 has potent anti-fibrotic effects against pulmonary fibrosis.
循环纤维细胞在肺纤维化的发病机制中起关键作用。纤维细胞是源自骨髓的白细胞，它们响应其趋化因子CXCL12进入肺部，并分化为成纤维细胞或肌成纤维细胞，导致富含胶原蛋白的细胞外基质过度沉积。纤维细胞分泌的基质金属蛋白酶（MMP）-9和MMP-2可降解内皮下基底膜，并促进纤维细胞流入肺部。在此，我们证明了R1R2，一种源自细菌粘附素SFS的新型肽，通过阻止纤维细胞分化为肌成纤维细胞以及减少纤维细胞通过类基底膜蛋白的侵袭来减轻肺纤维化。此外，我们的研究结果揭示了R1R2对MMP-9的双重调节作用，即通过降低对明胶的酶活性和增加对CXCL12的裂解来实现。这些数据表明，R1R2对肺纤维化具有强大的抗纤维化作用。
