Kotarkonda Lakshmi Kanth, Kulshrestha Ritu, Ravi Krishnan
Department of Physiology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110007, India; Department of Pathology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110007, India.
Department of Pathology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110007, India.
Exp Mol Pathol. 2017 Feb;102(1):86-96. doi: 10.1016/j.yexmp.2017.01.004. Epub 2017 Jan 7.
Alveolar epithelial cell injury has been proposed as a causative factor for the onset and progression of pulmonary fibrosis. However, the role of type II alveolar epithelial cells (AECs) in the epithelial mesenchymal transition (EMT) is controversial.
The present study performed in rats instilled with bleomycin investigated a) the expressions of the insulin growth factor (IGF-1) and insulin growth factor binding protein 5 (IGFBP-5) and transforming growth factor (TGF-β1) in the type II AECs, b) the role of type II AECs in EMT and extracellular matrix (ECM) formation and, c) the effect of pioglitazone on all the above parameters.
Male Wistar rats were divided into three Groups: Group I (saline control), Group II (Bleomycin, given as a single intratracheal instillation, 7U/kg) and Group III (Bleomycin+Pioglitazone (40mg/kg/day orally, starting 7days post bleomycin instilled as in Group II). From lung tissues, the protein expressions of IGF-1, IGFBP-5, TGF-β1, surfactant protein C (SP-C, as a marker for type II AECs) and α-smooth muscle actin (α-SMA, as a marker for EMT), were determined on day 7 in Groups I and II and on days 14, 21 and 35 in all the three groups.
IGFBP-5 and IGF-1 expressions were reduced significantly and TGF-β1 expression increased significantly in type II AECs in Group II from day 7 till day 35 as compared to Group I. An increase in SP-C and α-SMA expression and their co-localization were seen in the type II AECs undergoing EMT from day 7 till day 35. A concomitant remodeling and laying down of ECM was observed also. In Group III, with pioglitazone, there was a reversal with significant up-regulation in IGFBP-5 and IGF-1 expressions and down-regulation of TGF-β1 in the type II AECs along with a significant decrease in the solid area fraction, EMT and ECM in the lung tissue.
IGFBP-5, IGF-1 and TGF-β1 in the type II AECs play a key role in lung injury caused by bleomycin and pioglitazone attenuates the lung injury/fibrosis by restoring IGFBP-5 and IGF-1 and decreasing TGF-β1 expressions in the type II AECs.
肺泡上皮细胞损伤被认为是肺纤维化发生和进展的一个致病因素。然而，II型肺泡上皮细胞（AECs）在上皮-间质转化（EMT）中的作用存在争议。
本研究在经博来霉素气管内注入的大鼠中进行，旨在研究：a）II型AECs中胰岛素生长因子（IGF-1）、胰岛素生长因子结合蛋白5（IGFBP-5）和转化生长因子（TGF-β1）的表达；b）II型AECs在EMT和细胞外基质（ECM）形成中的作用；c）吡格列酮对上述所有参数的影响。
将雄性Wistar大鼠分为三组：第一组（生理盐水对照组）、第二组（博来霉素，单次气管内注入，7U/kg）和第三组（博来霉素+吡格列酮（40mg/kg/天，口服，自博来霉素注入后第7天开始，方式同第二组）。在第一组和第二组的第7天以及所有三组的第14、21和35天，测定肺组织中IGF-1、IGFBP-5、TGF-β1、表面活性蛋白C（SP-C，作为II型AECs的标志物）和α-平滑肌肌动蛋白（α-SMA，作为EMT的标志物）的蛋白表达。
与第一组相比，从第第7天到第35天，第二组II型AECs中IGFBP-5和IGF-1表达显著降低，TGF-β1表达显著增加。从第7天到第35天，在发生EMT的II型AECs中可见SP-C和α-SMA表达增加及其共定位。同时还观察到ECM的重塑和沉积。在第三组中，使用吡格列酮后，出现了逆转，II型AECs中IGFBP-5和IGF-1表达显著上调，TGF-β1下调，同时肺组织中的实性面积分数、EMT和ECM显著降低。
II型AECs中的IGFBP-5、IGF-1和TGF-β1在博来霉素所致肺损伤中起关键作用，吡格列酮通过恢复II型AECs中IGFBP-5和IGF-1并降低TGF-β1表达来减轻肺损伤/纤维化。
